NOVEL FORMULATIONS

The present invention relates to compounds which possess potent SSRI (Selective Serotonin Reuptake Inhibitor) activity and as such these compounds have been approved for use in medical therapy in particular for their use in the treatment or prevention of disorders such as depression and the disorders listed herein including but not limited to OCD, panic and social anxiety disorders

Whilst this patent application is broad and covers all SSRI's the main focus of this patent is on duloxetine (Cymbalta) which is a neuroleptic agent is used to treat depression and a raft of anxiolytic disorders including premature ejaculation (PE).

At the end of its patent life (US6596756 B 1) duloxetine was tested by many investigators and found to be useful for treating PE.

There are numerous studies which show that duloxetine is highly effective as a treatment for PE and for use as a combination therapy with duloxetine for the treatment of PE associated with comorbid use for the treatment of male erectile dysfunction (MED). There is almost lOOpc chance that if the tablet is presented properly, that it will deliver a product which has a lOOpc chance of delivering a PE clinical effect.

A controlled release version of duloxetine was launched to address the issue of side effects, however, this version only addressed delaying the release of the active from the dosage form and did not address the issues of rapidity of onset of action in any event it takes duloxetine around 7 to 14 days to reach a steady state PK profile This means that disorders requiring immediate action are inadequately serviced by duloxetine because it takes time for the active to be released from the pill, there is a bolus release of duloxetine which causes side effects and in addition there are issues with respect to the duloxetine dwindling in potency towards the end of its dose to dose life

The present invention focuses on developing medical uses using SSRI's in general and specifically duloxetine these medical uses are male premature ejaculation. The SSRI's covered by the present patent application are all those SSRI's that are found in the literature which include but are not limited to fluoxetine which is sold under the trade name Prozac, sertraline, which is sold under the trade name Zoloft, and duloxetine which is sold under the trade name Cymbalta. A second choice of active for inclusion in the patented formulation is sertraline which is a powerful compound. The reason that duloxetine was never approved as an effective medication for premature ejaculation is because it is slow to act, does not work from dose to dose nor does it enable the duloxetine product to be within the therapy window from dose to dose, these new uses i.e., male premature ejaculation requires that duloxetine to work quickly , provide 24 hour efficacy from day 1 of treatment and not have to wait for 7 to 14 days for the duloxetine plasma level to reach a steady state . In addition, the drugs plasma level must remain within the therapeutic window from dose to dose rather than be subject to spikes in plasma levels which cause side effects and dips which cause a lack of efficacy. There is almost 100 per cent scientific and medical certainty that duloxetine will provide an effective treatment for the diseases herein mentioned since the compound has been shown to work and obtained FDA approval despite the fact the original product was slow to act ,had a short half-life and failed to work within the therapeutic window from dose to dose. However no one will invest the time effort and money to seek approval of the duloxetine without having knowledge that the product will have broad strong and valid patent cover which is not circumventable, and which is likely to be valid and enforceable. Whilst a patent on the use per se is un patentable because the use is described in the art, It is possible to patent the dose, salts, and the PK profile by way of the formulation i.e., a

multicomponent formulation containing three to five components or layers which accommodate active duloxetine and release it into the blood plasma to solve issues of rapidity of onset of action, bioavailability, longevity of effect, maintenance within the therapeutic window and dose to dose longevity and finally maintaining duloxetine substance within the therapeutic window from dose to dose. This lateral approach to patenting duloxetine allows it to be used as a treatment for premature ejaculation, without the need for direct patent cover. It is impossible for others to copy this approach without infringing this patent. Attempts to design around will cause the patent to be avoided but invoke regulatory laws to prevent the product from being approved by any abbreviated procedure leaving a full NDA as the only possible route to market.

Furthermore premature ejaculation requires rapidity of action and longevity of effect and

minimisation of side effects which are caused by working outside the therapeutic window from dose to dose. No currently marketed SRRTs has such a profile. Duloxetine has probably the worst clinical and PK profile because it has slow onset of action, a shorter than 12 hour half-life and the PK spike associated at 3 hours post ingestion makes for serious side effects The CR version has no faster onset of action, does not work from dose to dose and takes 7 to 14 days to reach steady state; this delay is unacceptable for sufferers of these diseases.

The incidence of these target disorders is such that there is a major unmet medical need to provide a medicine which treats and or prevents this male premature ejaculation.

For millions of Americans who suffer from male premature ejaculation, their quality of life drops. There are few drugs approved which tackle these disorders in a medically adequate way, Men suffering from PE need rapid long lasting relief these conditions affect around 5mm men a year Men who get the symptomatic signs of PE must get immediate and long lasting relief from symptomatic manifestations of their diseases. There are no FDA approved treatments but a dozen independent studies show that duloxetine is active as an anti-male premature ejaculation agent.

There is therefore a need to find a technical solution which delivers immediate relief from symptoms for PE. There is also an immediate need to develop a duloxetine delivery platform which allows duloxetine product to be absorbed into the blood plasma at levels which cause an effect from dose to dose and yet which is devoid of serious side effects.

The invention provides a series of technical solutions which address technical issues, clinical issues and provide commercially optimal solutions that rely on broad strong patent cover in multiple layers.

Thus the present invention focuses on providing technical solutions which are patentable in the following key areas. 1. The choice of salt, 2. The choice of formulation 3. The choice of dose. 4. The choice of route of administration.

It is an aspect of this invention that each issue is addressed in a way that causes a technical effect, a clinical effect which justifies the applicant seeking a broad scope of patent protection which cannot be easily circumvented. The resulting product therefore meets unmet medical needs and results in a sizeable market opportunity. It should be appreciated that 3 years data exclusivity attaches to such a product and that defacto, it will take the FDA further two years to approve a duloxetine of this type. Since this patent describes technology to achieve a desired effect and since such a product will defacto be exclusive for 5 years, it follows that there is a commercial reason to develop and launch a product of this type which contains duloxetine or another SSRI's such as duloxetine or sertraline. Duloxetine is a neuroleptic compound useful for treating psychiatric disorders such as depression and anxiety, and in particular for removing or ameliorating such symptoms as anxiety, agitation, excessive aggression, tension, and social or emotional withdrawal in patients. It has a unique mechanism of action and its pharmacological profile is highly selective at various receptors associated with SSRI activity. There have been anecdotal observations that duloxetine has neuroprotective and

neurodegenerative properties. The FDA never granted the innovator a license to treat PE with the duloxetine despite the fact that respected clinicians have published multiple studies showing that the duloxetine worked well for PE.

There are a number of side effects the most significant of which are 1.Withdrawal issues i.e.

discontinuation problems 2. The increased risk of suicide. It is an object of this invention to deal with three of the four PK issues which plague duloxetine which are 1. Rapidity of onset of action 2.

Duration of action between doses 3. Maintenance of blood plasma levels from dose to dose, and 4 that the formulation is adapted to keep the blood plasma level of active ingredient within the therapeutic window for a substantial amount of time. This technical effect is achieved by careful choice of dose, salt form and formulation. Each choice is critical and gives rise to separate patent claims and overarching patent claims which provide multi- layered protection.

Duloxetine has good bioavailability of almost lOOpc and a half-life of 12 hours. This means that the duloxetine plasma level is far less than half the level that it was after the first dose is taken prior to administration of a second dose, the design of the original product tablets means that they take around 2 hours to dissolve and release duloxetine therefore onset is delayed for 2 to 3 hours which for diseases like PE. The medical need is immediate and ongoing; the patient requires duloxetine from dose to dose rather than the PK level to dwindle below MIC. The current duloxetine product has a C max concentration after about 3 hours which is associated with side effects. The present invention provides a new formulation in conjunction with the new dose and salt. The present invention relates to new uses, combinations and product line extenders relating to the product which contains duloxetine. Particularly to new uses and combinations using the patented formulation described herein and exemplified by way of salt, dose and physical

characteristics of the tablet.

Duloxetine is a blockbuster duloxetine discovered, developed and marketed by Lilly. Duloxetine has a unique mechanism of action and its use as an anti-depressant agent.

Whilst duloxetine is a great compound with powerful biological action, it has a number of drawbacks in its biological profile, i.e., It has a half-life of 12 hours which means that before the next dose the whole of the active which was dumped into the blood stream would have decayed by half, it has good bioavailability and it has a number of undesirable side effects. By the time the next dose is taken there would be so little duloxetine left that it would not have any effect.

A compound like duloxetine is a prime candidate for incorporation into a life cycle maximisation programme. This is because duloxetine is a very active substance. It has also been tested in mass patient population for 25 years and so has a well-documented safety and efficacy profile. The object of the present invention is to improve the therapeutic window by making the duloxetine more efficacious and safer. This ratio of efficacy to safety is termed the therapeutic ratio, By making the duloxetine work faster, last all night long from dose to dose and keeping the active within the therapeutic window from dose to dose, in a substantial part, the present patent provides real technical solutions, which translate into medical advantages for new uses which have a high incidence and unsatisfactory solutions to date.

The current, known product, does not work rapidly, does not last from dose to dose and does not keep the duloxetine plasma levels within the therapeutic window, from dose to dose. The second point is that the present invention provides new technology which allows the PK profile of drugs to be designed in a customised manner to allow the duloxetine to act quickly last until the next dose is taken and remain within the therapeutic window from dose to dose. The present application describes in detail how this is achieved and provides supporting experimental data showing how this works. In addition the application describes the choice of optimum salts, optimum dose and other choices of parameters which result in a technically superior product when compared to the previously approved product i.e. the original duloxetine product.

It has been found that new multicomponent formulations - for instance a two- or three- component pill - can accommodate these agents in a manner which allows them to be administered rapidly, from dose to dose and within the therapeutic window.

Finding technology which enables the active ingredient to be engineered to deliver the perfect PK profile has been a long felt need in the industry. The five problems with PK profiles listed above are well documented and attempts to remedy the situation focus on individual issues. No one has thought of how to address all five issues in one single solution. Thus the present invention extends to a solution which addresses three to five of these PK issues in one pharmaceutical composition.

It has been surprisingly found that oral dosage forms, in particular tablets can be engineered to deliver duloxetine substance to the blood plasma in patients in a way which optimises the following.

1. Bioavailability of the active

2. Increases the rapidity of release of duloxetine substance promoting a faster onset of action 3. Increase the longevity of action of the duloxetine from dose to dose

4. Provides some measure of means to ensure that the duloxetine plasma level is maintained from dose to dose

5. The provision of means to ensure that the dose of duloxetine remains substantially within the therapeutic window from dose to dose. Despite the obvious advantages that such a delivery system would possess, there is no solution suggested for how technological means can be provided to enable this to occur.

The present invention provides a solution to this age old problem in a single pharmaceutical dosage form that enables the treatment of MPE which could not be treated adequately until these PK issues were solved. Accordingly, the present invention provides a pharmaceutical composition which comprises a selective serotonin reuptake inhibitor (SSRI) in a multicomponent formulation, wherein a first component is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action, and at least one further component is adapted to deliver the SSRI from dose to dose.

The pharmaceutical composition of the invention, which is typically a pharmaceutical dosage form, may be provided in multicomponent parts, said components are adapted to individually deliver the following technical effects or are adapted with other components to deliver the following technical effects to the SSRI (for instance, to duloxetine):

1. Increases the Bioavailability of the active

2. Increases the rapidity of release of the duloxetine substance promoting a faster onset of action

3. Increases the longevity of action of the duloxetine from dose to dose 4. Provides some measure of means to ensure that the duloxetine plasma level is maintained from dose to dose

The adaption of the components of the dosage forms are described herein more fully, for instance

1. Bioavailability of the active can be improved in the following ways by using new salts such as fatty acid esters or complexes of cyclodextrins. 2. Increases in the rapidity of release of duloxetine substance PR can be achieved in the following manner promoting a faster onset of action as herein after described.

3. Increases in the longevity of action of the duloxetine from dose to dose may be achieved. Where duloxetine has a short half-life it follows that the drug's effectiveness declines over time; where the half-life is short the declination in activity causes a lack of efficacy until the next dose is

administered; this issue can be addressed by adapting duloxetine in one or more component parts to release the duloxetine slowly for example by modifying the release for example by using delayed release, or prolonged release.

4. The dosage for provides means to ensure that the duloxetine plasma level is maintained from dose to dose. If a first component contains a portion of active which is modified in some way to release the duloxetine rapidly and a third component is adapted in some way to release the duloxetine by delaying the release, it may be possible for a second component to fill any gap in blood plasma level that occurs after onset of action and before the delayed release component kick in. This is called the maintenance dose and can be achieved by providing active admixed with excipients in a manner which allows this top up dose to be provided from dose to dose 5. The provision of means to ensure that the dose of duloxetine remains substantially within the therapeutic window from dose to dose. Despite the clear advantages that such a delivery system would possess, no solution is suggested in the art for how technological means can be provided to enable this to occur. By calculating what the therapeutic window should be, pharmaceutical dosage forms of the present invention can be provided comprising four components which deliver the first four technical effects listed above. A preferred embodiment is as follows. The present invention provides a pharmaceutic dosage form, preferably one which increases the rapidity of release of duloxetine substance. This can be achieved in the following manner promoting a faster onset of action as herein after described and which increases the longevity of action of the duloxetine from dose to dose, where a duloxetine has a short half-life it follows that the drug's effectiveness declines over time, where the half-life is very short the declination in activity causes a lack of efficacy until the next dose is administered, this issue can be addressed by adapting duloxetine in one or more component parts to release the duloxetine slowly for example by modifying the release for example by using delayed release, or prolonged release and which provides some measure of means to ensure that the duloxetine plasma level is maintained from dose to dose. If a first component contains a portion of active which is modified in some way to release the duloxetine rapidly and a third component is adapted in some way to release the duloxetine by delaying the release. It may be possible for a second component to fill the gap in blood plasma level that occurs after onset of action and before the delayed release component kick in. This is called the maintenance dose and can be achieved by providing active admixed with excipients in a manner which allows this top up dose to be provided from dose to dose and which The invention provides means to ensure that the dose of duloxetine remains substantially within the therapeutic window from dose to dose. Despite the clear advantages that such a delivery system would possess, no solution is suggested in the art for how technological means can be provided to enable this to occur. By calculating what the therapeutic window should be, pharmaceutic dosage forms of the present invention can be provided where four components deliver the following four technical effects listed above: increase in rapidity of release of duloxetine promoting a faster onset of action; increase in the longevity of action of the duloxetine from dose to dose; ensuring that the duloxetine plasma level is maintained from dose to dose; ensuring that the dose of duloxetine remains substantially within the therapeutic window from dose to dose. Despite the clear advantages that such a delivery system would possess, there is no solution suggested for how technological means can be provided to enable this to occur.

The tablets of the present invention are modified in a manner which is conducive to achieving the desired effects in a single product, which delivers duloxetine active from dose to dose, within the therapeutic window. This comes from the choice of the amount of active, the nature of the active, the amount and nature of the excipients and how the dosage form is assembled. BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows the dissolution profile in pH 6.8 buffer of the sustained-release core development formulation no. 17CF14/002 comprising duloxetine hydrochloride, as described in the Example.

Fig. 2 shows the dissolution profile in pH 6.8 buffer of the immediate-release development formulation no. 17CF14/003 comprising duloxetine hydrochloride, as described in the Example.

DETAILED DESCRIPTION OF THE INVENTION

The business of life cycle maximisation is where existing blockbuster compounds with proven efficacy and safety are repurposed for new uses, new combinations and product line extenders.

New chemical entities have a high risk of failing to obtain approval on efficacy and or safety grounds. Only 1 in 10,000 new chemical entities make it to the market. The cost of finding and developing new compounds is huge, at around lbb dollars each. Finally it takes 10 to 12 years to progress a compound from first discovery through to FDA approval. Since the patent covering the NCE, the commercial formulation, the dose and the medical use is filed immediately following discovery, the time remaining to recoup the massive investment in developing and launching the drug, is only 8 to 10 years. Because it also takes time from first launch to peak year sales, the full commercial potential of the compound is rarely if ever maximised. By the time the compound reaches block buster status, there are usually only 3 to 5 years of commercial life remaining for the innovator company to recoup costs and make a return.

Compounds that have high sales potential are rare. Duloxetine sales topped 3 bb dollars before it became generic in 2003. Thus the industry is suffering from a problem of a dearth of new compounds in therapeutic areas where sales potentials are high. Subjecting successful compounds to life cycle maximisation initiatives is a way to maximise value. However investment in such products can only be justified if development times are short around 3 years, the development costs are small around 30 to 100mm and there is a high chance that solid patent protection can be obtained. At the other end of the pharmaceutical conveyor belt, the patent cliff creates a major operational problem for blockbuster drugs, where huge mega blockbuster revenues are lost within days of a compound becoming generic. Duloxetine is a prime candidate for inclusion as an LCM candidate because it has strong patent cover for several years to come giving time to develop, approve, launch and switch sales prior to patent expiry. There is a compelling technical, commercial and legal rationale for harnessing the full potential of major biologically active compounds with proven safety efficacy and biological potential. Duloxetine is particularly suitable for subjecting to the LCM process because it is capable of being developed for new uses, new combinations and product line extenders. This patent application describes these new uses, combinations and product line extenders and also describes lateral thinking of how rock solid patent cover can be obtained using salts, dose or PK profile patenting to bolster the chances of patent cover against ab rated competition.

When new chemical entities are found there is a rush to commercialise them which means that companies often ignore product optimisation such as salts, dose, solid state form, formulations and medical uses and finally the use in combinations.

This results in sub optimal products being developed and approved.

Furthermore opportunities to improve delivery by tackling the problems of rapidity of onset of action, longevity of action and a PK profile within the therapeutic window from dose to dose.

In the case of SSRI's and particularly duloxetine, dampening the PK profile is critical to achieving commercial success currently there is a peak three hours after taking the duloxetine which leads to serious side effects. Dampening this peak using a multicomponent pill is critical to success of duloxetine since it would then have a profile which is ideal, i.e., rapidity, longevity and dose to dose maintenance within the therapeutic window. Such a product would be an ideal candidate for repurposing and this patent lists a whole sleuth of new uses for such a purpose. Lastly the issue of side effects the dose of the active is usually 50 to 100 pc more than necessary to ensure that it works, this leads to side effects. Reducing the dose will give a better product.Finally optimising new uses, new combinations and formulations allows for maximum product value to be derived. The present invention therefore also provides a number of patentable product line extenders which augment the action of the underlying active ingredient in duloxetine products. By switching the product into these life cycle maximisation products, it's possible to mitigate the effects of the patent cliff by switching sales into new uses, combinations or formulations prior to patent expiry. This is a huge potential to achieve new products with residual sales of 10 to 50 pc of sales compared to the underlying original product, which remain exclusive for up to a decade after the patents on the original product expire and sales plummet as the patent cliff kicks in. Apart from new uses, the therapeutic usefulness of Duloxetine can be improved by increasing its solubility by salting or the use of co crystal technologies or Nano particles. Increasing solubility allows the Duloxetine to be administered in smaller doses delivering the same therapeutic effect. The duloxetine products provides the basis for the development of a raft of new life cycle maximization products which are effectively like new chemical entities, but have the advantage of having been developed and tested in the mass patient populations albeit for a narrow range of uses and product presentations. The short half-life can be improved using delayed release techniques such as controlled release, prolonged release capsules and other conventional techniques, all of which form an aspect of the present invention. The new products derived through repurposing as new uses, new combinations or product line extenders can be patented , but this base patent cover can be augmented as herein described by developing specific new doses, new salts and improving the PK profile by adapting the active ingredient by incorporating it into formulations which have the effect of improving one or more of the following characteristics, i.e. rapidity of onset, longevity of action and preferably into a product which has both rapidity, longevity and most preferably where the rapidity and longevity provides dose to dose provision of the active substance within the blood plasma immediately upon administration and within the therapeutic window through the time period until the next dose is administered . This is the core platform in which the product can be improved for existing uses and for new uses, new combinations and in a host of PLE's these variations are patentable and form a central aspect of the present patent application. This provides a belt and braces approach to ensuring that comprehensive cover is obtained. The products of the present invention are described herein and are believed clearly to be patentable over prior art, being prima facie non obvious, having unexpected advantages and /or not being the subject of routine modifications. In addition, the inventions described herein are clearly sufficient in the disclosures teaching the skilled worker how to make and use the subject matter described herein. Each invention is described thoroughly so that a skilled worker can make and use the claimed inventions using materials and techniques described in the literature and the inventions can be made from readily available materials without the skilled worker having to resort to undue experimentation. The scope of the inventions claimed herein is commensurate with the disclosure contained in the patent. The commercial value of the new life cycle maximisation products described herein is potentially massive. The development times are short and the chances of commercial success are potentially high. However, the key and most pressing issue and the subject of this patent is that these new life cycle maximisation products are likely to be highly patentable. This patent application covers a raft of new products which could form a virtual pharmaceutical company of late stage pipeline projects which can be developed and approved and launched with license from the innovator or at patent expiry. Such products are termed Value Added Generics and are improved versions of duloxetine which can be launched without license at patent expiry of the base patent or alternatively, they can be launched earlier with a license from the innovator. The effective commercial life of such products is likely to be ten years or more. Sales are likely to be around 10 to 30 pc of original sales. Given these statistics, the effective commercial value of new products described herein could run into billions of dollars. Couple this great commercial potential with short development times, low costs and high technical chances of success, coupled with solid patent cover means that this patent application underpins a unique opportunity to fully maximise sales of duloxetine based products.

The products described herein are of great commercial interest both to the original innovator company, competitors to the innovator, generic companies, and formulation houses. They are also interesting to small and medium entities wishing to invest in low cost, low risk high return projects which have short development times

In particular all information concerned with preparing the duloxetine moiety from readily available starting materials is incorporated in full. In addition, it should be appreciated that all information concerning the incorporation of duloxetine into a formulation is herein incorporated by reference as is information on the use of such formulations in medical therapy.

Whilst SSRI's such as duloxetine are very potent and selective, their pharmacological profiles are often far from ideal. Duloxetine for example is slow in its absorption through the gut wall and can therefore take 1 to 2 hours for onset of action. Since it's delivered in a bolus from a swallow tablet it is absorbed all at once and is then metabolized quickly and expelled from the body leaving a deficit in the blood stream and causing potency to drop and then disappear long before the next dose is due. This is a real problem for sufferers of conditions to be treated with SSRI's, who are not adequately treated with existing products. The need for immediacy of action, longevity of action and keeping the blood plasma levels within the therapeutic window from dose to dose is critical for success. There is a need for a technical solution to this long standing problem and one which solves all three problems at the same time i.e. rapidity, longevity from dose to dose and one which delivers the duloxetine within the therapeutic window between dose to dose.

The invention provides a pharmaceutical composition which comprises a selective serotonin reuptake inhibitor (SSRI) in a multicomponent formulation, wherein a first component is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action, and at least one further component is adapted to deliver the SSRI from dose to dose.

In a preferred embodiment of the present invention the pharmaceutical composition - which is typically a unit dosage form - is adapted to ensure maintenance of the SSRI within the therapeutic window from dose to dose. The term "from dose to dose" herein, refers to the dosing interval. In once daily (OD) dosing the dosing interval is 24 hours and therefore maintaining the SSRI within the therapeutic window from dose to dose in that case means maintaining the SSRI in the therapeutic window until the next dose which is 24 hours after administration of the pharmaceutical composition to the subject. In terms of dose to dose maintenance within the therapeutic window, when

administering a conventional swallow tablet from which the active moiety is absorbed into the bloodstream, there is usually a minimum blood plasma concentration which is required to achieve a therapeutic effect. As the blood plasma level increases, so does the therapeutic effect in a dose-related manner until a maximal therapeutic effect has been achieved. However, when drug blood plasma levels exceed a certain concentration, undesired side-effects become apparent. When drug blood plasma levels drop below a certain concentration there is little or no therapeutic benefit. Drug blood plasma concentrations between these two levels are often referred to as the "therapeutic window". The term "therapeutic window" as used herein is defined accordingly, i.e. as the range of drug plasma concentrations that provide efficacy without unacceptable side effects. Hence, blood plasma levels outside the therapeutic window are associated with either a lack of efficacy or unacceptable side- effects. The pharmaceutical composition of the invention comprises a first component which is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action, and at least one further component is adapted to deliver the SSRI from dose to dose. Both the first component, and each of the at least one further components, comprise the SSRI. Thus, the pharmaceutical composition of the invention comprises a first component comprising an SSRI, which first component is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action; and at least one further component comprising the SSRI, which adapted to deliver the SSRI from dose to dose.

The SSRI in the first and further components is generally the same one, e.g. both duloxetine, as opposed to duloxetine in one component and a different SSRI in another. However, the same SSRI may be in different forms in the first component and the at least one further component, or of course it may be in the same form in the first component and the at least one further component.

For instance, the SSRI in the first component may be in the free base form and the SSRI in the at least one further component may be in the form of a pharmaceutically acceptable salt, or for example in the form of a co-crystal. Alternatively, the SSRI in the first component may be in the free base form and the SSRI in the at least one further component may also be in the free base form. Alternatively, the SSRI in the first component may be in the form of a pharmaceutically acceptable salt and the SSRI in the at least one further component may be in the form of a pharmaceutically acceptable salt. These may be the same salt, or different salts. Various particular different forms of SSRI's, including duloxetine, which can be employed in the first component, or in the at least one further component, or both, are discussed in detail hereinbelow. In one embodiment, for instance, the SSRI in the first component is duloxetine free base, and the SSRI in the at least one further component is a pharmaceutically acceptable salt of duloxetine.

Suitable salts of duloxetine are discussed herein, but the pharmaceutically acceptable salt of duloxetine may for instance be duloxetine hydrochloride. Thus in one embodiment, the SSRI in the first component is duloxetine free base, and the SSRI in the at least one further component is duloxetine hydrochloride.

In another embodiment, the SSRI in the first component is duloxetine free base, and the SSRI in the at least one further component is duloxetine free base. More typically, however, the SSRI in the first component is a pharmaceutically acceptable salt of duloxetine, and the SSRI in the at least one further component is a pharmaceutically acceptable salt of duloxetine. They are typically the same salt of duloxetine. Suitable salts of duloxetine are discussed herein, any one of which may be employed. In one embodiment, however, the SSRI in the first component is duloxetine hydrochloride, and the SSRI in the at least one further component is duloxetine hydrochloride.

The term "pharmaceutically acceptable salt thereof refers to salts which are physically, chemically and physiologically acceptable for either human or veterinary use. Generally, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, hydrobromic, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines. It should also be understood that reference herein to a selective serotonin reuptake inhibitor (SSRI), or to any particular SSRI, for instance duloxetine, includes (unless otherwise stated) pharmaceutically acceptable salts of that SSRI, as well as any particular pharmaceutically acceptable form of the SSRI including solutions, amorphous forms, and crystalline forms of the SSRI including solvates, hydrates, co-crystals and polymorphs. Typically, the pharmaceutical composition of the invention comprises: said first component, which is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action; and a further component, which is adapted to maintain a drug plasma level of the SSRI from dose to dose. Thus, the pharmaceutical composition of the invention typically comprises: said first component, which comprises the SSRI and is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action; and a further component, which comprises the SSRI and is adapted to maintain a drug plasma level of the SSRI from dose to dose.

The pharmaceutical composition of the invention may for instance comprise: said first component, which is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action, and a further component, which is adapted to provide longevity of action of the SSRI from dose to dose by causing delayed or prolonged release of the SSRI. Thus, the pharmaceutical composition of the invention typically comprises: said first component, which comprises the SSRI and is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action; and a further component, which comprises the SSRI and is adapted to provide longevity of action of the SSRI from dose to dose by causing delayed or prolonged release of the SSRI. The pharmaceutical composition of the invention may for instance comprise: said first component which comprises the SSRI and is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action; a further component which comprises the SSRI and causes delayed or prolonged release of the SSRI; and another further component which comprises the SSRI and causes a drug plasma level of the SSRI to be maintained in between said fast onset of action and said delayed or prolonged release.

Thus, the at least one further component may comprise a component which is suitable for causing delayed or prolonged release of the SSRI from the at least one further component after administration of the composition to a subject. The term "delayed release", in the context of controlled release or modified release in the context of this specification, is understood to indicate a formulation that is designed to retard the initial release of drug from the dosage form by a pre -determined interval of time. Delayed release may for instance be understood to mean retardation of release, when compared to a currently approved product. The term "prolonged release", in the context of controlled release or modified release in the context of this specification, may be understood to indicate a formulation that is designed to maintain the release of drug over a period of time that is substantially greater than is achieved in the currently marketed formulation. Typically, the, or at least one, further component in the pharmaceutical composition of the invention is adapted to provide longevity of action of the SSRI from dose to dose by causing delayed or prolonged release of the SSRI from the further component after administration of the composition to a subject. Often, prolonged release is employed, and therefore the, or at least one, further component is suitable for causing prolonged release of the SSRI from the further component after administration of the composition to a subject. The, or at least one, further component may be adapted to provide longevity of action of the SSRI from dose to dose by causing prolonged release of the SSRI from the further component after administration of the composition to a subject. The, or at least one, further component is typically adapted to release the selective serotonin reuptake inhibitor (SSRI) from the further component in vivo over a period of x hours from the time of administration of the composition to a subject. Generally, in this embodiment, all of the SSRI is released from the further component over the defined period. Typically, x is at least 8, so that it takes at least 8 hours for all of the SSRI to be released from the further component. However, x may be at least 9, or, for instance, at least 10, so that it takes at least 8 hours for all of the SSRI to be released from the further component, x may for instance be from 8 to 24, so that it takes from 8 to 24 hours for all of the SSRI to be released from the further component, x may for instance be from 9 to 24, or from 10 to 24. Often, x is at least 12, so that it takes at least 12 hours for all of the SSRI to be released from the further component, x may for instance be at least 15, for example at least 17, at least 18, or at least 20. x may for instance be from 12 to 24, or from 15 to 24, or for instance from 17 to 24, or from 20 to 24. The pharmaceutical composition is usually adapted to ensure maintenance of the SSRI within the therapeutic window from dose to dose, or at least for a certain, preferably high, proportion of the time during the dosing interval. Thus, in the pharmaceutical composition of the invention, the at least one further component is often adapted to ensure maintenance of the SSRI within the therapeutic window from dose to dose, or at least for a certain, preferably high, proportion of the time during the dosing interval.

Thus, in the pharmaceutical composition of the invention, the, or the at least one, further component is often adapted to ensure maintenance of the SSRI within the therapeutic window for a certain percentage - y % - of the time during the dosing interval. The dosing interval may be defined as, say, z hours beginning with administration of the composition to a subject. When the pharmaceutical composition is a unit dosage form suitable for once daily (OD) dosing, z is generally 24, i.e. the dosing interval is 24 hours. Accordingly, z is typically from 20 to 28, for instance about 24. Often, z is 24. However, other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and z may therefore have other values. Thus, z may for instance be 6, 8 or 12, or even 48. Thus, z may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, z is 24.

Typically, y is at least 50, such that the SSRI is maintained within the therapeutic window for at least 50% of the time during the dosing interval. It is of course preferred, however, that y is greater than 50. Preferably, for instance, y is at least 60, and more preferably at least 70, for instance at least 75.

Typically, y is at least 80, for instance at least 85. Often, y is at least 90, and is preferably at least 95. y may for instance be 100, such that the SSRI is maintained within the therapeutic window throughout the dosing interval, i.e. from dose to dose.

Typically, z is 24 and y is at least 50. More preferably, z is 24 and y is at least 60, and more preferably at least 70, for instance at least 75. Typically, z is 24 and y is at least 80, for instance at least 85. Often, z is 24 and y is at least 90, and is preferably at least 95. In some cases, z is 24 and y is 100.

In the compositions of the present invention, the, or the at least one, further component is usually adapted to maintain the SSRI at or above a drug plasma level, 1, in a subject for a certain percentage (q %) of the time during the dosing interval. The dosing interval may in this case be defined as t hours beginning with administration of the composition to the subject. The term "drug plasma level of the SSRI" refers to the plasma concentration of the active form of the SSRI. This is often the SSRI compound as administered to the subject, but it may be an active metabolite thereof. The drug plasma level, 1, of the SSRI, at or above which the, or the at least one, further component is adapted to maintain the SSRI for q % of the time during the dosing interval, may be any drug plasma level within the therapeutic window. Alternatively, it may be the plasma concentration required for obtaining 50% of a maximum therapeutic effect in vivo. This is known as the IC50, and as the skilled person will appreciate, an IC50 value is specific to a particular drug and to the therapeutic effect that is desired and therefore the condition being treated by the drug. For instance, the IC50 here may be the IC50 for duloxetine in connection with the treatment of an anxiety disorder, this being the plasma concentration of duloxetine required for obtaining 50% of a maximum therapeutic effect obtainable by duloxetine. Typically, therefore, the drug plasma level, 1, of the SSRI, at or above which the, or the at least one, further component is adapted to maintain the SSRI for q % of the time during the dosing interval, is the plasma concentration (IC50) required for obtaining 50% of a maximum therapeutic effect in vivo.

The drug plasma level, 1, may for instance be the plasma concentration (IC50) required for obtaining 50% of a maximum reduction in the symptoms of anxiety in vivo. This is generally the plasma concentration required for obtaining 50% of a maximum reduction in the symptoms in vivo that is obtainable by the SSRI in question.

The pharmaceutical composition is often a unit dosage form suitable for once daily (OD) dosing. Thus, t is generally 24, i.e. the dosing interval is 24 hours. Accordingly, t is typically from 20 to 28, for instance about 24. Often, t is 24. However, other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and t may therefore have other values. Thus, t may for instance be 6, 8 or 12, or even 48. Thus, t may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, t is 24.

Typically, q is at least 40, such that the SSRI is maintained at or above the drug plasma level, 1, for at least 40% of the time during the dosing interval. It is of course preferred, however, that q is greater than 40. Preferably, for instance, q is at least 45, and more preferably at least 50, for instance at least 60. Typically, q is at least 65, for instance at least 70. Often, q is at least 75. Typically, q is at least 80, for instance at least 85. Often, q is at least 90, and is preferably at least 95. q may for instance be 100, such that the SSRI is maintained at or above the drug plasma level, 1, throughout the dosing interval, i.e. from dose to dose. Typically, t is 24 and q is at least 45. More preferably, t is 24 and q is at least 50, and more preferably at least 60, for instance at least 65, at least 70, or for instance at least 75. Typically, t is 24 and q is at least 80, for instance at least 85. Often, t is 24 and q is at least 90, and is preferably at least 95. In some cases, t is 24 and q is 100. Typically, in the pharmaceutical composition of the invention, the first component is a rapid release fraction. Thus, the first component is usually adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action. As discussed below, rapid release may be achieved by a formulation of the SSRI comprising a rapidly dispersing wafer containing the SSRI or a

pharmaceutically acceptable salt thereof which is placed on the tongue and dissolves in the mouth, for example within the buccal fluids. Suitably the wafer is dispersed and/or dissolved over a period of from about 1 to about 120 seconds, typically within a period of from about 1 to about 60 seconds, for instance from about 1 to about 30 seconds, or from about 1 to about 10 seconds.

Thus, the first component is typically a rapidly disintegrating component comprising said SSRI. This component typically comprises the SSRI, for instance duloxetine, and a rapidly disintegrating carrier or excipient. The rapidly disintegrating carrier or excipient is typically one which dissolves rapidly in the saliva, for instance within a period of from about 1 to about 120 seconds, typically within a period of from about 1 to about 60 seconds, for instance from about 1 to about 30 seconds, or from about 1 to about 10 seconds. Usually, the pharmaceutical composition of the invention is a dosage form, for instance a unit dosage form. The dosage form is typically a solid dosage form. It is typically an oral dosage form, for instance a tablet or capsule. It is often a tablet.

The dosage form, which is typically an oral dosage form, for instance a tablet, often comprises an outer layer which comprises the first component. The dosage form typically further comprises one or more inner regions, which comprise the at least one further component. These inner regions are typically within the outer layer. The outer layer is typically disposed on all or part of the surface of the at least one further component. Thus, the outer layer is typically disposed on all or part of the surface of the inner region(s).

The dosage form, which is typically an oral dosage form, for instance a tablet, often comprises an outer layer which comprises the first component, and an inner region, which comprises the at least one further component. The outer layer is typically disposed on all or part of the surface of the inner region. The inner region is often completely within the outer layer.

Thus, the oral dosage form may have a core-shell structure wherein the at least one further component defines a core and the first component is disposed on the surface of the core to form a shell which surrounds the core.

The first component, i.e. the outer layer, or shell, in the above-mentioned embodiments, is typically capable of dispersing or dissolving in buccal fluid within a period of from about 1 second to about 120 seconds. It may for instance be capable of dispersing or dissolving in buccal fluid within a period of from about 1 second to about 90 seconds, particularly from about 1 second to about 60 seconds, for instance from about 1 second to about 45 seconds or, for example, from about 1 second to about 30 seconds, and preferably from about 1 second to about 10 seconds. It may for instance be capable of dispersing or dissolving in buccal fluid within a period of from about 1 second to about 120 seconds, for instance within a period of from about 15 seconds to about 120 seconds, particularly from about 30 seconds to about 90 seconds, or from about 30 seconds to about 60 seconds.

The first component, i.e. the outer layer, or shell, in the above-mentioned embodiments, is typically therefore suitable for sublingual administration.

Thus, the first component (the outer layer, or shell, in the above-mentioned embodiments) typically capable of dispersing or dissolving within a period of from about 1 second to about 120 seconds after the composition of the invention (which is typically an oral dosage form) is administered sublingually, i.e. placed under the tongue, or between the cheek and gum. It may for instance be capable of dispersing or dissolving within a period of from about 1 second to about 90 seconds, particularly from about 1 second to about 60 seconds, for instance from about 1 second to about 45 seconds or, for example, from about 1 second to about 30 seconds, and preferably from about 1 second to about 10 seconds, after the composition of the invention is administered sublingually, i.e. placed under the tongue, or between the cheek and gum. It may for instance be capable of dispersing or dissolving in buccal fluid within a period of from about 1 second to about 120 seconds, for instance within a period of from about 15 seconds to about 120 seconds, particularly from about 30 seconds to about 90 seconds, or from about 30 seconds to about 60 seconds, after the composition of the invention is administered sublingually, i.e. placed under the tongue, or between the cheek and gum.

The dosage form may advantageously further comprise a coating for delaying exposure of the SSRI in the one or more further components to the buccal, gastric, or intestinal fluids. Such a coating, which may be an enteric coating, is discussed in further detail hereinbelow. The coating for delaying exposure of the SSRI is typically disposed on the surface of the inner region, which comprises the at least one further component. It may then delay release of the SSRI from the inner region but not adversely affect rapid release of the SSRI from the first component. The coating may advantageously therefore be disposed between the first component and the one or more further components, in a core shell structure wherein the one or more further components define a core and the first component is a shell disposed around that core. In such a core-shell structure, the coating, which may be an enteric coating, may advantageously be disposed between the core and the shell.

In the pharmaceutical composition of the invention, the first component typically comprises from 2% to 45% by weight of the total amount of the SSRI in the first and further components. As will be appreciated, the total amount of the SSRI in the first and further components is generally the same as the total amount of the SSRI in the pharmaceutical composition of the invention, because generally the only components or portions of the pharmaceutical composition which comprise the SSRI are the first and further components. Thus, in the pharmaceutical composition of the invention, the first component typically comprises from 2% to 45% by weight of the total amount of the SSRI in the pharmaceutical composition. The other 98% to 55% by weight of the SSRI, that is not present in the first component, will be present in the at least one further component.

More typically, the first component comprises from 5% to 40% by weight of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition). The first component may for instance comprise from 10% to 40% by weight of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition). Typically, the first component comprises from 10% to 30% by weight of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition). The first component may for instance comprise from 15% to 25% by weight of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition). The first component may for example comprise about 20% by weight of the total amount of the SSRI in the first and further components.

Thus, in the pharmaceutical composition of the invention, the ratio of the mass of the SSRI in the at least one further component to the mass of the SSRI in the first component is typically from 98:2 to 55:45. More typically, in the pharmaceutical composition of the invention, the ratio of the mass of the SSRI in the at least one further component to the mass of the SSRI in the first component is from 95:5 to 60:40. The ratio of the mass of the SSRI in the at least one further component to the mass of the

SSRI in the first component may for instance be from 90: 10 to 60:40. Typically, the ratio of the mass of the SSRI in the at least one further component to the mass of the SSRI in the first component is from 90: 10 to 70:30. For instance, the ratio of the mass of the SSRI in the at least one further component to the mass of the SSRI in the first component may be from 85: 15 to 75:25, for example about 80:20.

The weights and masses of the SSRI here refer to the weight and mass of the SSRI in the free form, irrespective of whether the SSRI is present in the composition in salt form, co-crystal form, or indeed the free form. This is to allow for the possibility that the SSRI may be present in different forms in the first component and the further component(s), for instance it may be present in the free form in one component and in a salt form in another component. Thus, masses are quoted on a "free form" ("free base") basis.

Indeed, except where specified otherwise or is otherwise apparent from the context, all doses and masses of SSRI's are cited on a "free form" basis. Thus, for example, if the SSRI is in the free form (as opposed to a salt form or in the form of a co-crystal), reference to "60mg" of the SSRI, as used herein, means 60mg of the SSRI in the said free form. If on the other hand the SSRI is in the form of a salt or cocrystal, reference to "60mg" of the SSRI, as used herein, does not mean 60mg of that salt or cocrystal; rather, unless otherwise specified or unless it is otherwise apparent from the context, it refers to the particular amount of that salt that would provide 60mg of the SSRI in the free form. In other words, it refers to the mass of the salt or co-crystal of the SSRI which is the molar equivalent of 60mg of the SSRI in the free form.

Thus, in the pharmaceutical composition of the invention, the ratio of the number of moles of the SSRI in the at least one further component to the number of moles of the SSRI in the first component is typically from 98:2 to 55:45. Thus, typically, the first component comprises from 2 mol. % to 45 mol. % of the total amount of the SSRI in the first and further components, and the at least one further component comprises from 98 mol. % to 55 mol. % of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition).

More typically, in the pharmaceutical composition of the invention, the ratio of the number of moles of the SSRI in the at least one further component to the number of moles of the SSRI in the first component is typically from 95:5 to 60:40. Thus, more typically, the first component comprises from 5 mol. % to 40 mol. % of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition).

The ratio of the number of moles of the SSRI in the at least one further component to the number of moles of the SSRI in the first component may for instance be from 90: 10 to 60:40. Thus, the first component may comprise from 10 mol. % to 40 mol. % of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition).

Typically, the ratio of the number of moles of the SSRI in the at least one further component to the number of moles of the SSRI in the first component is from 90: 10 to 70:30. Thus, typically, the first component comprises from 10 mol. % to 30 mol. % of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition). For instance, the ratio of the number of moles of the SSRI in the at least one further component to the number of moles of the SSRI in the first component may be from 85: 15 to 75:25, for example about 80:20. The first component may for instance comprise from 15 mol. % to 25 mol. % of the total amount of the SSRI in the first and further components (i.e. of the total amount of the SSRI in the pharmaceutical composition). The first component may for example comprise about 20 mol. % of the total amount of the SSRI in the first and further components.

In the pharmaceutical composition of the invention, the total mass of the SSRI in the composition (in the first and further components thereof) is typically less than or equal to 300 mg, for instance less than or equal to 200 mg, and more typically less than or equal to 100 mg. It may for instance be less than or equal to 80 mg.

Usually, in the pharmaceutical composition of the invention, the total mass of the SSRI in the composition (in the first and further components thereof) is at least 5 mg, for instance at least 10 mg, and it is more typically at least 20 mg. It may for instance be at least 40 mg, for example at least 50 mg.

In the pharmaceutical composition of the invention, the total mass of the SSRI in the composition (in the first and further components thereof) is typically from 5 mg to 300 mg. More typically, the total mass of the SSRI in the composition (in the first and further components thereof) is from 5 mg to 200 mg, for instance from 10 mg to 100 mg.

Often, in the pharmaceutical composition of the invention, the total mass of the SSRI in the composition (in the first and further components thereof) is from 20 mg to 80 mg, for instance from 20 mg to 60 mg. In these embodiments, the ratio of the amount (in terms of number of moles, or in terms of mass) of the SSRI in the at least one further component to the amount of the SSRI in the first component may be as further defined above. The SSRI may be as further defined anywhere herein, but often, in this embodiment, it is duloxetine.

The total mass of the SSRI in the composition (in the first and further components thereof) may for instance be 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg or 100 mg. It may for instance be 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg. In each of these particular embodiments, the ratio of the amount (in terms of number of moles, or in terms of mass) of the SSRI in the at least one further component to the amount of the SSRI in the first component may be as further defined above. The SSRI may be as further defined anywhere herein, but often, in this embodiment, it is duloxetine.

The total mass of the SSRI in the composition (in the first and further components thereof) may for instance be from 50 mg to 80 mg, for example from 50 mg to 70 mg. The total mass of the SSRI in the composition (in the first and further components thereof) may for instance be about 60 mg. In these embodiments, the ratio of the amount (in terms of number of moles, or in terms of mass) of the SSRI in the at least one further component to the amount of the SSRI in the first component may be as further defined above. The SSRI may be as further defined anywhere herein, but often, in this embodiment, it is duloxetine. Further component adapted to deliver the SSRI from dose to dose

The at least one further component in the composition of the invention, which is adapted to deliver the SSRI from dose to dose, typically comprises a further component as defined in the following section. The further component may be referred to as a controlled-release fraction. The further component typically comprises said SSRI (typically in a particular defined dose amount as discussed above) and a matrix suitable for promoting prolonged release of the SSRI. The further component often further comprises a filler. It may also comprise a glidant, a lubricant, or both.

The matrix may be a hydrophilic matrix or an erodible matrix. Suitable hydrophilic and erodible matrix materials which may be employed are discussed further herein. The matrix may for instance be a hydrophilic matrix, which may for instance comprise a hydrophilic polymer, for instance a water- soluble polymer. Suitable polymers include cellulose ether and xanthan gum. Accordingly, the hydrophilic matrix may for example comprise a polymer which is a cellulose ether or xanthan gum. The further component typically comprises a hydrophilic polymer which is a cellulose ether.

Cellulose ethers are available from Dow under the trade name Methocel and are suitable for use for controlled release of drugs in hydrophilic matrix systems. The cellulose ether may be selected from carboxymethylcellulose (CMC), methylcellulose (MC) and derivatives thereof, hydroxyethylcellulose (HEC) and derivatives thereof, hydroxylpropyl cellulose (HPC), hydroxypropylmethylcellulose, and ethylcellulose (EC). Often, however, the cellulose ether is hydroxypropylmethylcellulose or ethylcellulose. Hydroxypropylmethylcellulose, in particular, is usually employed.

The further component may comprise the SSRI in an amount of from 4 wt. % to 20 wt. % based on the total weight of the further component, or for instance in an amount of from 5 wt. % to 15 wt. %, for example from 8 wt. % to 13 wt. %.

The further component may additionally comprise the matrix suitable for promoting prolonged release of the SSRI (which is typically a hydrophilic matrix, for instance a hydrophilic polymer as defined above, and may suitably be a cellulose ether, such as, for example,

hydroxypropylmethylcellulose or ethylcellulose) in an amount of from 15 wt. % to 45 wt. % based on the total weight of the further component. The further component may for instance comprise the matrix in an amount of from 15 wt. % to 35 wt. %. The further component may for example comprise the matrix in an amount of from 25 wt. % to 35 wt. %, for instance from 28 wt. % to 32 wt. %, based on the total weight of the further component. Alternatively, the further component may comprise the matrix in an amount of from 15 wt. % to 25 wt. %, for instance from 18 wt. % to 22 wt. %, based on the total weight of the further component.

Typically the hydrophilic polymer is said cellulose ether, and the further component comprises the SSRI in an amount of from 5 wt. % to 15 wt. % and comprises the cellulose ether in an amount of from 15 wt. % to 35 wt. %, and preferably in an amount of from 25 wt. % to 35 wt. %, for instance from 28 wt. % to 32 wt. %, based on the total weight of the further component.

The further component may additionally comprise a glidant. The further component typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a glidant, for instance from 0.1 wt. % to 0.9 wt. % of a glidant, or for example from 0.3 wt. % to 0.7 wt. % of the glidant, based on the total weight of the further component. Examples of suitable glidants include but are not limited to: colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc. Often, however, silicon dioxide (silica) is employed as a glidant in the further component. This is typically hydrophilic silica. It is often for instance hydrophilic fumed silica, which is commercially available under the trade name Aerosil 200.

The further component may additionally comprise a lubricant. The further component typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a lubricant, for instance from 0.1 wt. % to 0.9 wt. % of a lubricant, or for example from 0.3 wt. % to 0.7 wt. % of the lubricant, based on the total weight of the further component. Examples of suitable lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate,

microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Often, however, a stearate, usually a metal stearate, and typically magnesium stearate, is employed as a lubricant in the further component.

The balance of the further component typically comprises, and often consists of, one or more fillers. Examples of suitable fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol. Often, however, the fillers employed in the further component are selected from lactose and cellulose, and typically from anhydrous lactose and microcrystalline cellulose.

The balance of the further component typically comprises, and often consists of, a filler which comprises lactose. The filler is often for instance anhydrous lactose, which is commercially available from DFE Pharma under the trade name SuperTab® 24AN. Alternatively, the balance of the further component may comprise, for instance consist of, a filler which comprises cellulose. The filler is often for instance microcrystalline cellulose, which is commercially available as Microcrystalline Cellulose PH102 under the trade name Avicel® from FMC Corporation. More typically, however, the filler is anhydrous lactose, which is commercially available from DFE Pharma under the trade name SuperTab® 24AN.

The further component may for instance comprise, or consist of, the following:

the SSRI, in an amount of from 4 wt. % to 20 wt. % based on the total weight of the further component; a hydrophilic polymer, in an amount of from 15 wt. % to 35 wt. % based on the total weight of the further component; optionally, a lubricant, in an amount of up to 2 wt. % based on the total weight of the further component; optionally, a glidant, in an amount of up to 2 wt. % based on the total weight of the further component; and

a filler. The filler typically makes up the balance of the further component.

In this embodiment of the further component, the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler is usually anhydrous lactose. Additionally, in this embodiment of the further component, the SSRI may be as further defined anywhere herein. Often, however, it is duloxetine. It is typically a duloxetine salt, for instance duloxetine hydrochloride.

The further component may for instance comprise, or consist of, the following:

from 5 wt. % to 15 wt. % of the SSRI;

from 25 wt. % to 35 wt. %, for instance from 28 wt. % to 32 wt. %, of a hydrophilic polymer; optionally up to 2 wt. % of a lubricant;

optionally up to 2 wt. % of a glidant; and

a filler. The filler typically makes up the balance of the further component.

As would be understood by the skilled person, the percentages by weight here are the percentages by weight of the components in the further component, based on the total weight of the further component.

Again, in this embodiment of the further component, the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler usually comprises anhydrous lactose. The filler may comprise, or for instance consist of, anhydrous lactose. Additionally, in this embodiment of the further component, the SSRI may be as further defined anywhere herein. Often, however, it is duloxetine. It is typically a salt of duloxetine, for instance duloxetine hydrochloride.

The further component may for instance comprise, or consist of, the following:

from 5 wt. % to 15 wt. % of the SSRI;

from 15 wt. % to 25 wt. %, for instance from 18 wt. % to 22 wt. %, of a hydrophilic polymer; optionally up to 2 wt. % of a lubricant;

optionally up to 2 wt. % of a glidant; and a filler. The filler typically makes up the balance of the further component.

As would be understood by the skilled person, the percentages by weight here are the percentages by weight of the components in the further component, based on the total weight of the further component.

Again, in this embodiment of the further component, the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler usually comprises anhydrous lactose. The filler may comprise, or for instance consist of, anhydrous lactose. Additionally, in this embodiment of the further component, the SSRI may be as further defined anywhere herein. Often, however, it is duloxetine. It is typically a salt of duloxetine, for instance duloxetine hydrochloride.

First component adapted to provide rapid release

The first component is adapted to provide rapid release of the SSRI into the bloodstream to provide fast onset of action. Thus, the first component may be termed a rapid release component or a rapid release fraction.

The first, rapid release component typically comprises the SSRI (typically in a particular defined dose amount as discussed above) and a disintegrating agent, also known as a disintegrant. The disintegrant renders the first component rapidly disintegrable so that the first component disperses rapidly on contact with aqueous fluids. The first component is typically, for instance, capable of dispersing or dissolving in an aqueous fluid, in particular in buccal fluid, such as saliva, within a period of from about 1 second to about 120 seconds. Often, the period is from about 1 second to about 90 seconds, for instance from about 1 second to about 60 seconds, or for example from about 1 second to about 30 seconds. The first component often further comprises one or more fillers. It may also comprise a glidant, a lubricant, or both. It may also comprise one or more agents selected from taste masking agents and flavouring agents.

Any suitable disintegrant may be employed. A wide range of disintegrants are known to the skilled person. Examples of these include, but are not limited to, sodium starch glycolate,

polyvinylpyrrolidone (PVPP, crospovidone), alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate.

Often, a modified starch, for instance sodium starch glycolate, is employed as the disintegrant. The first component may comprise the SSRI in an amount of from 0.5 wt. % to 8 wt. % based on the total weight of the first component, or for instance in an amount of from 1 wt. % to 5 wt. %, for example from 1.5 wt. % to 4 wt. %, or from 2 wt. % to 4 wt. %, based on the total weight of the first component. The first component may additionally comprise the disintegrant (which is typically one of the types listed above and may for instance be sodium starch glycolate) in an amount of up to 15 wt.%, for instance from 0.5 wt. % to 10 wt. %, or more typically for example from 1 wt. % to 10 wt. %, based on the total weight of the first component. The first component may for instance comprise the disintegrant in an amount of from 2 wt. % to 6 wt. %, for instance from 3 wt. % to 5 wt. %, based on the total weight of the first component.

In one embodiment, the disintegrant is sodium starch glycolate, and the first component comprises the SSRI in an amount of from 0.5 wt. % to 8 wt. % and comprises the sodium starch glycolate in an amount of from 1 wt. % to 10 wt. %, based on the total weight of the first component. For instance, the disintegrant may be sodium starch glycolate, and the first component may comprise the SSRI in an amount of from 1 wt. % to 5 wt. % and the sodium starch glycolate in an amount of from 2 wt. % to 6 wt. %, based on the total weight of the first component.

The first component may further comprise one or more agents selected from taste masking agents and flavouring agents. The one or more agents may for instance comprise: a flavouring agent and one or more sweeteners. A peppermint flavouring agent may for instance be employed as the flavouring agent. An example of a suitable peppermint flavouring agent is Peppermint Flavour 501500 TP0504. Suitable sweeteners include natural sweeteners, for instance natural sugars and stevia (e.g.

TASTEVA ^® ), or artificial sweeteners. Any artificial sweetener may be employed, for instance a synthetic sugar substitute, such as, for example, sucralose. The one or more agents may for example comprise: a flavouring agent, a natural sweetener and an artificial sweetener. The one or more agents may for instance comprise stevia (e.g. TASTEVA ^® ), sucralose and a peppermint flavouring agent (e.g. Peppermint Flavour 501500 TP0504).

The total amount of the one or more agents selected from taste masking agents and flavouring agents in the first component is typically up to 7 wt %, for instance up to 5 wt. %, based on the total weight of the first component. It may for instance be from 0.1 wt. % to 5 wt. %, based on the total weight of the first component, for instance from 0.5 wt. % to 5 wt. %, or from 1.5 wt. % to 3 wt. %.

The first component may additionally comprise a lubricant. The first component typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a lubricant, for instance from 0.1 wt. % to 0.9 wt. % of a lubricant, or for example from 0.3 wt. % to 0.7 wt. % of the lubricant, based on the total weight of the first component. Examples of suitable lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Often, however, a stearate, usually a metal stearate, and typically magnesium stearate, is employed as a lubricant in the first component.

The balance of the first component typically comprises, and often consists of, one or more fillers. Examples of suitable fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, a sugar alcohol, a disaccharide sugar alcohol, sugar spheres, talc, tribasic calcium phosphate, xylitol. Often, however, the filler employed in the first component comprises a sugar alcohol. The sugar alcohol filler may be a disaccharide sugar alcohol, for instance isomalt. Thus, the balance of the first component typically comprises, and often consists of, a filler which comprises isomalt. A suitable isomalt filler which is commercially available is Isomalt 721.

The first component may for instance comprise, or consist of, the following:

the SSRI, in an amount of from 0.5 wt. % to 8 wt. % based on the total weight of the first component;

a disintegrant, which may be as further defined above (e.g. sodium starch glycolate), in an amount of from 1 wt. % to 10 wt. % based on the total weight of the first component;

one or more agents selected from taste masking agents and flavouring agents, which may be as further defined above (e.g. a flavouring agent, a natural sweetener and an artificial sweetener), wherein the total amount of the one or more agents in the first component is from 0.1 wt. % to 5 wt. %, based on the total weight of the first component;

optionally, a lubricant, which may be as further defined above (e.g. a metal stearate), in an amount of up to 2 wt. % based on the total weight of the first component; and

a filler, which may be as further defined above, optionally wherein the filler makes up the balance of the first component.

The first component may for instance comprise, or consist of, the following:

the SSRI, in an amount of from 1 wt. % to 5 wt. % based on the total weight of the first component;

a disintegrant, which may be as further defined above (e.g. sodium starch glycolate), in an amount of from 2 wt. % to 6 wt. % based on the total weight of the first component; one or more agents selected from taste masking agents and flavouring agents, which may be as further defined above (e.g. a peppermint flavouring agent, stevia and sucralose), wherein the total amount of the one or more agents in the first component is from 1.5 wt. % to 3 wt. %, based on the total weight of the first component;

optionally, a lubricant , which may be as further defined above (e.g. magnesium stearate), in an amount of up to 2 wt. % based on the total weight of the first component; and

a filler, which may be a disaccharide sugar alcohol, optionally isomalt, optionally wherein the filler makes up the balance of the first component.

As would be understood by the skilled person, the percentages by weight here are the percentages by weight of the components in the first component, based on the total weight of the first component. In this embodiment of the first component, the disintegrant is typically a modified starch, for instance sodium starch glycolate; the lubricant, when present, is typically a stearate, for instance a metal stearate such as magnesium stearate; the one or more agents selected from taste masking agents and flavouring agents, typically comprise a peppermint flavouring agent, stevia and sucralose; and the filler usually comprises a disaccharide sugar alcohol, typically isomalt. The filler may comprise, or for instance consist of, the disaccharide sugar alcohol, typically isomalt. Additionally, in this embodiment of the first component, the SSRI may be as further defined anywhere herein. Often, however, it is duloxetine. It is typically a salt of duloxetine, for instance duloxetine hydrochloride. Combined first and further component embodiments

Preferably, the at least one further component is a further component as defined above under the heading "further component adapted to deliver the SSRI from dose to dose" and the first component is as defined above under the heading "first component adapted to provide rapid release".

Thus, typically:

- the first component comprises, or consists of, the following:

the SSRI, in an amount of from 0.5 wt. % to 8 wt. % based on the total weight of the first component;

a disintegrant, which may be as further defined above (e.g. sodium starch glycolate), in an amount of from 1 wt. % to 10 wt. % based on the total weight of the first component;

one or more agents selected from taste masking agents and flavouring agents, which may be as further defined above (e.g. a flavouring agent, a natural sweetener and an artificial sweetener), wherein the total amount of the one or more agents in the first component is from 0.1 wt. % to 5 wt. %, based on the total weight of the first component;

optionally, a lubricant, which may be as further defined above (e.g. a metal stearate), in an amount of up to 2 wt. % based on the total weight of the first component; and

a filler, which may be as further defined above for the first component, optionally wherein the filler makes up the balance of the first component; and - the further component comprises, or consists of, the following:

the SSRI, in an amount of from 5 wt. % to 15 wt. % based on the total weight of the further component;

a hydrophilic polymer which may be a cellulose ether or xanthan gum, but is typically a cellulose ether, in an amount of from 15 wt. % to 35 wt. % based on the total weight of the further component;

optionally, a lubricant which may be as further defined above (e.g. a metal stearate), in an amount of up to 2 wt. % based on the total weight of the further component;

optionally, a glidant, which may for instance be hydrophilic silica, in an amount of up to 2 wt. % based on the total weight of the further component; and

a filler, which may be as further defined above for the further component, optionally wherein the filler makes up the balance of the further component.

Often, for instance:

- the first component comprises, or consists of, the following: the SSRI, in an amount of from 1 wt. % to 5 wt. % based on the total weight of the first component;

a disintegrant, which may be as further defined above (e.g. sodium starch glycolate), in an amount of from 2 wt. % to 6 wt. % based on the total weight of the first component;

one or more agents selected from taste masking agents and flavouring agents, which may be as further defined above (e.g. a peppermint flavouring agent, stevia and sucralose), wherein the total amount of the one or more agents in the first component is from 1.5 wt. % to 3 wt. %, based on the total weight of the first component;

optionally, a lubricant , which may be as further defined above (e.g. magnesium stearate), in an amount of up to 2 wt. % based on the total weight of the first component; and

a filler, which may comprise a disaccharide sugar alcohol, optionally isomalt, wherein the filler makes up the balance of the first component; and

- the further component comprises, or consists of, the following:

the SSRI, in an amount of from 5 wt. % to 15 wt. % based on the total weight of the further component;

a hydrophilic polymer which may be a cellulose ether or xanthan gum, but is typically a cellulose ether, in an amount of from 25 wt. % to 35 wt. % based on the total weight of the further component;

optionally, a lubricant which may be as further defined above (e.g. may be magnesium stearate), in an amount of up to 2 wt. % based on the total weight of the further component;

optionally, a glidant, which may for instance be hydrophilic silica, in an amount of up to 2 wt.

% based on the total weight of the further component; and a filler, which may for instance comprise lactose, for example anhydrous lactose, wherein the filler makes up the balance of the further component.

Often, the SSRI in the first and further components is duloxetine, for instance in the form of duloxetine free base or a pharmaceutically acceptable salt of duloxetine such as duloxetine hydrochloride, the disintegrant comprises sodium starch glycolate, the filler in the first component comprises isomalt, the one or more agents selected from taste masking agents and flavouring agents comprise a peppermint flavouring agent, stevia and sucralose, the lubricant in the first and further components comprises magnesium stearate, the hydrophilic polymer comprises a cellulose ether, the glidant comprises hydrophilic silica, and the filler in the further component comprises anhydrous lactose.

The total mass of the SSRI in the first and further components may, for instance, be from 20 mg to 100 mg but is more typically from 40 mg to 80 mg.

In some embodiments, the total mass of the SSRI in the first and further components is from 40 mg to 80 mg and: (i) the ratio of the mass of the SSRI in the further fraction to the mass of the SSRI in the first fraction is from 90: 10 to 60:40, preferably from 85: 15 to 75:25; or (ii) the mass of the SSRI in the first fraction is from 5 mg to 15 mg.

Additional embodiments of the first component, adapted to provide rapid release

Further rapid release formulations for use in the first component of the composition of the invention may be achieved by several different methodologies, as described below, which may be used alone or in combination.

For example, rapid release may be achieved by a dosage form of SSRI comprising a rapidly dispersing wafer containing the SSRI or a pharmaceutically acceptable salt thereof which is placed on the tongue and dissolves in the mouth, for example within the buccal fluids. Suitably the wafer is dispersed and/or dissolved within a period of from about 1 to 120 seconds, preferably within a period of from about 1 to 90 seconds, for instance within a period of from about 1 to 60 seconds, more preferably from about 1 to 30 seconds, most preferably within a period of from about 1 to 10 seconds. Suitably the wafer is made from a freeze-dried compact containing the SSRI or a pharmaceutically acceptable salt thereof, in a matrix of a buccal fluid-dispersible polymer such as gelatine and a polysaccharide such as mannitol. The SSRI is dissolved or dispersed into a suspension of mannitol and gelatine prior to filling into blister cavities. These liquid filled blisters are then conveyed through a liquid nitrogen freezing tunnel for freezing and then into a freeze dryer where the solvent is removed leaving behind a highly porous wafer loaded with the SSRI. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000), M J Rathbone, J Hadgraft & M S Roberts in Modified Release Drug Delivery Systems, Marcel Dekker, New York, 2003, US Patent No. 4,642,903 and US Patent No 5,738,875 which are incorporated herein by reference.

Alternatively, rapid release of the SSRI may be provided by the blending and compression of the SSRI with water soluble excipients, such as a sugar such as but not limited to mannitol, and an effervescence agent, at low compression forces. The low compression forces lead to the formation of a highly porous tablet which disintegrates rapidly. Rapid disintegration is further aided by the inclusion of the effervescence agent, which in the context of this specification is defined as one or more agents which produce carbon dioxide upon contact with buccal, gastric, or intestinal fluids. Typically, effervescence is derived by the reaction which takes place between alkali metal carbonates or bicarbonates and organic acids such as citric acid or tartaric acid to release carbon dioxide.

Examples of effervescent agents are effervescent couples such as an organic acid and a metal carbonate or bicarbonate. Suitable organic acids include but are not limited: citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L- lysine carbonate and arginine carbonate. Alternatively, only the base component of the effervescent couple may be present. Effervescence may also result from the inclusion of a carbonate or bicarbonate alone to react with acidic gastrointestinal fluids. Suitably the porous dosage form (typically a porous tablet) disperses within a period of from about 1 to 120 seconds, preferably within a period of from about 1 to 90 seconds, for instance within a period of from about 1 to 60 seconds, preferably from about 1 to 45 seconds, more preferably from about 1 to 30 seconds, most preferably within a period of from about 1 to 10 seconds. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000), M J Rathbone, J Hadgraft & M S Roberts in Modified Release Drug Delivery Systems, Marcel Dekker, New York, 2003, US Patent No. 5,178,878 and US Patent No 5,607,697 which are incorporated herein by reference.

Alternatively, rapid release of the SSRI may be achieved by blending and compressing the SSRI with a suitable sugar such as but not limited to sucrose which has been melt-spun to form a mass of thin filaments with a high surface area. The resulting tablets are highly porous. Upon contact with buccal fluids, they disintegrate rapidly as the mass of thin filaments dissolves. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000) and US Patent No 4,855,326 which are incorporated herein by reference. Alternatively, rapid release of the SSRI may be achieved by blending and compressing the SSRI with a low mould ability saccharide (e.g. such as but not limited to lactose and mannitol) which has been granulated using a high mould ability saccharide (e.g. such as but not limited to maltose and maltitol) as a binder. The resulting tablets possess characteristics which enable them to dissolve rapidly on contact with aqueous fluids, typically within a period of from about 1 to 120 seconds, preferably within a period of from about 1 to 90 seconds, for instance within a period of from about 1 to 60 seconds, preferably from about 1 to 45 seconds, more preferably from about 1 to 30 seconds, most preferably within a period of from about 1 to 10 seconds. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000) and US Patent No 5,576,014 which are incorporated herein by reference.

Alternatively, rapid release of the SSRI may be achieved by blending and compressing the SSRI with a disintegrating agent (e.g. such as but not limited to carboxymethylcellulose) and a swelling agent (e.g. such as but not limited to modified starch, e.g. Sodium Starch Glycolate) to produce a rapidly disintegrable tablet which preferably on contact with aqueous fluids disperses within a period of from about 1 to 120 seconds, preferably within a period of from about 1 to 90 seconds, for instance within a period of from about 1 to 60 seconds, preferably from about 1 to 45 seconds, more preferably from about 1 to 30 seconds, most preferably within a period of from about 1 to 10 seconds. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000) and US Patent No 5,464,632 which are incorporated herein by reference.

It should be appreciated that such tablets will afford advantages over the existing marketed swallow tablets even if swallowed before complete dissolution in the mouth, since dissolution in the gastric fluids will still allow a faster dissolution of the SSRI than is achievable from conventional swallow tablets.

One way of augmenting the rapid release achievable by a suitable choice of formulation, is to utilise a salt of the SSRI which is very soluble in saliva or in gastric fluid.

Yet another way of augmenting the rapid release achieved by a suitable choice of formulation is to utilise an amorphous form of a salt of the SSRI or the SSRI in the free form. In addition the amorphous or crystalline form of a salt of the SSRI or the SSRI in the free form may be dispersed or adsorbed in a thin layer over a high surface area inert substrate. Suitable substrates include but are not limited to: Amberlite ® XAD-4, Amberlite ® XAD-7, Amberlite ® XAD-16, AMBERSORB ® 348F, AMBERSORB ® 563, AMBERSORB ® 572, Activated carbon, Activated carbon Darco ®, Activated carbon Darco ® G-60, Activated carbon Darco ® KB, Activated carbon Darco ® KB-B, Activated carbon Norit ®, silica gel high purity grades with high pore volume, for example about 0.75 cc/g and average pore diameter 60A.

It will be appreciated that other materials with comparable properties may also be used as substrates.

Any of these "additional embodiments of the first component, adapted to provide rapid release" described above may be combined with any of the "further component adapted to deliver the SSRI from dose to dose" described further above or any of the "additional embodiments of the further component adapted to deliver the SSRI from dose to dose" described in the following text.

Additional embodiments of the further component adapted to deliver the SSRI from dose to dose

Further modified (prolonged or delayed) release formulations, which are suitable for use in the further component of the composition of the invention which is adapted to deliver the SSRI from dose to dose, may be achieved by several different methodologies, as described below, which may be used alone or in combination.

Controlled release may be provided in the form of prolonged release. A prolonged release dosage form may consist of a matrix dosage unit, such as a hydrophilic and/or an erodible matrix, usually in tablet form. Release from such a unit can be controlled by a number of mechanisms, such as dissolution, erosion, diffusion, osmotic pressure or any combination thereof. Embodiment of prolonged release dosage forms may utilise excipients which control release of the SSRI by more than one formal mechanism.

An erosion controlled prolonged release dosage unit can be achieved by compressing the SSRI with a slowly dissolvable and/or erodable polymeric material into a tablet form. Release of the SSRI occurs as the polymer dissolves and/or erodes away. Suitable polymers include but are not restricted to glyceryl monostearate, acrylic resins, ethylcellulose, stearyl alcohol, hydroxypropylcellulose, carboxymethylcellulose, hypromellose, methylcellulose, hydroxyethylmethylcellulose, sodium carboxymethylcellulose. Further information can be found in Controlled Drug Delivery, second edition, J R Robinson & V H Lee (editors), Marcel Dekker, New York, 1987, in Drug Delivery

Systems, second edition, V Ranade & M A Hollinger, CRC Press, Boca Raton, 2004, and in Modified Release Drug Delivery Systems, M J Rathbone, J Hadgraft & M S Roberts, Marcel Dekker, New York, 2003 which publications are incorporated herein by reference.

A diffusion controlled prolonged release dosage form may be produced by compressing a water- swellable hydrophilic polymer in combination with the SSRI drug substance. Such systems are often referred to as "hydrophilic matrices" or "swellable -soluble" systems. Water continues to penetrate the matrix causing the swelling of the hydrophilic polymer. The gelatinous layer that is formed, retards the rate of ingress of water into the matrix and the flux of drug out of the matrix. The SSRI is released from such matrices either by diffusion through the gel layer or by erosion and/or dissolution of the gel layer. Suitable materials would include any pharmaceutically acceptable excipient which can swell and form a gelatinous mass upon hydration, for example, hydroxypropylmethylcellulose, and xanthan gum. Further information and descriptions of such dosage forms can be found in Controlled Drug Delivery, second edition, J R Robinson & V H Lee (editors), Marcel Dekker, New York, 1987 which publication is incorporated herein by reference.

An osmosis controlled prolonged release dosage form may be produced by compressing the SSRI in combination with an osmagent into a tablet matrix core formulation. This matrix core is then in part coated with a semi-permeable membrane in known manner, utilising such polymers such as methacrylates, ethylcellulose, and cellulose acetate. Aqueous fluids are drawn by osmosis from the exterior environment across the membrane at a controlled rate into the core, causing dissolution of both the SSRI and the osmogent and increased pressure within the matrix core. The pressure forces the solubilised SSRI out through a specially created aperture or passageway. Examples of osmagents include but are not restricted to sodium chloride, potassium chloride, lithium chloride, magnesium chloride, magnesium sulphate, lithium sulphate, sodium sulphate, potassium sulphate, citric acid, mannitol, ribose, arabinose, galactose, leucine, glycine, fructose, sucrose, sodium and other bicarbonates. Further information can be found in the scientific and patent literature, for example: Controlled Drug Delivery, second edition, J R Robinson & V H Lee (editors), Marcel Dekker, New York, 1987, Modified Release Drug Delivery Systems, M J Rathbone, J Hadgraft & M S Roberts, Marcel Dekker, New York, 2003, and US Patents 3,760,984, 3,845,770, 3,987,790, 3,916,899,

4008,719, 4,036,227, 4,576,604, 4,578,075, 4,673,405, 4,681,583, 4,693,895, 4,705,515, 4,773, 907, 5,229, 133 which documents are incorporated herein by reference.

Prolonged release can also be achieved by applying a porous or semipermeable membrane coat onto a tablet surface by the application of such polymers such as methacrylates, ethylcellulose, and cellulose acetate. Release from such systems can occur by more than one of the mechanisms described above, for example a combination of dissolution, diffusion, erosion, and osmosis. Alternatively, prolonged release can be achieved by coating multiparticulates with semipermeable membranes. The multiparticulates include drug-coated substrates, such as lactose beads, and drug-containing substrates, such as drug-containing lactose spheres. Delayed release of the SSRI can be achieved by means of a physical barrier or coating which delays exposure of the active material to the buccal, gastric, or intestinal fluids. One technique which provides delayed release involves the application of a coating of a fluid resistant barrier to a single dosage unit, or to a multiparticulate dosage unit, for example one composed of beadlets, pellets, spheroids, minitablets and/or granules. These coatings can be designed to dissolve at a specific pH range, for example an enteric coating which dissolves at a pH greater than 5.0. Typical pH-dependent polymers suitable for coating dosage forms (single or multiparticulate) include the following: cellulose acetate phthalate, which dissolves at pH 6.0-6.4 hydroxypropylmethylcellulose phthalate 50, which dissolves at about pH 4.8 hydroxypropylmethylcellulose phthalate 55, which dissolves at about pH 5.2 polyvinylacetate phthalate, which dissolves at about pH 5.0 methacrylic acid-methyl methacrylate copolymer (1 : 1), which dissolves at about pH 6.0 methacrylic acid-methyl methacrylate copolymer (2: 1), which dissolves at pH 6.5-7.5 methacrylic acid-ethyl acrylate copolymer (2: 1), which dissolves at about pH 5.5 hydroxypropylmethylcellulose acetate succinate, which dissolves at about pH 7.0 poly(methylvinylether/maleic acid) monoethylester, which dissolves at pH 4.5 -5.0 poly(methylvinylether/maleic acid)n -butyl ester, which dissolves at about pH 5.4 shellac, which dissolves at about pH 7.0

Alternatively a non-pH-dependant coating may be used, which initially impedes the ingress of aqueous fluid, but subsequently erodes and/or dissolves to expose the active agent to dissolution.

Typical non-pH-dependent polymers suitable for coating dosage forms (single or multiparticulate) to provide a fluid resistant barrier which subsequently erodes or dissolves include, but are not restricted to acacia, alginate, amylase, beeswax, carboxymethylcellulose, carnuba wax, cellulose acetate, cholesterol, ethylcellulose, fatty acids, gelatine, glyceryl behenate, glyceryl monostearate, glyceryl monodistearate, glyceryl tripalmitate, hypromellose, hydroxypropylcellulose, hydrogenated vegetable oil, lecithin, methylcellulose, paraffin wax, pectin, polyethylene glycol, polycaprolactone, polyglycolic acid, polylactic acid, polygly elide -co -lactide co-polymers, polyvinylprroylidone, starch, stearic acid, stearyl alcohol, partially hydrogenated cottonseed oil/soyabean oil (melting at 51-55°C), partially hydrogenated palm oil (melting at 58-63°C), partially hydrogenated cottonseed oil (melting at 61-65°C), partially hydrogenated soyabean oil (melting at 67-71°C), partially hydrogenated castor oil (melting at 85-88°C), polyethylene glycol 3350 (melting at 54-58°C).

Delayed release of the SSRI may also be achieved by a fluid resistant barrier which combines one or more pH-dependant polymers optionally with one or more non-pH-dependant polymers. Examples of delayed release dosage forms include enteric coated tablets or enteric coated multiparticulate formulations, in which drug-loaded multi -particulate spheres are coated with methacrylic acid-methyl methacrylate co-polymers such as Eudragit L100-55, Eudragit L30D-55, or Eudragit FS 30D or Eudragit S100/S12.5. Such formulations will not release the SSRI in the acidic environment of the stomach but only on exposure to the higher pH typically found in the small and large intestine (pH range 5 to 8). An enteric coated tablet illustrating one aspect of this invention may be a single-layer tablet or a multi-layer tablet, such as a bi- or tri-layer tablet, wherein the active agent is present in one or more discrete layers within the compressed tablet form. The discrete tablet layers can be arranged to provide modified or non-modified release of active agent. General descriptions and methods for the preparation of suitable tablets may be found in Aqueous polymeric coatings for pharmaceutical dosage forms, J W McGinty (ed), Marcel Dekker, 1989, New York, and in in Microencapsulation and related drug processes, P Deasy, Marcel Dekker, 1984, New York, which publications are incorporated herein by reference.

Similarly, a capsule can be prepared in which the active dose is provided in the form of beads of the SSRI and is divided into two or more parts, each part having a non-pH-dependant protective coat of different thickness, which takes a different time to erode. Suitable non-pH-dependent coating materials have already been described above. Further information can be found in J R Robinson & V H Lee (eds) in Controlled Drug Delivery, second edition, Marcel Dekker, New York, 1987 , V Ranade & M A Hollinger in Drug Delivery Systems, second edition, CRC Press, Boca Raton, 2004 and M J Rathbone, J Hadgraft & M S Roberts in Modified Release Drug Delivery Systems, Marcel Dekker, New York, 2003 which are incorporated herein by reference.

Any of the "additional embodiments of the further component adapted to deliver the SSRI from dose to dose" described above may be combined with any embodiment of the "first component adapted to provide rapid release" described further above or any of the "additional embodiments of the first component, adapted to provide rapid release" described above.

Preferably, the compositions of the invention are in unit dosage form. Unit dosage forms for oral administration may be in tablet or capsule form and may as necessary contain conventional excipients such as binding agents, fillers, lubricants, glidants, disintegrants, effervescent agents, and wetting agents. Examples of binding agents include but are not limited to: acacia, alginic acid,

carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate, sorbitol, starch, syrup, tragacanth. Examples of fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol. Examples of lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Examples of glidants include but are not limited to: colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc. Examples of disintegrants include but are not limited to: alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycolate. Examples of effervescent agents are effervescent couples as described hereinbefore.

The solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may be coated according to methods known in normal pharmaceutical practice. For example see Pharmaceutical dosage forms: tablets, Volume 1 second edition, H A Lieberman, L Lachman and J B Schwartz (eds) Marcel Dekkker, 1989, New York and G C Cole & J Hogan in Pharmaceutical coating technology, Taylor & Francis, London, 1995 which are herein included by reference.

The quantity of the SSRI required in each component of each formulation can be determined by the skilled worker from the information provided herein. Firstly the target pharmacokinetic profile for the formulation is selected in line with the objects of the present invention. Then, from knowledge of the therapeutic window as defined herein, the mean rate of elimination of the SSRI in the body, and the release profile of the SSRI from each component, the necessary quantity of SSRI in each component in light of the information provided herein may be established. Information on particular preferred dosages overall and in the first and further components is nonetheless also provided herein. Selective serotonin reuptake inhibitor (SSRI)

In the pharmaceutical composition of the invention, any SSRI may in principle be employed. A range of SSRIs are known to the skilled person, and the skilled person is also readily able to test candidate compounds for SSRI activity. Often, however, the SSRI employed in the composition of the invention is duloxetine, fluoxetine or sertraline.

Preferably, the SSRI employed in the composition of the invention is duloxetine.

The SSRI may be the free form (free base) of an SSRI. Alternatively, the SSRI may be in the form of a pharmaceutically acceptable salt of an SSRI. Thus, the SSRI may be duloxetine, fluoxetine or sertraline in the free form (duloxetine free base, fluoxetine free base or sertraline free base) or a pharmaceutically acceptable salt of duloxetine, fluoxetine or sertraline.

It should be understood that "or a pharmaceutically acceptable salt thereof in this context includes amorphous forms and crystalline forms of the SSRI including solvates, hydrates, co-crystals and polymorphs of the SSRI.

Any SSRI described herein may be in the free form (the "free base" of the SSRI), or it may be in the form of a pharmaceutically acceptable salt of the SSRI, a cocrystal of the SSRI, or a complex of the SSRI with a cyclodextrin. Thus, the SSRI may be duloxetine, fluoxetine or sertraline in the free form (duloxetine free base, fluoxetine free base or sertraline free base), a pharmaceutically acceptable salt of duloxetine, fluoxetine or sertraline, a cocrystal of duloxetine, fluoxetine or sertraline with a co- crystal former, or a complex of duloxetine, fluoxetine or sertraline with a cyclodextrin. The SSRI may for instance be duloxetine free base, a pharmaceutically acceptable salt of duloxetine, a cocrystal of duloxetine with a co-crystal former, or a complex of duloxetine with a cyclodextrin. The co-crystal former may be any suitable co-crystal former. The co-crystal former is typically however a compound which comprises a phenol moiety.

The pharmaceutically acceptable salt of the SSRI may be a salt of the SSRI, for instance a salt of duloxetine, fluoxetine or sertraline, or for instance a salt of duloxetine, with any one of the following acids: l-hydroxy-2 -naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzene sulfonic acid; benzoic acid; camphoric acid (+); camphor- 10- sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane -1,2- isulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid;

glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid;

glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-l,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

Typically, it is a salt of the SSRI, for instance a salt of duloxetine, fluoxetine or sertraline, or for instance a salt of duloxetine, with a mineral acid, for instance a salt of the SSRI, for instance a salt of duloxetine, fluoxetine or sertraline, or for instance a salt of duloxetine, with hydrochloric acid or hydrobromic acid.

As discussed above, the SSRI in the first and further components may be the same SSRI but in different forms in the first and further components of the composition of the invention respectively. The SSRI in the first component may be in a first form selected from the forms of SSRI's defined in any of the preceding paragraphs, and the SSRI in the (or in the at least one) further component may be in a second form selected from the forms of SSRI's defined in the preceding paragraphs, wherein the second form is different from the first form.

Often, the SSRI is duloxetine free base.

Alternatively, the SSRI is typically a pharmaceutically acceptable salt of duloxetine. The SSRI may for instance be a salt of duloxetine with a mineral acid. The SSRI may for instance be duloxetine hydrochloride or duloxetine hydrobromide. The SSRI is typically duloxetine hydrochloride.

Whilst duloxetine is a very potent and selective its pharmacological profile is far from ideal.

It is slow in its absorption through the gut wall and therefore it can take 1 to 2 hours for onset of action. Since it has previously been delivered in a bolus from a swallow tablet it is absorbed all at once and is then metabolized quickly and expelled from the body leaving a deficit in the blood stream and causing potency to drop and then disappear long before the next dose is due.

This is a real problem for suffers of the new uses described above which are not adequately treated with existing products. The need for immediacy of action, longevity of action and keeping the blood plasma levels within the therapeutic window from dose to dose is critical for success. There is a need for a technical solution to this long standing problem and one which solves all three problems at the same time i.e. rapidity, longevity from dose to dose and one which delivers the duloxetine within the therapeutic window between dose to dose.

A product line extender having such superior properties would be a commercial success The fact that no such product has ever been made or described before is testament to the fact that there are no obvious solutions to this issue.

One step in solving this problem is finding variants of the product i.e. rapidity maintenance which possess physical and chemical characteristics which are conclusive to addressing one or more of the problems associated with Duloxetine such as rapidity of action duration of effect and sustenance within the therapeutic window for prolonged periods of time from dose to dose.

Duloxetine is commercially available as the free base and is the obvious choice as a starting material. Few alternative salts of duloxetine have been disclosed in the art however none have been tested for rapidity or duration of effect or for any tendency to be within the therapeutic window from dose to dose. It has been surprisingly found that one class of salts lends itself to forming superior adduct with duloxetine and which adducts possess superior properties.

We have found phenol co-crystals improve the solubility profile to bring about rapid onset of action the phenol co-crystals improve solubility at all levels of PH therefore improving the performance of the duloxetine during fasted and non -fasted stomach conditions.

It has also been surprisingly found that septic formulation technologies can be used in conjunction with co crystals of phenolic compounds and or fatty acid salts of duloxetine to engineer a superior product possessing superior properties as outlined above, that is to say a more rapidly acting product , having a PK profile within the therapeutic window from dose to dose. An estimated 50% of all duloxetine molecules used in medicinal therapy are administered as salts.

This fact indicates that the salification, or salt formation, of a duloxetine substance is a critical step in duloxetine development and since the choice of salt is not a matter of routine then the choice of salt will lead to an invention. The diversity of selection is almost as wide as there are numbers of salts available. A duloxetine substance often has certain suboptimal physicochemical or biopharmaceutical properties that can be overcome by pairing a basic or acidic duloxetine molecule with a counter ion to create a salt version of the duloxetine The process is a simple way to modify the properties of a duloxetine with ionisable functional groups to overcome undesirable features of the parent duloxetine This fact underlines the importance of salt formation for drugs that are designed, developed, and marketed after a rigorous research and development program

Basic concepts in salt formation

The salt form is separated into individual entities (i.e., the ionized duloxetine and the counter ion) in liquid medium, and its solubility depends upon the solvation energy in the solvent. The solvent must overcome the crystal lattice energy of the solid salt and create space for the solute. Thus, the solubility of a salt depends on its polarity, lipophilicity, ionization potential, and size. A salt's solubility also depends on the properties of solvent and solid such as the crystal packing and presence of solvates

The importance of salt formation

Salt forms of drugs have a large effect on the drugs' quality, safety, and performance. Ahead of salt selection these properties cannot be predicted ab initio or in advance the properties of salt-forming species (i.e., counter ions) significantly affect the pharmaceutical properties of a duloxetine

Generation of salt forms.

Salts can be prepared on a small scale using various methods. Forming salts from free acid or base is the most common method. The free acid or base of the duloxetine substance is combined with the counter ion base or acid in specific molar ratios in a suitable solvent system. The salt form is then isolated, and the solid precipitate is recrystallized. A less common method is to form salts through salt exchange. In this method, a counter ion salt is treated with a free acid or base in a specific molar concentration in a suitable solvent. The solid is then isolated and recrystallized. The sulphate salt of methyl pyridinium-2-aldoxime should be prepared using silver sulphate as a counter ion. The unwanted silver ions were removed as insoluble iodide salt, and the desired sulphate salt was precipitated by adding anti solvent A wide range of salts are generally prepared for each new substance. Their properties are compared during a pre formulation program that improves the chances of selecting the optimal salt form. However, a balanced approach should be adopted because limited resources are available at this early stage of duloxetine development. Commonly used salts such as hydrochlorides and sodium have advantages over other salt-forming moieties. For example, they have low molecular weight and low toxicity. However, other salt forms such as meslate may sometimes offer advantages such as higher solubility and bioavailability

High -throughput synthesis has gained greater importance in the salt-selection process. This technique allows many counter ions and crystallization solvents to be evaluated using as little as 50 mg of duloxetine substance. After the optimum drug -substance form is selected at the micro level, the synthesis of the compound can be scaled up to several hundred grams to test for other stages of pre- formulation. In situ salt screening also offers a viable alternative to traditional salt screening. This method has a special relevance for poorly soluble compounds because it can rapidly rank compounds based on their solubility, effectively screening out insoluble compounds immediately In spite of the abundance of available counter ions, few are used frequently. The preference for pharmaceutical counter-ions is explained by studying the distribution of different counter ions of medicinal compounds in USP 2006 (38) (see Table III). The table shows that salt forms of drugs (56.15%) are preferred over free forms (43.85%). Hydrochloride and sodium remain the favourite counter ions for the salt formation of medicinal compounds. However, the availability of many pharmaceutically acceptable counter ions makes the salt-selection process difficult and cumbersome.

Salt-form selection. The generated salt forms are compared for the desired physio-chemical and biopharmaceutical properties, which guide the final selection of an optimal salt form.

The selection of an appropriate salt form for a potential duloxetine candidate is an opportunity to modulate its characteristics to improve bioavailability, stability, manufacturability, and patient compliance. Salt Selection in duloxetine Development

The selection of an appropriate salt form for a potential duloxetine candidate is an opportunity to modulate its characteristics to improve bioavailability, stability, manufacturability, and patient compliance.

Selecting an optimal salt form for development is a critical step in ensuring the efficient and successful development of a robust product. Salt selection requires a well-designed screening strategy that fulfils the essential and desirable criteria that set the standard for salt screening. In addition, salt selection procedures must also assess the regulatory, intellectual, and marketing considerations to balance the drug's physicochemical and biopharmaceutical properties against commercial considerations.

The following salts have been chosen as a preferred sub set of salts which are particularly useful in salting with the compounds listed below.

l-hydroxy-2 -naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10 -sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2- isulfonic acid;

ethane sulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methane sulfonic acid; naphthalene-l,5-disulfonic acid; naphthalene-2 -sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); undecylenic acid. Hydrochloric acid in particular is preferred.

The preferred salts are the fatty acid esters. This can be placed in a formulation which is adapted for multicomponent delivery of actives using a formulation which is adapted into multiple components which is further adapted to administer the active rapidly, from dose to dose i.e. longevity and maintain amounts of active adapted accordingly and within the therapy window another preferred salt type are those which have a camphor sulphonate as an active moiety.

A further aspect provides duloxetine adapted in a multi component dosage form such a tablet said dosage form being adapted in a first way to provide rapid release of duloxetine into the bloodstream said dosage form being adapted to further provide a second way a maintenance dose of duloxetine within the therapeutic window and the dosage form being adapted in a third way to provide a modified or delayed release format of the duloxetine product which lasts from dose to dose. Any one of the three components including combinations and including all three may be modified to ensure that the active is released within the therapeutic window from dose to dose.

The exact dose of each component is dependent on the choice of formulation but in general the choice of each component will be made so that the amount of active ingredient in each component delivers the right amount of Duloxetine product to ensure rapidity longevity from dose to dose and maintenance of dose , with the totality of duloxetine being adapted to be released within the therapeutic window so that there is fairly immediate rise of blood plasma level above MIC and which stays above mic and below saturation point from dose to dose substantially within the therapeutic window for almost all the time . It is believed that doses can be reduced from around the level that they were commercially to around 35 pc to 50 pc of this level.

Product line extenders of the present invention are designed to give a new product with superior biological profiles over the existing duloxetine product in terms of efficacy, safety and or side effect profile.

Salts The active ingredient in Cymbalta is duloxetine this compound has a basic centre i.e., an amine function and is therefore capable of forming of salts with acids. Such suitable acids which form an aspect of the present invention include common mineral acids such as hydrochloric, hydrobromic and sulfuric acids, small organic acids such tartrate and maleic and more exotic salts such as fatty acid esters and those listed. Typically, the duloxetine employed in the present invention is in the form of a salt of duloxetine with a mineral acid, for instance as the hydrochloric, hydrobromic or sulfuric acid salt of duloxetine. Alternatively, it may be in the form of a salt of duloxetine with an organic acid, for instance in the form of duloxetine citrate, duloxetine tartrate or duloxetine maleate, or in the form of a salt of duloxetine with a fatty acid. Often, the duloxetine employed in the present invention is in the form of the hydrochloric acid salt, i.e. it is duloxetine hydrochloride (duloxetine HC1). The PK profile is described in the product information leaflet which is herein incorporated by reference. The PK profile which is delivered by the present invention is from dose to dose and is calculated and drawn using conventional means known in the art.

Duloxetine side effects have a number of serious side effects which are described below.

Starting materials and how to make and use the products of the present invention. The active ingredient in duloxetine is prepared from readily available starting material using active duloxetine that is commercially available. The active is extracted using solvent extraction and evaporation techniques or it is precipitate using non polar co solvents Specific examples Rapidity.

The product should have a fast onset of action in order for the active ingredient to have a biological effect at the earliest possible opportunity. This patent describes various inventions to enable this to occur. A multi component tablet containing a portion of active which is admixed with conventional excipients is preferred. The active is preferably salted as described above. The split of active in the delayed release component to the immediate release component is suitably 20 to 80 split such tablets are made using the procedures described herein.

Longevity. Some products such as duloxetine have limited possibilities for a long acting product due to its half- life and other problems. The present invention addresses these issues and provides a product with a long duration of action, preventing issues such as nocturnal deficit from becoming an issue.

An optimal profile for all pharmaceutical products is dose to dose maintenance within the therapeutic window, thus addressing the issues of rapidity, longevity and preventing a bolus blip of high concentration of active ingredient which may cause serious side effects. The present invention provides technical solutions to this issue.

Combinations of two or more from rapidity, longevity and dose to dose maintenance within the therapeutic window are preferred. Addressing two or preferably all three issues results in a superior product. This is a highly preferred aspect of this invention. Additionally, such product line extenders include those which are adapted for oral route of administration such as tablet or capsule and non-oral routes of administration such as patches, depots or suppositories.

It should be appreciated that this patent provides specific examples of new uses, combinations and product line extenders. Since a product must be in a formulation and have a use on the label the present patent application provides many thousands of new concept products which provide patent cover for a range of new LCM products and defensive cover to these products. This grid system approach to patenting provides strong deep cover as well as broad cover. This provides very strong cover for specific examples of the product which are selected and offensive patent cover and defensive cover to prevent copies of the underlying inventive concepts, thereby preventing circumvention of the specific product which is developed and launched as an AB rated, or non AB rated version. This patent describes patentable areas such as salts forms, dosage forms, and specific embodiments of tablets which are multicomponent tablets adapted to deliver active in a manner herein before described.

Product line extenders which address the issues above can be made using techniques known in the art and specifically described in well-known texts such as Remington, the seminal text book on

Pharmaceutical science. These include but are not limited to PLE's which address rapidity, longevity and dose to dose maintenance, finally where the active is provided within the therapeutic window from dose to dose.

Oral and non-oral dosage forms are also described widely in the literature and these techniques are incorporated herein by reference. Common disk-shaped tablets are preferred. A tablet is a pharmaceutical dosage form. The present invention extends to all pharmaceutical dosage forms which are capable of delivering active rapidly, from dose to dose and within the therapeutic window.

Tablets may be defined as the solid unit dosage form of medicament or medicaments with or without suitable excipients and prepared either by moulding or by compression. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose.

The excipients can include diluents, binders or granulating agents, glints (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive or aid in visual identification of an unknown tablet. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet's appearance.

Caplet

A caplet is a smooth, coated, oval-shaped medicinal tablet in the general shape of a capsule. Many caplets have an indentation running down the middle so they may be split in half easier.

Orally disintegrating tablet

Olanzapine ODT blister pack with "wafer" tablets that rapidly dissolve in saliva are examples of the types of tablet that fall within the scope of this invention where the different layers accommodate different amounts of active admixed with different amounts of excipients. An orally disintegrating tablet or dispersible tablet (ODT) is a duloxetine dosage form available for a limited range of over-the-counter (OTC) and prescription medications. Tabletting formulations

In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders segregate during manufacturing operations due to different densities, which can result in tablets with poor duloxetine or active pharmaceutical ingredient (API) content uniformity but granulation should prevent this.

Content uniformity ensures that the same API dose is delivered with each tablet.

Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include excipients. Normally, a pharmacologically inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch,

microcrystalline cellulose, povidone polyvinylpyrrolidone and modified cellulose (for example hydroxypropyl methylcellulose and hydroxyethylcellulose) this is the case here.

Often, an ingredient is also needed to act as a disintegrant to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants.

Tablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Coloured coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets with special properties, for example, sustained release or fast dissolving formulations.

Some drugs may be unsuitable for administration by the oral route. For example, protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the "first pass effect"), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosa, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract, this is the case here

Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. A proportion of the population have difficulties swallowing tablets either because they just don't like taking them or because their medical condition makes it difficult for them (dysphagia, vomiting). In such instances it may be better to consider alternative dosage form or administration route. Tablets can be made in virtually any shape, although requirements of patients and tableting machines mean that most are round, oval or capsule shaped. More unusual shapes have been manufactured but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems. Tablet diameter and shape are determined by the machine tooling used to produce them - a die plus an upper and a lower punch are required. This is called a station of tooling. The thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, and the greater the pressure applied during compression and sometimes the harder the tablet. Tablets need to be hard enough that they don't break up in the bottle, yet friable enough that they disintegrate in the gastric tract.

Tablets need to be strong enough to resist the stresses of packaging, shipping and handling by the pharmacist and patient. The mechanical strength of tablets is assessed using a combination of (1) simple failure and erosion tests, and (2) more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase. Standards for tablet properties are published in the various international pharmacopeias (USP/NF, EP, JP, etc.). The hardness of tablets is the principle measure of mechanical strength. Hardness is tested using a tablet hardness tester. The units for hardness have evolved since the 1930s, but are commonly measured in kilograms per square centimetre. Models of tester include the Monsanto (or Stokes) Hardness Tester from 1930, the Pfizer Hardness Tester from 1950, the Strong Cob Hardness Tester and the Heberlain (or Schleeniger) Hardness Tester.

Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall, as well as between granules, which helps in uniform filling of the die.

Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatine capsules. [

Manufacture of the tableting blend In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active ingredient is in each tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression.

Wet granulation Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis. Procedure

The active ingredient and excipients are weighed and mixed.

The wet granulate is prepared by adding the liquid binder-adhesive to the powder blend and mixing thoroughly. Examples of binders/adhesive s include aqueous preparations of corn-starch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, gelatine, and povidone. Screening the damp mass through a mesh to form pellets or granules.

Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most commonly used.

After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size.

Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state. High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders. It is used because it allows close control of the granulation process.

Dry granulation Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a 'dry binder' may need to be added to the formulation to facilitate the formation of granules.

Hot melt extrusion Hot melt extrusion is utilized in pharmaceutical solid oral dose processing to enable delivery of drugs with poor solubility and bioavailability. Hot melt extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier increasing dissolution rates and bioavailability. The process involves the application of heat, pressure and agitation to mix materials together and 'extrude' them through a die. Twin-screw high shear extruders blend materials and simultaneously break up particles. The extruded particles can then be blended and compressed into tablets or filled into capsules.

Granule lubrication

After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during the tableting process. This usually involves low shear blending of the granules with a powdered lubricant, such as magnesium stearate or stearic acid. Manufacture of the tablets

Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very similar. First, the powder is filled into the die from above. The mass of powder is determined by the position of the lower punch in the die, the cross-sectional area of the die, and the powder density. At this stage, adjustments to the tablet weight are normally made by repositioning the lower punch. After die filling, the upper punch is lowered into the die and the powder is uniaxial compressed to a porosity of between 5 and 20%. The compression can take place in one or two stages (main compression, and, sometimes, pre -compression or tamping) and for commercial production occurs very fast (500-50 ms per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from the die by lifting the lower punch until its upper surface is flush with the top face of the die. This process is repeated for each tablet.

Common problems encountered during tablet manufacturing operations include:

Fluctuations in tablet weight, usually caused by uneven powder flow into the die due to poor powder flow properties.

Fluctuations in dosage of the Active Pharmaceutical Ingredient, caused by uneven distribution of the API in the tableting blend (either due to poor mixing or separation in process). Sticking of the powder blend to the tablet tooling, due to inadequate lubrication, worn or dirty tooling, or a sticky powder formulation

Capping, lamination or chipping. This is caused by air being compressed with the tablet formulation and then expanding when the punch is released: if this breaks the tablet apart, it can be due to incorrect machine settings, or due to incorrect formulation: either because the tablet formulation is too brittle or not adhesive enough, or because the powder being fed to the tablet press contains too much air (has too low bulk density).

Capping can also occur due to high moisture content. Tablet compaction simulator Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a

Compaction Simulator reduces the amount of powder required for product development.

Tablet presses

The tablet pressing operation An old Cad Mach rotary tablet press

Tablet presses, also called tableting machines, range from small, inexpensive bench-top models that make one tablet at a time (single -station presses), with only around a half-ton pressure, to large, computerized, industrial models (multi -station rotary presses) that can make hundreds of thousands to millions of tablets an hour with much greater pressure. The tablet press is an essential piece of machinery for any pharmaceutical and nutraceutical manufacturer. Common manufacturers of tablet presses include Natoli, Stokes, Fette Compacting, Korsch, Kikusui, Manesty, B&D, PTK, IMA and Courtoy. Tablet presses must allow the operator to adjust the position of the lower and upper punches accurately, so that the tablet weight, thickness and density can each be controlled. This is achieved using a series of cams, rollers, and/or tracks that act on the tablet tooling (punches). Mechanical systems are also incorporated for die filling, and for ejecting and removing the tablets from the press after compression. Pharmaceutical tablet presses are required to be easy to clean and quick to reconfigure with different tooling, because they are usually used to manufacture many different products. There are 2 main standards of tablet tooling used in pharmaceutical industry: American standard 'TSM' and European standard ΈΙΓ. TSM and EU configurations are similar to each other but cannot be interchanged.

Tablet coating Nowadays many tablets today are coated after being pressed. Although sugar-coating was popular in the past, the process has many drawbacks. Modern tablet coatings] are polymer and polysaccharide based, with plasticizers and pigments included. Tablet coatings must be stable and strong enough to survive the handling of the tablet, must not make tablets stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets. Coatings are necessary for tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to swallow.

Tablet coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation. Special coatings (for example with pearlescent effects) can enhance brand recognition.

If the active ingredient of a tablet is sensitive to acid, or is irritant to the stomach lining, an enteric coating can be used, which is resistant to stomach acid, and dissolves in the less acidic area of the intestines. Enteric coatings are also used for medicines that can be negatively affected by taking a long time to reach the small intestine, where they are absorbed. Coatings are often chosen to control the rate of dissolution of the duloxetine in the gastrointestinal tract. Some drugs are absorbed better in certain parts of the digestive system. If this part is the stomach, a coating is selected that dissolves quickly and easily in acid. If the rate of absorption is best in the large intestine or colon, a coating is used that is acid resistant and dissolves slowly to ensure that the tablet reaches that point before dispersing.

There are two types of coating machines used in the pharmaceutical industry: coating pans and automatic coaters. Coating pans are used mostly to sugar coat pellets. Automatic coaters are used for all kinds of coatings; they can be equipped with a remote control panel, a dehumidifier, and dust collectors. An explosion-proof design is required for applying coatings that contain alcohol.

Pill-splitters

It is sometimes necessary to split tablets into halves or quarters. Tablets are easier to break accurately if scored, but there are devices called pill -splitters which cut unscored and scored tablets. Tablets with special coatings (for example enteric coatings or controlled-release coatings) should not be broken before use, as this will expose the tablet core to the digestive juices, circumventing the intended delayed-release effect.

Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers duloxetine with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific target in the body (targeted-release dosage).

Extended-release dosage consists of sustained-release (SR) and controlled-re lease (CR) dosage. SR maintains duloxetine release over a sustained period but not at a constant rate. CR maintains duloxetine release over a sustained period at a nearly constant rate.

Sometimes these and other terms are treated as synonyms, but the United States Food Administration has in fact defined most of these as different concepts. Sometimes the term "depot tablet" is used by non-native speakers, but this is not found in any English dictionaries and is a literal translation of the term used in Swedish and some other languages. Modified-release dosage and its variants are mechanisms used in tablets (pills) and capsules to dissolve duloxetine over time in order to be released slower and steadier into the bloodstream while having the advantage of being taken at less frequent intervals than immediate-release (IR) formulations of the same drug. For example, extended-release morphine enables people with chronic pain to only take one or two tablets per day. Most commonly it refers to time dependent release in oral dose formulations. Timed release has several distinct variants such as sustained release where prolonged release is intended, pulse release, delayed release (e.g. to target different regions of the GI tract) etc. A distinction of controlled release is that not only prolongs action but it attempts to maintain duloxetine levels within the therapeutic window to avoid potentially hazardous peaks in duloxetine concentration following ingestion or injection and to maximize therapeutic efficiency.

In addition to pills, capsules and injectable drug carriers (that often have an additional release function), forms of controlled release medicines include gels, implants and devices The release technology scientific and industrial community is represented by the Controlled Release Society (CRS). The CRS is the worldwide society for delivery science and technologies. CRS serves more than 1,600 members from more than 50 countries. Two-thirds of CRS membership is represented by industry and one-third represents academia and government. CRS is affiliated with the Journal of Controlled Release and duloxetine delivery and Translational Research scientific journals.

History

The earliest SR drugs are associated with a patent in 1938 by Israel Lipowski, who coated pellets which led to coating particles.] The science of controlled release developed further with more oral sustained-release products in the late 1940s and early 1950s, the development of controlled release of marine anti-foulants in the 1950s and controlled release fertilizer in the 1970s where sustained and controlled delivery of nutrients following a single application to the soil. Delivery is usually affected by dissolution, degradation or disintegration of an excipient in which the active compound is formulated. Enteric coating and other encapsulation technologies can further modify release profiles.

List of abbreviations

There is no industry standard for these abbreviations, and confusion and misreading have sometimes caused prescribing errors. For some drugs with multiple formulations, putting the meaning in parentheses is advisable.

Abbreviation Meaning Notes

CD controlled delivery

CR controlled release

DR delayed release

ER extended release

IR immediate release

LA long-acting

LAR long-acting release

MR modified release

PR prolonged release

SA sustained action Ambiguous, can sometimes mean short-acting

SR sustained release

TR timed release

XL extended release

XR extended release

XT extended release

The present invention extends to tablets which contain a first component which is an immediate rapid release component and a second component which is of a type listed above

A few other abbreviations are similar to these (in that they may serve as suffixes) but refer to dose rather than release rate. They include ES and XS (extra strength). Methods

Most time -re lease drugs are formulated so that the active ingredient is embedded in a matrix of insoluble substance(s) (various: some acrylics, even chitin; these substances are often patented) such that the dissolving duloxetine must find its way out through the holes in the matrix. In some SR formulations, the duloxetine dissolves into the matrix, and the matrix physically swells to form a gel, allowing the duloxetine to exit through the gel's outer surface.

Micro-encapsulation is also regarded as a more complete technology to produce complex dissolution profiles. Through coating an active pharmaceutical ingredient around an inert core and layering it with insoluble substances to form a microsphere one can obtain more consistent and replicable dissolution rates in a convenient format that can be mixed and matched with other instant release pharmaceutical ingredients in to any two piece gelatine capsule.

There are certain considerations for the formation of sustained-release formulation:

If the absorption of the active compound involves an active transport, the development of a time- release product may be problematic. The half-life of the duloxetine refers to the drug's elimination from the bloodstream which can be caused by metabolism, urine, and other forms of excretion. If the active compound has a half-life (over 12 hours), it is sustained on its own. If the active compound has a short half-life, it would require a large amount to maintain a prolonged effective dose. In this case, a broad therapeutic window is necessary to avoid toxicity; otherwise, the risk is unwarranted and another mode of administration would be recommended.

The therapeutic index also factors whether a duloxetine can be used as a time release drug. A duloxetine with a thin therapeutic range, or small therapeutic index, will be determined unfit for a sustained release mechanism in partial fear of dose dumping which can prove fatal at the conditions mentioned for a duloxetine that is made to be released over time, the general goals is to stay within the therapeutic range as long as needed.

There are many different methods used to obtain a sustained release.

Diffusion systems

Diffusion systems rate release is dependent on the rate at which the duloxetine dissolves through a barrier which is usually a type of polymer. Diffusion systems can be broken into two subcategories, reservoir devices and matrix devices. Reservoir devices coat the duloxetine with polymers and in order for the reservoir devices to have sustained release effects, the polymer must not dissolve and let the duloxetine be released through diffusion The rate of reservoir devices can be altered by changing the polymer and is possible be made to have zero-order release; however, drugs with higher molecular weight have difficulty diffusing through the membrane.

Matrix devices forms a matrix (drug(s) mixed with a gelling agent) where the duloxetine is dissolved/dispersed. The duloxetine is usually dispersed within a polymer and then released by undergoing diffusion. However, to make the duloxetine SR in this device, the rate of dissolution of the duloxetine within the matrix needs to be higher than the rate at which it is released. The matrix device cannot achieve a zero-order release but higher molecular weight molecules can be used. The diffusion matrix device also tends to be easier to produce and protect from changing in the gastrointestinal tract but factors such as food can affect the release rate.

Dissolution systems

Dissolution systems must have the system dissolved slowly in order for the duloxetine to have sustained release properties which can be achieved by using appropriate salts and/or derivatives as well as coating the duloxetine with a dissolving material. It is used for duloxetine drug compounds with high solubility in water. When the duloxetine is covered with some slow dissolving coat, it will eventually release the drug. Instead of diffusion, the duloxetine release depends on the solubility and thickness of the coating. Because of this mechanism, the dissolution will be the rate limiting factor here for duloxetine release. Dissolution systems can be broken down to subcategories called reservoir devices and matrix devices.

The reservoir device coats the duloxetine with an appropriate material which will dissolve slowly. It can also be used to administer beads as a group with varying thickness, making the duloxetine release in multiple times creating a SR. The matrix device has the duloxetine in a matrix and the matrix is dissolved instead of a coating. It can come either as duloxetine impregnated spheres or duloxetine impregnated tablets.

Osmotic systems

Main article: Osmotic controlled-re lease oral delivery system

A system utilizing a semipermeable membrane that does not allow the drug defuse through the membrane, but where the water on the exterior of the membrane can diffuse through the membrane, allowing the duloxetine to be released through channels through the membrane. Most drugs utilizing this design are enclosed in polymer-based tablets with one or more laser-drilled holes on one side. Water travels through the semipermeable membrane via osmosis, thereby pushing the duloxetine out through the laser-drilled hole. In time, the entire duloxetine dose releases into the system while the polymer container remains intact, to be excreted later. This method is used for hydrophilic duloxetine and allows zero-order release. This method can be in two forms: the core of the membrane contains the duloxetine as a solid or in a solution. The osmotic system (solid duloxetine core) will have electrolytes which provide high osmotic pressure and is dissolved by incoming fluids.

Ion-exchange resin

Main article: Ion -exchange resin

In the ion-exchange method, the resins are cross-linked water-insoluble polymers that contain ionisable functional groups that form a repeating pattern of polymers, creating a polymer chain. The duloxetine is attached to the resin and is released when an appropriate interaction of ions and ion exchange groups occur. The area and length of the duloxetine release and number of cross-link polymers dictate the rate at which the duloxetine is released, determining the SR effect

Floating systems

A floating system is a system where it floats on gastric fluids due to low -density. The density of the gastric fluids is about lg/mL; thus, the drug/tablet administered must have a smaller density. The buoyancy will allow the system to float to the top of the stomach and release at a slower rate without worry of excreting it. This system requires there are enough gastric fluids present as well as food Many types of forms of drugs use this method such as powders, capsules, and tablets.

Bio-adhesive systems Bio-adhesive systems generally are meant to stick to mucus and can be favourable for mouth based interactions due to high mucus in the general area but not as simple for other areas. Magnetic materials can be added to the duloxetine so another magnet can hold it from outside the body to assist in holding the system in place. However, there low patient compliance with this system.

Matrix systems The matrix system is the mixture of materials with the drug, which will cause the duloxetine to slow down. However, this system has several subcategories: hydrophobic matrices, lipid matrices, hydrophilic matrices, biodegradable matrices, and mineral matrices.

A hydrophobic matrix is duloxetine mixed with a hydrophobic polymer. This causes SR because the drug, after being dissolved, will have to be released by going through channels made by the hydrophilic polymer. A hydrophilic matrix will go back to the matrix as discussed before where a matrix is a mixture of a duloxetine or drugs with a gelling agent this system is well liked because of its cost and broad regulatory acceptance. The polymers used can be broken down into categories: cellulose derivatives, non-cellulose natural, and polymers of acrylic acid. A lipid matrix uses wax or similar materials. Duloxetine release happens through diffusion through, and erosion of, the wax and tends to be sensitive to digestive fluids.

Biodegradable matrices are made with unstable, linked monomers that will erode by biological compounds such as enzymes and proteins.

A mineral matrix which generally means the polymers used are obtained in seaweed. Stimuli inducing release

Examples of stimuli that may be used to bring about release include pH, enzymes, light, magnetic fields, temperature, ultrasonics, osmosis and more recently electronic control of MEMS and NEMS.

Pharmaceutical companies that do not supply a range of half-dose and quarter-dose versions of time- re lease tablets can make it difficult for patients to be slowly tapered off their drugs. The present invention is generally directed to horizontally layered tablets, methods of making the horizontally layered tablets, and tableting equipment capable of producing the horizontally layered tablets. An alternative is that the present invention provides a central core which is adapted as a modified release format with an outer core modified as an immediate release format. There may be multiple component parts layered like a gobstopper tablet with a central core, an outer layer and intermediate layers in between each modified in a manner which addresses three issues rapidity, longevity and maintenance, all with an overarching need for the provision of tablets which ensure that duloxetine is released within the therapy window from dose to dose .

Traditional multilayer compacted tablets often are produced by the sequential addition of the separated components into a tablet die cavity using separate component gravity feed or force feed delivery devices to form the separate layers. Punch position changes may be required to form the desired layer at each component delivery device. In addition, there may be pre-compression of previously introduced layers, prior to the addition of subsequent layers, until a final compression is used to form a single multilayer tablet in which the separated components are arranged into vertical layers. Hence, such conventional tableting techniques are directed to vertically layered tablets, and the use of multiple compression or compaction steps results in reduced production rates.

The production of vertically layered tablets requires the use of tablet presses which have been purposely designed to produce multilayer tablets, or single layer tablet presses that have been significantly modified. Either option increases manufacturing complexity and equipment costs compared to single layer tablet presses. In addition to equipment complexity and cost, the production rate of multilayer tablets, as mentioned above, is often significantly slower than the production rate of single layer tablets. Therefore, there is a need to develop processes to manufacture combined, separated components into a single compacted tablet form without the increased complexity, increased equipment cost, and reduced production rates associated with conventional multilayer tablet production. There is also a need to develop processes to manufacture combined, separated components into a single compacted tablet form (that is distinct from tablets with vertically arranged layers) in which horizontally arranged layers are formed in order to add aesthetic options to the products being produced, as well as to provide product performance enhancements associated with horizontal layer orientation.

Accordingly, it is to these ends, as well as other benefits, that the various aspects and embodiments consistent with this invention are directed.

This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify required or essential features of the claimed subject matter. Nor is this summary intended to be used to limit the scope of the claimed subject matter.

Both the foregoing summary and the following detailed description provide examples and are explanatory only. Accordingly, the foregoing summary and the following detailed description should not be considered to be restrictive. Further, features or variations may be provided in addition to those set forth herein. For example, certain aspects and embodiments may be directed to various feature combinations and sub-combinations described in the detailed description.

The terms "a," "an," and "the" are intended to include plural alternatives, e.g., at least one. For instance, the disclosure of "a layer," "a tablet die," etc., is meant to encompass one or more than one layer, tablet die, etc., unless otherwise specified.

All publications and patents mentioned herein are incorporated herein by reference for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the presently described invention. The publications discussed throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.

Applicants disclose several types of ranges in the present invention. When Applicants disclose or claim a range of any type, Applicants' intent is to disclose or claim individually each possible number that such a range could reasonably encompass, including end points of the range as well as any subranges and combinations of sub-ranges encompassed therein. Tablets of this invention often can have a hardness (or break strength) in a range from about 10 to about 500, from about 10 to about 475, from about 15 to about 500, from about 10 to about 50, or from about 150 to about 500 lbf The hardness is the force required to break the tablet when the tablet is placed on its side surface and the force applied to the directly opposing side surface. Unlike extruded or moulded tablets, the tablets disclosed herein have a distinct break in aspects of this invention. Additionally or alternatively, the tablets disclosed herein, in particular aspects of this invention, do not have a vicat softening point or a glass transition temperature. These characteristics are typically related to extruded or moulded tablets, which have a polymeric or plastic component in the tablet matrix. Thus, as distinguished from extruded tablets and moulded tablets, the multilayer tablets disclosed herein can be categorized as compacted tablets (or compressed tablets). The tablet hardness (or break strength) depends upon the size of the tablet: a 3-inch diameter tablet can have a break strength that is 10-20 times that of a 1-inch diameter tablet. If desired, any of the tablets disclosed herein also can have a have an additional layer (a top layer) covering at least a portion of the top surface of the tablet. Additionally or alternatively, any of the tablets disclosed herein, optionally, can further comprise a coating layer (e.g., an enteric coating) on at least a portion of the outer surfaces of the tablet. This coating layer can cover the top surface, the bottom surface, the side surface, or all outer surfaces of the tablet. In accordance with another aspect of this invention, tablets disclosed herein (e.g., horizontally layered tablets) can be characterized by a first layer comprising a first composition, a second layer comprising a second composition, an interface between the first layer and the second layer, and wherein the first composition and the second composition are different. In further aspects, such tablets can have any of the features, properties, or characteristics provided above (e.g., density, width: height ratio, hardness, layer ratio, etc.) and in any combination.

In aspects of this invention, the first composition and/or the second composition independently can comprise any suitable water treatment chemical, non -limiting examples of which can include a disinfectant, a sanitizer, a pH adjuster, a buffer, a hardness modifier, an algaecide, a corrosion inhibitor, a scale inhibitor, a dispersant, a flocculent, a clarifier, an oxidizer/shock, a sequestrant, a chelant, an emulsifier, a demulsifier, and the like, as well as combinations thereof. Accordingly, illustrative multilayer tablets can include: a tablet with a first layer containing a sanitizer, and a second layer containing an oxidizer/shock; In another aspect, the first composition and/or the second composition independently can comprise any suitable halogenated (e.g., with active halogens such as chlorine and/or bromine) biological control agent, such as provided in U.S. Pat. Nos. 6,426,317, 6,852,238, and 8,492,419, the disclosures of which are incorporated herein by reference in their entirety. Illustrative compounds that can be used in the first layer and/or the second layer can include, but are not limited to, trichloroisocyanuric acid (TCCA), sodium dichloroisocyanurate (anhydrous, dihydrate salt), 1 -bromo-3 -chloro-5 ,5 -dimethylhydantoin, 1 -chloro-3 -bromo-5 ,5 -dimethylhydantoin, 1 -bromo-3 -chloro-5 -methyl-5 -ethylhydantoin, 1 -chloro-3 -bromo-5 -methyl-5 -ethylhydantoin, 1 - bromo-3 -chloro-5 ,5 -diethylhydantoin, 1 -chloro-3 -bromo-5 ,5 -diethylhydantoin, 1 -bromo-3 -chloro-5 - ethyl-5 -methylhydantoin, 1 -chloro-3 -bromo-5 -ethyl-5 -methylhydantoin, 1 ,3 -dichloro-5 -ethyl -5 - methylhydantoin, 1 ,3 -dibromo-5 -ethyl-5 -methylhydantoin, 1 ,3 -dichloro-5 -methyl-5 -ethylhydantoin, 1 ,3 -dibromo-5 -methyl-5 -ethylhydantoin, 1 ,3 -dichloro-5 ,5 -dimethylhydantoin, 1 ,3 -dibromo-5 ,5 - dimethylhydantoin, l,3-dichloro-5,5-diethylhydantoin, l,3-dibromo-5,5-diethylhydantoin, calcium hypochlorite, lithium hypochlorite, and the like, as well as combinations thereof. Solid chlorine donors and other strong oxidizers also are suitable ingredients.

The layered tablets of invention are not limited compositionally to the materials and components noted hereinabove. Notably, the first composition and/or the second composition independently can comprise any active pharmaceutical ingredient (API) or nutraceutical ingredient suitable for tableting, and this includes any suitable prescription or over-the-counter (e.g., acetaminophen, aspirin) pharmaceutical ingredient, as well as vitamins and other nutritional supplements that are suitable for tableting. As would be recognized by those of skill in the art, any of the tablets and the respective layers and compositions described herein can further contain suitable tablet excipients, such as binders, lubricants, disintegrators, and the like, as well as combinations thereof. A potential benefit of the multilayer tablets can be a tailoring of different release profiles of the respective layers for different end-use applications. In one aspect, for example, the first layer can be a quick release layer (or immediate release, or fast dissolving). Additionally or alternatively, the second layer can be a slow release layer (or delayed release, or slow dissolving). As disclosed herein, the tablet can contain an intermediate layer (or third layer) between the first layer and the second layer; this intermediate layer can be an inert layer or a barrier layer, if desired, to prevent any reaction or interaction between components of the first layer with components of the second layer.

Producing Multilayer Tablets

Methods of making multilayer tablets also are provided herein. One such method for making a horizontally layered tablet having a first layer and a second layer can comprise (a) providing a first composition and a second composition; (b) simultaneously feeding a segregated flow of the first composition and the second composition to a tablet die; and (c) compressing the first composition and the second composition under sufficient pressure in the tablet die to the form the horizontally layered tablet. In this method, the first layer comprises the first composition and the second layer comprises the second composition. The tablets producing in accordance with this method can have any of the features, properties, materials, or characteristics of the tablets described hereinabove and in any combination.

In step (b), the segregated flow of the first composition and the second composition can be simultaneously fed to the tablet die. In one aspect, the segregated flow can be gravity fed, while in another aspect, the segregated flow can be force fed.

Advantageously, in particular aspects of this invention, the method for making the horizontally layered tablet can comprise a single compression step. Hence, in such aspects, the method does not comprise a pre-compression step in order to form the tablet. While not wishing to be bound to theory, Applicants believe that this method, which can involve only a single compression in step (c), can result in an increase in the production rate of the multilayer tablets.

In step (c), the first composition and the second composition are compressed under sufficient pressure in the tablet die to form the horizontally layered tablet. Typically, though not required, this step is conducted using mechanical or hydraulically driven compression. The amount of pressure needed to form the tablet can be readily determined by those of skill in art, and generally, the pressure to form the tablet is uniform between the first layer and the second layer (e.g., within specifications based on percent variability of a particular press when operated in single layer mode).

This method also can further comprise, after step (c), a step of ejecting the (compressed or compacted) tablet from the tablet die. Typically, the interface between the first layer and the second layer is generally perpendicular to the bottom of the tablet die, for example, an angle of about 90°, or from about 75° to about 105°, between the interface and the bottom of the tablet die.

Advantageously, in aspects of this invention, the method of making the horizontally layered tablet does not include an extrusion step, and/or a moulding step, and/or an external heating step. For example, the tablet die can be at ambient temperature, where no external heating or cooling of the tablet die is either utilized or required. Tableting Equipment

An apparatus suitable for forming the multilayer tablets disclosed and described herein also is provided. For instance, an apparatus for forming a horizontally layered tablet (the tablet having a first layer comprising a first composition and a second layer comprising a second composition) can comprise (i) a tablet die, (ii) a first feed chamber containing the first composition and a second feed chamber containing the second composition, (iii) a reciprocating and segmented feed device for simultaneously directing a segregated flow of the first composition from the first feed chamber and the second composition from the second feed chamber to the tablet die, and (iv) a compaction device for compressing the first composition and the second composition in the tablet die under sufficient pressure to form the horizontally layered tablet having the first layer and the second layer. The tablets produced using this apparatus can have any of the features, properties, materials, or characteristics of the tablets described hereinabove and in any combination.

As shown and described herein, the tableting apparatus in aspects of this invention is not a rotary tablet press, in which multilayer tablets are typically formed in a vertical and sequential fashion (i.e., one layer or composition on top of another layer or composition). Beneficially, however, due to the segregated and simultaneous flow of the respective compositions (and layers) in accordance with this invention, multilayer tablets can be formed at relatively high output rates. Generally, the tableting apparatus is capable of forming (horizontally layered) tablets in a output rate range, based on each tablet die, of from about 30 to about 70, from about 35 to about 65, or from about 40 to about 60 tablets/minute, and the like.

Also advantageously, the tableting apparatus does not require a heating or cooling system, as would be the case for extruded or moulded tablets, in contrast with the compacted tablets produced in aspects of this invention. The invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations to the scope of this invention. Various other aspects, embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill worker in the art without departing from the spirit of the present invention or the scope of the appended claims. Oral tablet intended for ingestion

Compressed tablets: Tablets can be made by compression of one or more active pharmaceutical ingredient with excipients by basic methods of tablet manufacturing. These types of tablets usually intended to provide rapid duloxetine release and disintegration. Tablets are coated after compression.

Multiple compressed tablets: Multiple compressed tablets are prepared by compressing the material more than once. These are known as multiple layered tablets or tablet within tablet. Layered are depends on the number of fills. Layered tablets are prepared by compaction of fill material in die followed by additional of fill material and compression.

Delayed action or Enteric coated tablets: These types of tablets contain a coating which resist dissolution of tablets in Gastro Intestinal Track (GIT) and disintegrate in intestinal fluids thus rendering delayed release features. Enteric coating is generally apply when duloxetine substance is unstable in gastric fluid and may destroyed or may cause irritation in gastric mucosa or to extent absorption of duloxetine e from intestine. Normally coating materials mixed with acid and acid functionality or modified natural polymers. Most commonly used coating polymers are: Cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP) and hydroxyl propyl methyl cellulose phthalate.

Sugar coated tablet: Compressed tablets may be coated with coloured or uncoloured sugar coating and the coater is water soluble and dissolve quickly after swallowing. Sugar coat protects duloxetine from environment, remove bitter taste and odour, enhance the appearance of tablet and permit identifying information. Sugar coating has some disadvantages like increase coat of production, require expertise for coating, increase size and weight.

Film coated tablets: Tablets can be compressed with a thin layer of polymer which forms a skin like film over tablet. The film is usually coloured, more durable and less bulky. The coating is designed to rupture and expose of tablet at desired location within GIT. Most commonly used polymers are Hydroxy propyl cellulose, Hydroxy ethyl and propyl methyl cellulose.

Chewable tablet: These types of tablets have smooth surface, creamy base and usually flavoured and coloured mannitol, rapid disintegration which allow dissolving quickly in mouth.

Buccal and sublingual tablets are flat in shape and intended to dissolve duloxetine in buccal cavity or beneath the tongue for mucosa absorption. These techniques useful for drugs which are destroyed by gastric fluid or poor absorption in GIT. Buccal tablets erode slowly and sublingual tablets dissolve quickly and produce rapid effect.

Troches and Lozenges: They are intended to slowly dissolution mostly for local effect but sometimes for systemic absorption. Troches and Lozenges are disc shaped which contain active ingredient and flavouring agent in hard candy or sugar base.

Dental cones: dental cones are designed to place in the empty socket for prevention of bacterial growth and sometime bleeding by containing coagulant. Dental cones release slowly for long duration.

Tablets for other routes Implantation tablet: Implantation tablets are injected under the skin by giving a small surgical cut into the skin. A special injector a hallow needle and plunger may require for administration. Purpose of these tablets is to prolong duloxetine effect from month to year. These tablets are implanted intramuscularly or subcutaneous so they must be sterile and packed in sterile container.

[Pharmaceutics - 1, P.V. KASTURE, S R. PARAKH, S.A. HASAN, S B. GOKHALE, June 2008, pp- 14-7,21

Tablets for solution Effervescent tablet: Effervescent tablets can be prepared by compression of granular salts which release in contact with water.

Hypodermic tablets: Hypodermic tablets are soft moulded tablets which contain soluble ingredient and used for extemporaneous parenteral preparation by physician. They are no longer in use because it is difficult to achieve sterility and availability of stable liquid.

Tablet triturates: tablet triturates are rarely use now a days because they are obsolete. They are small, cylindrical, moulded which contain small amount of potent drug. They must be readily soluble in water and minimum amount pressure require during manufacture. Triturates inserted into capsules or dissolved in liquid to provide accurate potent drug. Tablet E cipients:

Excipients are substance other that active ingredient in formulation of tablet. The roles of excipients are to ensure tabletting operation satisfactory and ensure that tablets of specified quality are prepared. Depend on intended use; they are subcategorised in different groups. However excipients affect properties of tablets. Diluents or filler

A small amount of powder requires forming suitable size tablet for easy handling. Normally tablet weigh 50mg so some amount of bulk duloxetine requires to be incorporated in formulation of tablet which enhance size of tablet. These powders are known as diluents or fillers. The ideal dilute should have following properties- cheap, chemically inert, acceptable taste, good compact ability and dilution capacity, biocompatible, good biopharmaceutical properties and non-hygroscopic.

A single substance cannot fulfil all these requirements so different substance have gained use as diluents mainly carbohydrates and inorganic salts sometimes. The most common diluent is lactose because it possess a sires of good properties like dissolves readily in water, has a pleasant taste, non- hygroscopic is fairly non-reactive and shows good compact ability. Its main limitation is that some people have intolerance to lactose. Basically lactose exists in two forms crystalline and amorphous. Other sugar and sugar alcohols such as glucose, sucrose, and mannitol have been used as alternative fillers, mostly in chewable tablets or lozenges because of their pleasant taste. Other important example of the filler is an inorganic substance, dicalcium phosphate dehydrate. It is insoluble in water and also non hygroscopic but have hydrophilic property i.e. easily wetted by water. It also has good flow ability and therefore it is used mostly in direct compaction. [Michael, Pharmaceutics: the design and manufacture of medicines 3rd ed. - Edinburgh: Churchill Livingstone, 2007.] [ Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig. (1991). the theory and practise of industrial pharmacy. 3rd addition: Varghese publishing house. Page no. 293- 303.] Leon Lachman et al, 1991, suggested that other group of disintegrants may function by producing gas, normally carbon dioxide, in contact with water. This types of disintegrants used in effervescent tablets and normally not in tablets that should be swallowed as a solid. The liberation of carbon dioxide is achieved by the decomposition of carbonate salts or bicarbonate in contact with acidic water. The acidic pH is obtained by adding citric acid and tartaric acid. [ Michael, Pharmaceutics: the design and manufacture of medicines.- 3rd ed. - Edinburgh : Churchill Livingstone, 2007. 3. Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig. (1991). the theory and practise of industrial pharmacy. 3rd addition: Varghese publishing house. Page no. 293- 303]

Binder Binder is added to the tablet or filler mixture to ensure that tablets and granules have sufficient mechanical strength. There are several ways to add it in powder- Mixed with powder before wet granulation which completely or partially dissolves during agglomeration process by agglomeration liquid.

Mixed with other ingredient as a dry powder solution before compaction process As a solution used as agglomeration liquid during wet granulation.

Typically 2-10% of binders or dry binders are used in formulation. Most tradition common binders are starch, sucrose and gelatine but now most common are polyvinylpyrrolidone and cellulose derivatives which have improved adhesive properties. Examples of dry binders are microcrystalline cellulose and crosslinked polyvinylpyrrolidone. Solution binders are most effective therefore it is incorporated in granules.

Glidant

The role of the Glidant is to improve the flow ability of the powder. Glidants are used in formulation for direct compaction but they are also used in granulation process before tabletting which ensure flow ability of tablet mass for high speed production. Traditionally talc has been used as glidant about 1-2% concentration in formulation but nowadays the most commonly used glidant is colloidal silica added in very low proportion about 0.2% by weight.[ Michael, Pharmaceutics: the design and manufacture of medicines.- 3rd ed. - Edinburgh Churchill Livingstone, 2007. 3. Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig. (1991). the theory and practise of industrial pharmacy. 3rd addition: Varghese publishing house. Page no. 293- 303] Lubricant The function of lubrication is to ensure low lubrication between solid and the die wall during tablet formation and ejection. High friction during tabletting can cause a series of problems such as inadequate tablet quality and may even stop production. Lubrication is most important which included in most of production. Lubrication can get by mainly by two mechanism, fluid lubrication and boundary lubrication. In fluid lubrication, liquid is achieved between die surface and tablet surface which separates the moving surfaces of the solids from each other and reduces the friction. While in boundary lubrication, it is considered as a surface phenomenon, as here moving surface is separated by a very thin layer of lubricants. Such boundary lubricants are Stearic acid salts, primarily Magnesium Stearate which is most widely used due to its superior lubrication properties. Besides reducing friction, lubricants may also causes undesirable changes such as reducing tablet strength with bonding between the particles during compaction. Because of hydrophobic properties of lubricants, tablet disintegration and dissolution are often retarded by the addition of lubricants. Thus, minimum amount of lubricants are used, i.e. concentrations of 1% or below, often 0.25-0.5%.in order to avoid these negative effects, more hydrophilic substances have been suggested as alternatives to the hydrophobic lubricants. For example, surface active agents and polyethylene glycols and sometimes a combination of hydrophilic and hydrophobic substances might also be used. [M. E Aulton, Pharmaceutics, The Science of Dosage Form Design, Second Edition, 2002, pp.408-412]

Antiadherent Antiadherent are substance which reduce adhesion between powder and punch faces which prevent sticking of particles to punches. The sticking is mainly affected by moisture content of the powder. Such adherence especially prone to happen if the tablet punches have marking or symbols which lead to a build of thin layer of powder on the punches which in turn will lead to an uneven and matt tablet surface with unclear markings or symbols. Some lubricants such as Magnesium Stearate have also antiadherent properties. However, other substances with limited ability to reduce friction can also act as antiadherent such as talc and starch. [M. E Aulton, Pharmaceutics, The Science of Dosage Form Design, Second Edition, 2002, pp.408-412]

Sorbents

Sorbents are substances which has capacity to sorbing some quantities of fluid into dry state. So oil and oil-duloxetine solutions can be incorporated into mixture of powder and compacted into tablets. Most commonly used sorbents are Microcrystalline Cellulose and Silica. [M. E Aulton,

Pharmaceutics, The Science of Dosage Form Design, Second Edition, 2002, pp.408-412]

Flavouring agents Flavouring agents are incorporated into a formulation to remove unpleasant taste of bitter duloxetine or to make tablet more pleasant or mask. This can be achieved by coating or by adding some duloxetine particles. Most of the flavouring agents are thermolabile so it cannot be added in process which involves heating. They are mixed with granules as alcoholic solution. Colouring agents

The aim to add colourant is to aid identification of tablet, improve looks of tablet and patient compliance. Mostly, colourant are added during coating of tablet but some of colourant may be added in formulation prior to compaction. Colourant may be added as an insoluble powder or dissolved in granulation liquid and the latter procedure may produce colour variation by migration of soluble dye during drying stage.

Method of tablet preparation

Three types method of tablet preparation- [1] Direct compression method [2] Wet granulation [3] Dry granulation

Direct compression method

Some chemicals have free flowing and cohesive properties so they are enable to compress directly in a tablet machine without granulation of it. Some chemicals lacking of these qualities so some excipients like filler, disintegrants agents, lubricants and glidants are used to impart these qualities for production of tablets by direct compression.

Steps of direct compression tableting

Some precaution must be taken during direct compression to avoid air entrapment which cause capping, splitting, or laminating of tablets. Forced feeders or induced feeders are used to reduce air entrapment, make filling powder more dense and amenable to compaction. Capping also may be caused by punches that are not perfectly clean and flawlessly smooth or by too much fines granulation. Some aged or improperly stored tablets also may exhibit splitting and other physical deformations.

Wet granulation Granulation is process in which primary powder particles are made to form large and these types of multi particle called granules. In pharmaceutical industry, granules are useful in production of tablets and capsules in ranges of particle size betweenO.2 to 0.5mm.

Granulation prevents segregation of constituents of powder, improve flow ability of powder, improve compaction characteristics of mixture and reduce toxic dust.

Wet granulation is widely used method for production of compressed tablets which include flowing steps-

Weighting and blending

In this step, specified quantities of active ingredient, diluents or fillers, and disintegrating agents are mixed by mechanical powder blender or mixture until uniform.

Most widely used fillers are lactose, microcrystalline cellulose, starch, powdered sucrose,and calcium phosphate. Selections of filler depend on the experience of manufacture, cost and compatibility with formulation. Among the fillers, lactose is most preferred because of its solubility and compatibility, and microcrystalline cellulose, because of its easy compaction compatibility and consistent uniformity of supply.

Disintegrating agents include croscarmellose, corn and potato starches, sodium starch glycolate, sodium carboxymethylcellulose, polyvinyl polypyrrolidone (PVP), cation exchange resins, alginic acid and other materials which swell or expand on exposure to moisture and helps to breakup tablets in gastrointestinal track (GIT). Mainly croscarmellose and sodium starch glycolate are used because of their high water uptake and rapid action. Mostly up to 5-10% of starch is suitable for formulation, but up to about 20% may be used to facilitate more rapid tablet disintegration. The total amount of disintegrant is not always used but sometime it added in preparation of granulation and sometime half of it added to tablet formation which called double disintegration of tablet. One portion of disintegrant assist the breakup of tablet into pieces and other portion breakup pieces into particles. Preparation of Damp Mass

A liquid binder is now added to the powder to facilitate adhesion of powder particles. A damp mass resembling dough is formed and used to prepare the granulation. A good binder is very important for hardness of tablet and does not hinder the release of duloxetine from the tablet.

Most widely used binders are povidone, an aqueous preparation of corn starch (10-20%), methyl cellulose (3%), carboxymethylcellulose, and microcrystalline cellulose. Some drugs may be adversely affected by an aqueous binder then non-aqueous solutions or dry binder may be used. The amount of binders is a part of operation which maintains integrity of tablet after compression. However, care must be exercised not to over or underwet powder otherwise underwet can result too hard granules for proper tablet formulation and overwet can result too soft and tend to crumble in under wetting. After getting desired dump mass a colorant or flavorant may be added to prepare a granulation with an added features. Screening Damp Mass into Pellets and Granules

The Dump Mass is pressed through 6 or 8 mesh size to prepare granules. This process may be done by hand or by special equipment which prepares granules by extrusion process. The final product are spread on large piece of paper in trays and dried.

Drying the granulation Granules may be dried in special drying cabinets which is thermostatically controlled at constantly record the time, temperature and humidity. Fluid bed drier and tray drier are commonly used for during process.

Sizing the granulation by Dry Screening

After drying, the granules are passed through a screen of a smaller mess than that used to prepare the original granulation. The size of granules depends upon the size of the punches to be used. Usually 12 to 20 mesh sizes are used for granulation. Sizing of the granules is necessary so that the die cavities for tablet compression may be completely or rapidly filled by the free flowing granules. Voids or air spaces left by too large a granulation result in production of uneven tablets.

Adding Lubrication and Blending After dry screening, a dry lubricant is spread over the granulation through a fine mess screen which contributes to preparation of compressed tablets. Among the most commonly used lubricants are talc, magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate in ranges of 0.1% to 5%. Lubricants improve flow property of granules form hooper ti die, prevent adhesion during compaction, reduce friction between die and punch and provide a sheen final product. Tablet compression by wet granulation [Pharmaceutics - 1, P.V. KASTURE, S.R. PARAKH, S.A. HASAN, S.B. GOKHALE, June 2008, pp-14-7, 21]

Some special wet granulation techniques

High shear mixture granulation

Fluid bed granulation Extrusion- spheronisation Spray drying

Dry granulation

In this method, powder mixer is compressed in large pieces and subsequently broken down or sized into granules. In this method, either active ingredient or diluent must have cohesive properties. This method is basically applied to materials which cannot be prepared by wet granulation because of moisture degradation properties or thermo -mobile properties of granules. It is carried out by two steps:

Slugging:

After weighing and the mixing of ingredients, the powder mixture is slugged or compressed into large flat tablets about one inch in diameter. Slugs are than broken up hand or mill and passed through a screen of desired mess for sizing and sometimes lubricant are added and prepared by compression.

Roller compaction:

Instead of slugging, powder compactors may be used to increase the density of a powder by pressing it between rollers at 1 ton to 6 tons of pressure. The compact material is broken up, sized, and lubricated, and tablets are prepared by compression. Commonly used binding agents are methyl cellulose or hydroxylmethyl cellulose (6-12%) which produces good hardness and friability of tablet.

Figure (C) Tablet compression by Dry Granulation [Pharmaceutics - 1, P.V. KASTURE, S.R.

PARAKH, S.A. HASAN, S B. GOKHALE, June 2008, pp-14-7, 21]

Tableting of granulation: There are different types of tabletting machines which are used in the productivity but similar in basic function and operation. They all compress tablet formulation within steel die cavity by the pressure exerted by the movement of two steel punches, lower punch and an upper punch.

Problems in manufacture of tablet

Capping and lamination: Capping means partial and complete separation of the top or bottom crowns of a tablet from main body of a tablet. While lamination is term used to describe the separation of the two or more distinct layers. Some reasons which are responsible for these problems are as follows:

Air is entrapped among the particles during the compression process and does not escape until compression pressure is released. Die wall pressure causes enough internal stress to cause a crack which is due to plastic deformation of the particles during compaction.

Sometimes due to deep concave or bevelled edge punches.

Development of 'wear ring'. This problem can reduced or eliminated by slowing tabletting rate, granules with sufficient moisture, pre-compression, using flat punches, correct adjustment punches. [Porter, S C, 1981, Tablet coating, Weight variation:

This is very important in process control measurement. If anything that can alter the die filling process can alter tablet weight, it causes weight variation because the weight of the tablet being compressed is determined by the amount of the granulation in the die prior to compression. Some causes of variation are large granules, poor mixing of granules with lubricants and glidants, poor granulation flow from hopper, double impression and punch variation.

Picking

Picking is the term used to describe the surface material from tablet that is sticking to being removed from the tablet's surface by a punch. It concerns when punching tips have engraving or embossing Sticking

Sticking is usually referred to adhesion of tablet material to die wall. Because of that, lower punch cannot move freely and additional force is required to overcome friction between die wall and the tablet. These problems can be solved by design large lettering, adding polishing agent such as colloidal silica or additional lubricants. Some low melting point substances such as polyethylene glycol may also cause sticking at the heat of compression. Such Remedies are addition of high melting point materials and consequently increasing size of tablet.

Mottling:

Mottling is term used unequal distribution of colour on a tablet with light and dark areas. It's due to colour difference of duloxetine with excipients or drugs whose degradation product is coloured. Such problems might be solved by using colorants but it can cause mottling on the top of surface when granulation undergoes drying. To overcome difficulties, it require to change solvent system, binder system and by reducing temperature.

Tablet coating

Tablet coating is application of coating of material to the exterior of tablet with some intentional benefits. It is also intended for modified release applications. Main three types of coating are- Film coating Sugar coating Press coating Coating of tablets is for following purposes-

[1] Protection from environment, light and moisture

[2] To remove bitter taste of some tablets and for easy swallowing of tablets [3] Colour coating mask differences in appearance which effect on patient compliance [4] Rapid identification by manufacturer, pharmacist and patient [5] Functional films can enable sustained and enteric protection

[6] Improve looks (elegance), masks and minor difference in raw material appearance [7] Enhance strength, reduce dust and cross contamination Film coating

This is more modern and widely used for tablet coating. Most of newly launched coated products are film coated rather than sugar coating.

Film coating involves covering of tablet by thin film layer of coating liquid (polymer). Coating liquid is sprayed in a rotating tablet bed or bed fluidised tablet which contains plasticizer, polymer, colourant and solvent. The drying condition permits removal of solvent and leaves a thin layer around each tablet. Sometimes aqueous solution or organic solutions are used to reduce elimination of volatile organic compound, health and safety and cost reduction purposes. Film coating polymer should have following properties-

[1] Optimum solubility to facilitate dissolution of final product. High soluble for immediate release and low soluble for controlled release.

[2] Optimum viscosity to permit and trouble free spraying of solution. [3] Optimum permeability to optimize shelf life of tablet preparation and some tuned to provide an effective barrier oxygen and water vapour. [4] Good mechanical strength to withstand the impact and abrasion encountered in normal handling which avoids cracks and imperfections.

Cellulose derivatives like Hydroxypropylmethylcellulosa (HPMC), methylcellulose,

hydroxypropylcellulose (HPC) and Methacrylate amino ester copolymer are available polymer for film coating.

Sugar coating

Sugar coating involves the successive application of sucrose based solutions to tablet cores in suitable equipment. Some stages in production of sugar coated tablets are-

[1] Sealing of tablet core- provide water proofing core from coating process and shellac, cellulose acetate phthalate are normally used in sealing process.

[2] Sub coating- it is the actual start of sugar coating which provides necessary build-up to roundup the tablet edge. Bulking agents such as calcium carbonate or talc added in sucrose solution with gum.

[3] Smoothing - it increases tablet size to predetermined dimension by syrup solution. This solution contains pigments, starch, gelatine, acacia or pacifier. [4] Colouring- dyes or pigments

[5] Polishing- tablets need to be polished to achieve final elegance by waxes like beeswax, carnubawax or hard paraffin.

Difference between sugar and film coating

Press coating Press coating involves compaction of granules material around core of tablet with the use of compressing equipment like Manesty Drycota. Today press coating is used in to separate incompatible placed core and coating layer. This process requires some care and large or irregularly sized agglomerate of granules may cause core to tilt in die. Disadvantages of process arise from complexities of mechanism used in compression equipment. [M. E Aulton, Pharmaceutics, The Science of Dosage Form Design, Second Edition, 2002, pp.441-448]

Enteric coating

According to Biju et al 2004, [BIJU, S. S.; SAISIVAM, S.; RAJAN, M. G.; MISHRA, P. R. Dual coated erodible microcapsules for modified release of Diclofenac sodium. Eur. J. Pharm Biopharm., v.58, n. l, p.61-67, 2004. ] enteric polymer technique is safe and widely used in duloxetine products. Enteric coating prefers small intestine so it prevents the disintegration of tablet in the acidic environment of stomach and release into small intestine for some reasons such as

Prevention of acid attack on active constituents at low pH

Protect stomach from irritation from drug Facilitate absorption of duloxetine which is preferentially absorbed distal to stomach.

Most commonly used enteric coating polymers are Cellulose acetate phthalate, Polyvinyl acetate phthalate, suitable acrylic derivatives and Hydroxypropyl methyl cellulose phthalate because they are free from carboxylic acid group and different pH solubility profile. They are almost insoluble at low pH and increases solubility at specific pH such as pH 5.2 for cellulose acetate phthalate. Enteric coating is possible for both sugar and film coating.

Peters et al, 1993[PEETERS, R.; KINGET, R. Film -forming polymers for colonic duloxetine e delivery: I Synthesis and physical and chemical properties of methyl derivatives of Eudragit S. Int. J. Pharm., v.94, n.1-3, p.125-134, 1993. ] stated that there are number of polymers are available which are insoluble at low pH but dissolve at pH around or below 7. Shellac ia natural enteric polymer which is gastric resistance. Hydroxypropyl methyl cellulose was first polymer in contract to ethyl cellulose which is used a novel enteric coating agents for acid protection because it is water soluble and leach of film coating which diffuses duloxetine more rapidly than ethyl cellulose. [ Kokubo et al, 1997, Gunder, Lippold, 1995] . [ KOKUBO, H.; OBARA, S.; MINEMURA, K.; TANAKA, T.

Development of cellulose derivatives as novel enteric coating agents soluble at pH 3.5-4.5 and higher. Chem. Pharm. Bull. (Tokyo), v.45, n.8, p.1350-1353, 1997., GUNDER, W.; LIPPOLD, B. H.;

LIPPOLD, B. C. Release of drugs from ethyl cellulose microcapsules (diffusion pellets) with pore formers and pore fusion. Eur. J. Pharm. Sci., v.3, n.12, p.203-214, 1995.] A continuous technology coating is use to water instead of organic solvents to minimize environmental and safety hazards so Baudoux et al 1990, [BAUDOUX, M.; DECHESNE, J. P.; DELATTRE L. Film Coating with Enteric Polymers from Aqueous Dispersions. Pharm. Tech. Int., v.12, n.11, p.18-26, 1990. stated that water based technology is being widely used instead of organic system.

Evolution of tablets

After production, tablets must be evaluated to check qualitative and quantitative analysis and chemical, physical and bioavailability properties. For that reason, evaluation is classified in three different categories

General appearance:

Size and shape Unique identification markings

Organoleptic properties such as colour, odour and taste.

Mechanical strength:

Hardness test Friability test

Tensile test

Brittle fracture index

Duloxetine content and its release:

Active duloxetine content in tablet Dissolution and disintegration

These evolution tests are specific standard in each pharmacopeia. Specification may vary to one country from other. All products have regulatory aspects which must be complied for that particular product.

The pharmaceutical industry is ever thirsty to satisfy patients therapeutically needs and apart from active ingredients, inactive excipients play a major role in formulation development. Pharmaceutical excipients are substances other than the pharmacologically active duloxetine or pro duloxetine which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form.

In addition to transporting the active duloxetine to the site in the body where the duloxetine is intended to exert its action, excipients play an important part in the manufacturing process. They may also be important for keeping the duloxetine from being released too early in the assimilation process in places where it could damage tender tissue and create gastric irritation or stomach upset.

Others help the duloxetine to disintegrate into particles small enough to reach the blood stream more quickly and still others protect the product's stability so it will be at maximum effectiveness at time of use. In addition, some excipients are used to aid the identification of a duloxetine product.

Last, but not least, some excipients are used simply to make the product taste and look better. This improves patient compliance. Although technically "inactive" from a therapeutic sense,

pharmaceutical excipients are critical and essential components of a modern duloxetine product. In many products, excipients make up the bulk of the total dosage form apart from the drug's active ingredient, other essential components include diluents or fillers, binders, disintegrants, lubricants, colouring agents and preservatives Diluents or fillers are inert ingredients that can significantly affect the chemical and physical properties of the final tablet thus affecting the biopharmaceutical profile.

One classic example of this is calcium salts, which can be utilized as fillers, which interfere with the absorption of tetracycline from the gastrointestinal tract. This example emphasizes that excipients may not always be inert, as they may be perceived.

Usually tablets are designed so that the smallest tablet size which can be conveniently compressed is formed. Thus, if the dose is small more diluents are required and if the dose is high less diluents are required as not to increase the tablet size, which might make it difficult to swallow. Diluents selection should be made carefully as physical -chemical changes might render the product unstable and might cause problems in manufacturing. Binders are added to tablet formulations to add cohesiveness to powders thereby providing the necessary bonding to form granules which under compaction form a compact mass as tablet. In other words, binders are essential to achieve the "hardness" of the tablet. Binders are usually selected on basis of previous experience, particular product needs, literature or vendor data or the preference of individual scientists or manufacturing unit. The primary criterion when choosing a binder is its compatibility with other tablet components.

It must add sufficient cohesion to the powders to allow for normal processing yet allow the tablet to disintegrate and the duloxetine to dissolve upon ingestion, releasing the active ingredients for absorption. Disintegrants facilitate the breakup of a tablet after oral administration.

They can be added prior to granulation or during the lubrication step prior to compression or at both processing steps. The effectiveness of many disintegrants is affected by their position within the tablet. Since disintegration is the opposite operation to granulation (agglomeration) and the subsequent formation of strong compacts, one must carefully weigh these two phenomena when designing a tablet. Lubricants prevent sticking of the tablets to the tablet punches during the compression phase of the tablet manufacturing process.

When lubricants are added to a powder mass, they form a coat around individual particles which remains more or less intact during compression. Lubricants are mostly hydrophobic. The presence of lubricant coating may cause an increase in the disintegration time and a decrease in duloxetine dissolution rate. The choice of a lubricant may depend upon the type of tablet being manufactured, dissolution, flow characteristics and requirements of the formulation in terms of hardness, friability and compatibility. Glidants are the materials that have good flow properties and poor lubrication properties. Glidants improve the flow of powder into the tableting machines for compaction. They act to minimize the tendency of a granulation to separate or segregate due to excessive vibration. High speed tablet machine require smooth even flow of material to die cavities (tablet mold). The uniformity of tablet weights directly depends on how uniformly the die cavity is filled. In general many materials commonly referred to as lubricants possess only a minimal lubricating activity and are better glidants or anti -adherents.

Thus a blend of two or more materials may be necessary to obtain these properties. Pharmacists should be familiar with the components of pharmaceuticals products, beyond their active ingredients

The choice of the specific dose of a compound is made after the dose range finding studies which ill be performed in phase 2a of the clinical trials process. The overarching criteria for selection of dose is that the dose must cause the duloxetine to be efficacious, it would make the developer look lacking in competency, if they chose a dose which was too low and the compound did not work at all yet increasing the dose by a small amount would have solved the problem and the compound would have been effective. So the choice of dose in the development phase usually builds in a vast excess of duloxetine to ensure that the duloxetine actually is effective. That being the case this excess usually causes side effects which makes the duloxetine work but which causes the duloxetine to have undesirable side effects.

We have found that the reduction in dose for an approved duloxetine of between 35 to 50 pc leads to a product which is still efficacious but which has far less side effects and therefore has an improved therapeutic ratio. Thus in developing the duloxetine for new line extenders or new uses or combinations we have found that reducing the dose by 35 to 50 pc leads to a much improved product . Therefore the present invention has found that the drugs listed herein can be repurposed using a dose which is reduced by 35 to 50pc leading to a product which is both efficacious and safe. A suitably optimum reduction in dose for repurposing is around 35 to 50 pc, more suitably around 40 to 45 pc and most suitably around 40pc.

Thus if the original dose of the active was lOOmg, then a reduced dose would be suitable down to 60 mg. The preferred range would be 50 mg to 65mg. The present invention has found that its sweet spot reduces the side effects and increases efficacy i.e. it defines the perfect therapeutic ratio for the duloxetine between efficacy and safety. There are many articles which reflect this situation that duloxetine companies chose outsized doses to ensure that their drugs show efficacy in clinical trials,

Pharmacological data the new uses, new combinations and PLE's of the present inventions are made from readily available starting materials as described herein. Such specific examples are shown to have utility in a range of uses using invitro, animal and human models for the use in question, these methods are well known by skilled workers and are herein incorporated by reference.

Pharmacological Data

The neuroleptic activity of the compound of the invention may be demonstrated by methods well known to those of ordinary skill in the art, such as the methods described in T.F. Seeger, et al., Journal of Pharmacology and Experimental Therapeutics, 275, (1), 101-113 (1995).

Specifically, the standard methods for determining neuroleptic activity are based on Dopamine D-2, Dopamine D-3, Dopamine D-4, 5-hydroxytryptamine- 1A (5-HT- 1A), 5-27C1745

hydroxytryptamine-2C (5-HT- 2C), and 5-hydroxytryptamine- 2A (5-HT- 2A) receptor binding studies. Tissues or membranes used to perform these studies are derived from rat, pig, or from cell lines expressing human receptor subtypes. LTK-cells expressing the human D2 Long receptor are obtained from Dr. Olivier Civelli, Oregon Health Sciences University, Portland, Oreg. Chinese hamster ovary cells (CHO) expressing the human D3 receptor are obtained from Dr. J. C.

Schwartz,. Unite de Neurobiologie, Institut National de la Sante' et de la Recherche Medicale, 2 ter Rue D'Ale' Sia, Paris, France, 75014.

The following protocol describes one possible method for determining activity for the compounds of this invention. Specific assay conditions for each receptor are described in Table 1, below. Tissues or cell lines of interest are homogenized in various buffer solutions (details are given in Table 1) using a Brinkman Polytron at setting 6 for 20 sec. Membranes are recovered after multiple rounds of separation by centrifugation and resuspension in fresh ice-cold buffer. The resulting tissue homogenates are added to test tubes containing incubation buffer, various concentrations of test drug, and the appropriate triturated or iodinated ligand. Non-specific binding is determined by radio ligand binding in the presence of a saturating excess of a known competitor for the receptor of interest (as listed in Table 1). After allowing sufficient time to attain equilibrium at the appropriate temperature, incubations are terminated by rapid filtration through Whatman GF/B filters using a Brandelcell harvester. The membranes are washed three times with four ml aliquots of ice-cold buffer. Membrane-bound ligand is determined by liquid scintillation counting of the filters in

Ready-Safe scintillation cocktail (for triturated ligands), or by direct counting in a gamma counter (for [ 125 I] ligands). For all receptor types, the dissociation constant (K d ) for the radioligand is previously determined by saturation analysis in the tissue of interest, and used to calculate apparent K i 's by means of the Cheng-Prusoff equation (Cheng and Prusoff, 1973). In some cases the IC 50 concentration (concentration of compound required to displace specific binding by 50%) can be interpolated by linear regression analysis of the concentration-response curves from competition binding studies.

Assay Conditions for Radio ligand Binding Studies ligand Concen- Receptor tration Tissue Blank Buffer pH 28C1745 Dopamine D-2 3H- rat caudate (+)- 50 mM spiroperidol butaclamol TrisHCl,.2 nM + 5μΜ 100 mM 1 μΜ NaClprazosin + 1 mM MgCl 2 , 500 nM pH 7.2 cinanserin Dopamine D-3 3H- human (+)- 50 mM spiroperidol D3- butaclamol TrisHCl 0.1 nM transfected 2μΜ pH 7.4, CHO cells 120 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 2 mM CaCl 2Dopamine D-4 3H- human (+)- 50 mM spiroperidol D4- butaclamol TrisHClO.1 nM transfected 2μΜ pH 7.4, COS-7 120 mM cells NaCl, 5 mM KC1,2 mM MgCl 2 , 2 mM CaCl 2 5HT-1A 3H-80H- rat cortex serotonin 50 mM DPAT 10μΜ TrisHCl, 1.5 nM 0.1% ascorbate, 4 mM CaCl 2

10 μΜ pargyline pH 7.7 5HT-2C 3H- pig serotonin 50 mM mesulergine choroid 10μΜ TrisHCl, 1 nM plexus 0.1% ascorbate 4 mM

The excipients which promote modified release in the second component may be polymers. The duloxetine in the second component is often a pharmaceutically acceptable salt of duloxetine and is one preferred choice for the second component. Alternatively, the duloxetine in the second component may be a fatty acid salt of duloxetine in another embodiment, the duloxetine in the second component is duloxetine free base. In yet another embodiment, the duloxetine in the second component is in the form of a co-crystal of duloxetine, for instance a co-crystal of duloxetine with a compound which comprises a phenol moiety. For all these forms of duloxetine, the dosage of duloxetine quoted on a free base basis, may be as defined herein.

Another aspect of the invention provides duloxetine adapted in a multi component dosage form, such as a tablet, said dosage form being adapted in a first way to provide rapid release of duloxetine into the bloodstream, said dosage form being adapted in a second way to further provide a maintenance dose of duloxetine within the therapeutic window, and the dosage form being adapted in a third way to provide a modified or delayed release format of the duloxetine product which lasts from dose to dose.

The exact dose of each component is dependent on the choice of formulation but in general the choice of each component will be made so that the amount of active ingredient in each component delivers the right amount of duloxetine product to ensure rapidity, longevity from dose to dose and maintenance of dose within the therapeutic window.

As a different principle the total amount of duloxetine in a formulation (i.e. in the first and further components thereof) is at least 20mg and usually 50mg to lOOmg. A preferred aspect of the invention is a product (usually a multi component dosage form, such as a tablet) which comprises: duloxetine in the form of a co-crystal suitable for rapid release of duloxetine, which co-crystal is optional as further defined herein; a fatty acid salt of duloxetine, suitable for delivering duloxetine between onset of action from said rapid release and onset of a bolus amount of a delayed release component. a delayed release component, comprising of a bolus dose of duloxetine.

Another preferred aspect of the invention is a product (usually a multi component dosage form, such as a tablet) which comprises the following: from 2.5mg to 25mg duloxetine in the form of a co-crystal suitable for rapid release of duloxetine which co-crystal is optional as further defined herein; from 2.5mg to 25mg duloxetine in the form of a fatty acid salt of duloxetine as defined herein, suitable for delivering duloxetine between onset of action from said rapid release and onset of a bolus amount of a delayed release component; and said delayed release component, comprising a bolus dose of duloxetine.

The bolus dose of duloxetine may be from 20mg to 95mg; in particular, it may be a commercial doses of duloxetine of, for example, 20, 30, 40, or 60 mgs in a bolus dose, and may be in the form of duloxetine free base or a salt of duloxetine such as duloxetine hydrochloride.

Another preferred aspect of the invention is a product (usually a multi component dosage form, such as a tablet) which comprises: from 2.5 to 5mg duloxetine in the form of a co-crystal suitable for rapid release of duloxetine, which co-crystal is optionally as further defined herein.

Normal commercially recommended doses of duloxetine for treating depression and the other approved indications are as follows, 20, 30 40 and 60mg.

It should be appreciated that these doses are apportioned between the various components in the multicomponent tabletting system, examples of such an apportionment are 10 to 20 pc in a first component for rapid release, 20 to 60 pc in a second component for maintenance of the dose of between 20 to 60pc and a third component containing 20 to 60 pc with the proviso that all three components add up to lOOpc.

The pharmaceutical composition of the invention comprises a selective serotonin reuptake inhibitor (SSRI) and may therefore be used for the treatment or prophylaxis of any condition or disorder which is treatable using an SSRI. The pharmaceutical composition of the invention provides for maintenance of the SSRI in the therapeutic window from dose to dose, i.e. throughout the dosing interval, for such conditions and disorders such that an improved treatment for such conditions and disorders, with increased efficacy, reduced side effects, or both, is obtained compared to prior art formulations.

Conditions and disorders which are treatable using an SSRI, and for which improved treatments can therefore be provided by the present invention, include: mental health conditions, for instance: depression; generalised anxiety disorder (GAD); obsessive compulsive disorder (OCD); panic disorder; severe phobias, including but not limited to agoraphobia and social phobia; post-traumatic stress disorder (PTSD); eating disorders, in particular: bulimia and binge eating disorder; premature ejaculation, in particular male premature ejaculation; premenstrual syndrome (PMS); fibromyalgia; irritable bowel syndrome (IBS); and pain. Accordingly, the invention provides a pharmaceutical composition of the invention for use in a method for treatment of the human or animal body by therapy.

The invention further provides a pharmaceutical composition of the invention for use in the treatment or prophylaxis of a condition or disorder which is treatable using a selective serotonin reuptake inhibitor (SSRI). Typically, the pharmaceutical composition of the invention is for use in a method for the treatment or prophylaxis of a condition selected from premature ejaculation, a mental health condition, an eating disorder, premenstrual syndrome, fibromyalgia, irritable bowel syndrome and pain. Typically, the mental health condition is depression; generalised anxiety disorder (GAD); obsessive compulsive disorder (OCD); panic disorder; severe phobias; or post-traumatic stress disorder (PTSD). The eating disorder may be bulimia, for instance bulimia nervosa, or binge eating disorder. Often, the pharmaceutical composition of the invention is for use in a method for the treatment or prophylaxis of a mental health condition. The mental health condition may for instance be depression.

In a preferred embodiment, the invention provides the pharmaceutical composition of the invention for use in the treatment or prophylaxis of premature ejaculation. Thus, the invention provides the pharmaceutical composition of the invention for use in the treatment or prophylaxis of male premature ejaculation.

As discussed hereinbefore, the at least one further component in the pharmaceutical composition of the invention is usually adapted to ensure maintenance of the SSRI within the therapeutic window from dose to dose, or at least for a certain, preferably high, proportion of the time during the dosing interval.

Accordingly, in all of the above -defined medical uses for the composition of the invention, the method for the treatment or prophylaxis of the condition in question typically comprises administering the composition to a subject in need thereof once every dosing interval, and thereby ensuring maintenance of the SSRI within the therapeutic window throughout each dosing interval. This ensures maintenance of the SSRI within the therapeutic window from dose to dose. The dosing interval (i.e. the interval of time between administration of consecutive doses of a drug) may be as defined above for z. However, the dosing interval is often 24 hours. Typically, therefore, the method for the treatment or prophylaxis of the condition comprises administering the composition to a subject in need thereof once every 24 hours, and thereby ensuring maintenance of the SSRI within the therapeutic window throughout each 24 hours.

Often, the method for the treatment or prophylaxis of the condition comprises administering the pharmaceutical composition of the invention to a subject in need thereof, and thereby releasing the SSRI from the controlled-release fraction in vivo over a period of x hours from the time of administration of the composition to the subject. Generally, in this embodiment, all of the SSRI is released from the controlled-release fraction over the defined period. Typically, x is at least 8, so that it takes at least 8 hours for all of the SSRI to be released from the controlled-release fraction.

However, x may be at least 9, or, for instance, at least 10, so that it takes at least 8 hours for all of the SSRI to be released from the controlled-release fraction, x may for instance be from 8 to 24, so that it takes from 8 to 24 hours for all of the SSRI to be released from the controlled-release fraction, x may for instance be from 9 to 24, or from 10 to 24. Often, x is at least 12, so that it takes at least 12 hours for all of the SSRI to be released from the controlled-release fraction, x may for instance be at least 15, for example at least 17, at least 18, or at least 20. x may for instance be from 12 to 24, or from 15 to 24, or for instance from 17 to 24, or from 20 to 24. The method for the treatment or prophylaxis of the condition may comprise administering the pharmaceutical composition of the invention to a subject in need thereof once every dosing interval, and thereby maintaining the SSRI within the therapeutic window for y % of the time during each dosing interval. The dosing interval may be defined as, say, z hours beginning with administration of the composition to a subject. When the pharmaceutical composition is a unit dosage form suitable for once daily (OD) dosing, z is generally 24, i.e. the dosing interval is 24 hours. Accordingly, z is typically from 20 to 28, for instance about 24. Often, z is 24. However, other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and z may therefore have other values. Thus, z may for instance be 6, 8 or 12, or even 48. Thus, z may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, z is 24. Typically, y is at least 50, such that the SSRI is maintained within the therapeutic window for at least 50% of the time during the dosing interval. It is of course preferred, however, that y is greater than 50. Preferably, for instance, y is at least 60, and more preferably at least 70, for instance at least 75.

Typically, y is at least 80, for instance at least 85. Often, y is at least 90, and is preferably at least 95. y may for instance be 100, such that the SSRI is maintained within the therapeutic window throughout the dosing interval, i.e. from dose to dose. Typically, z is 24 and y is at least 50. More preferably, z is 24 and y is at least 60, and more preferably at least 70, for instance at least 75. Typically, z is 24 and y is at least 80, for instance at least 85. Often, z is 24 and y is at least 90, and is preferably at least 95. In some cases, z is 24 and y is 100.

The method for the treatment or prophylaxis of the condition may comprise administering the pharmaceutical composition of the invention to a subject in need thereof once every dosing interval, and thereby maintaining the SSRI at or above a drug plasma level, 1, in the subject for q % of the time during each dosing interval.

The dosing interval may in this case be defined as t hours beginning with administration of the composition to the subject. The pharmaceutical composition is often a unit dosage form suitable for once daily (OD) dosing. Thus, t is generally 24, i.e. the dosing interval is 24 hours. Accordingly, t is typically from 20 to 28, for instance about 24. Often, t is 24. However, other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and t may therefore have other values. Thus, t may for instance be 6, 8 or 12, or even 48. Thus, t may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, t is 24. Typically, q is at least 40, such that the SSRI is maintained at or above the drug plasma level, 1, for at least 40% of the time during the dosing interval. It is of course preferred, however, that q is greater than 40. Preferably, for instance, q is at least 45, and more preferably at least 50, for instance at least 60. Typically, q is at least 65, for instance at least 70. Often, q is at least 75. Typically, q is at least 80, for instance at least 85. Often, q is at least 90, and is preferably at least 95. q may for instance be 100, such that the SSRI is maintained at or above the drug plasma level, 1, throughout the dosing interval, i.e. from dose to dose. Typically, t is 24 and q is at least 45. More preferably, t is 24 and q is at least 50, and more preferably at least 60, for instance at least 65, at least 70, or for instance at least 75. Typically, t is 24 and q is at least 80, for instance at least 85. Often, t is 24 and q is at least 90, and is preferably at least 95. In some cases, t is 24 and q is 100. The drug plasma level, 1, may be any drug plasma level within the therapeutic window. Alternatively, it may be an IC50, i.e. a plasma concentration required for obtaining 50% of a maximum therapeutic effect in vivo. Usually, 1 is the plasma concentration (IC50) required for obtaining 50% of a maximum therapeutic effect in vivo. The maximum therapeutic effect in vivo is the maximum therapeutic effect in vivo that is obtainable by the SSRI in question when treating the condition in question.

The method, which may be as further defined anywhere herein, generally comprises administering a therapeutically effective amount of the pharmaceutical composition of the invention to the subject. The subject is generally a human or animal. Usually the subject is a human or mammal. The subject is typically human, i.e. a human patient. As discussed throughout, the pharmaceutical compositions of the invention are typically oral dosage forms and are typically therefore administered orally.

Typically, therefore, the method for the treatment or prophylaxis of the condition comprises administering the composition to a subject in need thereof orally. This may comprise placing the composition in the mouth for a period of time long enough to allow the first (rapid release) component - which may be a component that is suitable for sublingual administration - to dissolve completely, or to disperse completely, in the buccal fluid.

Accordingly, administering the composition to the subject orally typically comprises placing the composition in the mouth for a period of time during which the first component completely dissolves or disperses in the buccal fluid. The oral administration may be sublingual administration. Therefore, administering the composition to the subject orally may comprise placing the composition under the tongue, or placing the composition between the cheek and gum.

Accordingly, administering the composition to the subject orally typically comprises placing the composition under the tongue, or placing the composition between the cheek and gum, for a period of time during which the first component completely dissolves or disperses in the buccal fluid.

The period of time is usually less than or equal to 120 seconds. It may for instance be less than or equal to 90 seconds, for example less than or equal to 60 seconds.

The period of time is usually at least 1 second, for instance at least 15 seconds, because it must be sufficiently long enough for the first component to dissolve or disperse in the buccal fluid. In some embodiments, the period of time is at least 30 seconds. Thus, the period of time may for instance be from 15 seconds to 120 seconds, for example from 15 seconds to 90 seconds, for instance from 15 seconds to 60 seconds, or for example from 30 seconds to 60 seconds.

The method typically further comprises swallowing the composition after the period of time has elapsed. This ensures that the at least one further component of the composition, which typically comprises a core adapted for prolonged release of the SSRI, is swallowed so that the prolonged release can be effected such that the SSRI may be delivered from dose to dose. The method typically therefore further comprises swallowing the composition after the period of time has elapsed, and optionally thereby releasing the SSRI from the at least one further component in vivo over a period of x hours from the time of administration of the composition to the subject wherein x may be as further defined herein.

As will be understood, in these embodiments of the invention the composition of the invention will generally be an oral dosage form as further defined herein.

Often, in the method for the treatment or prophylaxis of the condition, the SSRI is duloxetine. Often, the SSRI is duloxetine and the condition is male premature ejaculation. Often, the pharmaceutical composition is an oral dosage form of duloxetine which comprises (i) a core which comprises duloxetine and a component which causes delayed or prolonged release of the duloxetine, wherein the core may be as further defined herein for the at least one further component, and (ii) a shell disposed on the surface of the core which comprises duloxetine and an excipient suitable for dissolving rapidly in saliva. The shell may be as further defined herein for the first component.

The invention further provides the use of a pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment or prophylaxis of a condition selected from premature ejaculation, a mental health condition, an eating disorder, premenstrual syndrome, fibromyalgia, irritable bowel syndrome and pain. Optionally, the treatment or prophylaxis of said condition, and the condition itself, is as further defined anywhere herein. The pharmaceutical composition of the invention may be as defined anywhere herein.

The invention further provides a method for the treatment or prophylaxis of a condition selected from premature ejaculation, a mental health condition, an eating disorder, premenstrual syndrome, fibromyalgia, irritable bowel syndrome and pain, which method comprises administering a pharmaceutical composition of the invention to a subject in need thereof. The method and its various features may be as further defined anywhere herein.

The following Example illustrates the invention. It does not however, limit the invention in any way. EXAMPLE

Part 1: Duloxetine HC1 sustained release core tablet formulation and dissolution data

Aim: To produce dissolution profiles in pH 6.8 buffer for sustained release development formulations of duloxetine HQ. The sustained release formulations 17CF 14/001-2 in this Example may be employed as the further component in the compositions of the invention for delivering the duloxetine from dose to dose.

Formulation details

Batch: 17CF14/001 Sustained Release (20% Methocel in lactose filler; 53.884 mg duloxetine hydrochloride, equivalent to 48.0 mg duloxetine free base):

Method of manufacture: the components in the table above were blended and then compressed to a hardness of approximately lOkp

Table 1: Formulation details for sustained release core tablet (batch 17CF 14/001)

Batch: 17CF14/002 Sustained Release (30% Methocel in lactose filler; 53.884 mg duloxetine hydrochloride, equivalent to 48.0 mg duloxetine free base):

Method of manufacture: the components in the table above were blended and then compressed to a hardness of approximately lOkp

Table 2: Formulation details for sustained release core tablet (batch 17CF14/002)

Analytical Testing

Tablets were tested using dissolution with UV endpoint to obtain drug release profiles. Sustained release formulation dissolution conditions are given in the following Table 3.

Table 3: Sustained Release Formulation Dissolution conditions

Dissolution Results

Dissolution testing was performed on tablet batch 17CF14/002 (30% Methocel in lactose filler; 53.884 mg duloxetine hydrochloride, equivalent to 48.0 mg duloxetine free base). The experiment was carried out three times (i.e. was repeated twice) giving three dissolution results per time point. The three results for each time point are shown in Table 4 below together with the mean result. Results are also plotted in Figure 1.

Table 4 : Batch 17CF 14/002 - Sustained Release Core Tablet (Theoretical 53.884mg duloxetine hydrochloride (equivalent to 48.0mg duloxetine base) per tablet, 500mg nominal tablet weight) Part 2: Duloxetine HCl immediate release formulation and dissolution data

Aim: To produce dissolution profiles in pH 6.8 buffer for immediate release development formulations of duloxetine HCl. The immediate release formulation 17CF 14/003 in this Example may be employed as the first, rapid release component in the composition of the invention.

Formulation details

Batch: 17CF14/003: Immediate Release component tablet (13.47 mg duloxetine hydrochloride, equivalent to 12.0 mg duloxetine free base):

Method of manufacture: the components in the table above were blended and then compressed to a hardness of approximately 5kp

Table 5: Formulation details for immediate release component tablet (batch 17CF14/003)

Analytical Testing

Tablets were tested using dissolution with UV endpoint to obtain drug release profiles. Immediate release formulation dissolution conditions are given in Table 6 below.

Table 6: Immediate Release Formulation Dissolution conditions Dissolution Results

Dissolution testing was performed on tablet batch 17CF14/003 (13.470 mg duloxetine hydrochloride, equivalent to 12.0 mg duloxetine free base). The experiment was carried out three times (i.e. was repeated twice) giving three dissolution results per time point. The three results for each time point are shown in Table 7 below together with the mean result. Results are also plotted in Figure 2.

Table 7: Batch 17CF14/003 - Immediate Release Tablet (Theoretical 13.47 mg duloxetine hydrochloride (equivalent to 12.0 mg duloxetine base) per tablet, 500mg nominal tablet weight)

Part 3: Final proposed manufacture combing the two formulations

• The duloxetine HC1 sustained release core is made as described above in part 1 of this Example.

• Depending on the final size required, the tooling is changed to 10 - 20mm Flat tooling.

• The tablet die is filled with approximately 50% of the immediate release blend described in part 2 of this Example.

• The sustained release core is placed centrally into the pre-filled die.

• The remaining immediate release blend (approximately 50% thereof) is added.

• Tablet is compressed to a suitable hardness.