MIXED SALTS

FIELD OF THE INVENTION

The present invention generally relates to an orally administrable modified release pharmaceutical composition comprising pellets containing one or more active ingredients. More particularly, such modified release pharmaceutical composition comprises one or more amphetamine salts as the active ingredients.

BACKGROUND OF THE INVENTION

Continued development and improvement of modified release pharmaceutical compositions has long been a focus in the field of pharmaceutical formulations. Modified release pharmaceutical formulations have several advantages, including increased convenience of administration, increased patient compliance with a prescribed dosage regimen, and also a more consistent therapeutic effect throughout a desired period of time (i.e., maintain the desired plasma concentration). Amphetamines are non-catecholamine, sympathominetic amines with central nervous system stimulant activity. Such active ingredients have been widely utilized in treating narcolepsy and Attention-Deficit/Hyperactivity Disorder (ADHD). The amphetamine salts generally include the neutral sulfate salts of dextroamphetamine and amphetamine, the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate.

Commercially available medicinal products that contain, or metabolize into, amphetamine include Adderall ^® , Dexedrine®, Dextrostat®, Desoxyn ^® and ProCentra ^® , Vyvanse®. Currency marketed oral products to treat narcolepsy and/or ADHD include both immediate-release and modified-release forms. The Dexedrine® product is marketed as a sustained-release formulation with dextroamphetamine sulfate as the sole active ingredient. Adderall XR is a once a day sustained-release, single-entity dosage form containing mixture of four amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate, which is indicated for treatment of of Attention Deficit Hyperactivity Disorder in children from 3-10 years of age.

Adderall ^® is an immediate release composition, which includes a mixture of four amphetamine salts. Drug absorption is different in various gastrointestinal segments: is moderately slow in the stomach, rapid in the small intestine, and sharply declining in the large intestine. Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs. Several amphetamine dosage forms with plurality of modified release units, particularly extended release dosage forms, mixed salts of amphetamine extended-release capsules, where it is formulated by mixing two types of pellets, immediate release pellets and delayed release pellets in 1 :1 ratio to have a dual type of release, are known. The immediate release pellets release the amphetamine salts immediately after ingestion and the delayed release pellets releases the amphetamine salts once the pellets reach the intestine. For example, see the following prior art references:

PCT Publication No. WO2005/044238, is entitled "Modified Release Solid Dosage Form of Amphetamine Salts" and published May 19, 2005. This application is directed to solid dosage forms of amphetamine salt that include a plurality of modified release units and processes for their preparation. Each modified release unit includes an inert core, a first amphetamine salt later, a modified release polymer layer and a second amphetamine salt layer. U.S. Publication No. 2006/0204575, is entitled "Amphetamine Formulations" and published September 14, 2006. This application is directed to amphetamine formulations comprising a plurality of particles comprising two or more amphetamine salts. The dosage form, when administered under fed conditions, provides a reduced variability in bioavailability as compared to the dosage form when administered under fasted conditions.

Canadian Patent Application No. 2,651 ,890 is entitled "Controlled Drug Delivery System" and published November 22, 2007 (this application corresponds to PCT Publication No. WO2007/133203). This application is directed to a multiple pulsed drug delivery system for pharmaceutically active amphetamine salts, comprising a pharmaceutically active amphetamine salt covered with an immediate release coating and a pharmaceutically active amphetamine salt covered with an enteric coating. The immediate release coating and the enteric coating provide for multiple pulsed dose delivery.

PCT Publication No. WO2006/107593 (corresponds to Canadian Patent Application No. 2,605,185) is entitled "Matrix-Based Pulse Release Pharmaceutical Formulation" and published October 12, 2006. This application is directed to an oral pulse release pharmaceutical composition comprising a polymer matrix core, wherein at least one pharmaceutically active ingredient is distributed within the core and on the outer surface of the core. The pharmaceutically active ingredient may be amphetamine base, an amphetamine salt, a mixture of amphetamine salts, or a combination thereof. Canadian Patent No. 2,348,090 (corresponds to U.S. Patent No. 6,322,819) is entitled "Oral Pulsed Dose Drug Delivery System" and issued to Shire Laboratories Inc. on April 13, 2004. This patent is directed to a multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts. The drug delivery system comprises immediate-release pellets for releasing the active ingredients in the stomach and an enteric delayed-release pellets for releasing the active ingredients in the small intestine, and a person skilled in the art would recognize an inherent food effect.

Canadian Patent No. 2,432,178 (corresponds to U.S. Patent No. 6,287,599) is entitled "Sustained Release Pharmaceutical Dosage Forms with Minimized pH Dependent Dissolution Profiles" and issued April 20, 2010 to Supernus Pharmaceuticals Inc. (now owned by Shire Laboratories Inc.). This patent discloses pharmaceutical composition comprising at least one pharmaceutically active agent that is pH dependent, at least one non-pH dependent sustained release agent, and at least one pH dependent agent that increases the dissolution rate of the at least one pharmaceutically active agent at pH in excess of 5.5.

United States Patent No. 6,384,020 (corresponds to Canadian Patent Application No. 2,378,336) is entitled "Rapid Immediate Release Oral Dosage Form" and issued to Shire Laboratories Inc. on May 7, 2002. This patent discloses an immediate-release oral dosage form comprising amphetamines and their salts. This dosage form solves particular process problems and has an adequate stability profile. A number of factors may influence the efficacy of pulse drug release and thus, represent a source of variability. Such factors include the complexity of the process for drug formulation, reproducibility of the manufacturing process, and uniformity of the product produced by the manufacturing process. Among some disadvantages of manufacturing process is the fact that the filling of the two or more pellets requires specialized equipment, machinery and change parts and could bring variability in dissolution if the correct amount is not filled into each type of pellet.

In addition, gastrointestinal transit times vary not only from patient-to-patient but also within patients as a result of food intake, stress, and illness. Thus, while a variety of formulations have been proposed in consideration of one or more of these factors, there remains room for further improvement.

Therefore, a need exists to provide alternative modified release formulations of amphetamine mixed salts.

SUMMARY OF THE INVENTION

The present invention provides a modified release pharmaceutical composition comprising pellets containing one or more active ingredients, said pellets comprising:

(a) an inert core;

(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and

(c) a modified enteric coating disposed over the first layer, said modified enteric coating comprising an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient once the dosage form is exposed to a media of pH less than 5.5 and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more. Preferably, the pharmaceutically active ingredients present in said modified release pharmaceutical compositions are amphetamine base salts. More preferably, the amphetamine salts are selected from the group consisting of: amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.

According to a further aspect of the present invention, there is provided a modified release pharmaceutical composition which provides dual type release of the active ingredients, including: - a continuous release of the pharmaceutically active ingredient at a pH of less than 5.5, and

- a pulsatile release of the pharmaceutically active ingredient at pH of 6.0 or more. In a preferred embodiment of the present invention, the dual type of release of said modified release pharmaceutical composition is provided from a single type of pellet containing one or more active ingredients.

According to yet a further aspect of the present invention, there is provided a modified release pharmaceutical composition comprising pellets containing one or more active ingredients, the pellets comprising: an inert core; a first layer disposed over the inert core and a modified enteric coating disposed over the drug layered pellet, wherein said composition provides: a continuous release of the pharmaceutically active ingredient at a pH of less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at a pH of 6.0 or more, and has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours of administration as measured by USP Type II Apparatus (sinkers), with 750 ml of 0.08 N HCI for 2hrs, and then 200ml of buffer concentrate to adjust the solution to pH 6.0 for the next two hours, at 37°C, at a paddle speed of 50 rpm. According to a further aspect of the present invention, there is provided a modified release pharmaceutical composition with dual type of release from a single type of pellets containing one or more active ingredients, wherein the pellets comprise: an inert core; a first layer disposed over the inert core; and a modified enteric coating disposed over the drug layered pellet, wherein said modified enteric coating comprises an enteric polymer, a channeling agent and at least one pharmaceutically acceptable excipient.

Preferably, the modified enteric coating comprises an enteric polymer selected from the group consisting of: amminoalkyl methacrylate copolymers, methacrylate copolymers, and a combination thereof. More preferably, the enteric polymer is Eudragit L30D 55 ^® .

Also, preferably the channeling agent of the modified enteric coating is selected from the group consisting of: hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof. More preferably, the channeling agent is mannitol.

Preferably, one or more pharmaceutically acceptable excipients are selected from the group consisting of: binders, plasticizers, lubricants, disintegrants, diluents, glidants, anti-adherents and acidifying agents. More preferably, the plasticizer is triethyl citrate.

More preferable, the modified release pharmaceutical composition comprising pellets containing one or more active ingredients, which comprises: about 50 % w/w to about 90 % w/w of an inert core, about 2 % w/w to about 15 % w/w of a pharmaceutically active ingredient, about 1.0 % w/w to about 12.0 % w/w of an enteric polymer, about 0.1 % w/w to about 3.0 % w/w of a channeling agent, about 0.1 %w/w to about 3 % w/w of a hydrophilic binder, about 0.1 % w/w to about 3.0 % w/w of Plasacryl®, about 0.1 % w/w to about 2.0 % w/w of a plasticizer, and optionally a colorant Opadry® beige, all based on the total weight of the modified release pharmaceutical composition.

According to another aspect of the present invention, there is provided a modified release pharmaceutical composition comprising pellets containing one or more active ingredients. The pellets comprise: an inert core; a first layer disposed over the inert core; said first layer comprising at least one pharmaceutically active ingredient and at least one hydrophilic binder; a protective coating disposed over the drug layered core, said coating comprises a hydrophilic polymer and at least one pharmaceutically acceptable excipient; and a modified enteric coating disposed over the protective coating, said modified enteric coating comprising an enteric polymer, a channeling agent, and at least one pharmaceutically acceptable excipient, wherein said composition provides continuous release of the active ingredient at pH less than 5.5, and pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.

Preferably, the pellet further comprises a protective coating disposed over the first layer, in between the first layer and the modified enteric coating.

Also, preferably the hydrophilic polymer is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof. More preferably, the hydrophilic polymer of the protective coating is hypromellose and one of pharmaceutically acceptable excipients is colloidal silicon dioxide. According to a further aspect of the present invention, there is provided a modified release pharmaceutical composition comprising pellets containing one or more active ingredients and at least one pharmaceutically acceptable excipient, wherein said composition has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours of administration as measured by USP Type II Apparatus (sinkers), with 750 ml of 0.08 N HCI for 2 hours and then 200ml of buffer concentrate added to adjust the solution to pH 6.0 for the next 2 hours, at 37°C, at a paddle speed of 50 rpm.

Preferably, the modified release pharmaceutical composition comprises pellets containing one or more active ingredients, wherein the pellets comprise: about 50 % w/w to about 90 % w/w of an inert core, about 2 % w/w to about 15 % w/w of a pharmaceutically active ingredient, about 1.0 % w/w to about 12.0 % w/w of an enteric polymer, about 0.1 % w/w to about 3.0 % w/w of a channeling agent, about 0.1 % w/w to about 3 %w/w of a hydrophilic binder, about 1.0 % w/w to about 8.0 % w/w of a hydrophilic polymer, about 0.1 % w/w to about 2.0 % w/w of an anti-adherent, about 0.1 % w/w to about 3.0 % w/w of Plasacryl®, and about 0.1 % w/w to about 2.0 % w/w of a plasticizer, all based on the total weight of the modified release pharmaceutical composition.

Preferably, said pharmaceutical composition has an in vitro dissolution profile:

- about 10% to about 40% of the pharmaceutically active ingredient is released after 60 min;

- about 40% to about 50% of the pharmaceutically active ingredient is released after 120 min;

- about 80% to about 95% of the pharmaceutically active ingredient is released after 180 min; and

- about 100% of the pharmaceutically active ingredient is released after 240 min, as measured by Apparatus USP Type II (sinkers), with 750 ml of 0.08 N HCI for two hours and then 200ml of buffer concentrate added to the solution to adjust the pH to pH 6.0 for the next two hours, at a paddle speed of 50rpm.

Another aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients and at least one pharmaceutically acceptable excipient, wherein the in vitro dissolution profile of said composition provides at least 95% of the active ingredient dissolved within 4 hours, which is substantially the same as provided by an equivalent dose of Adderal ® XR, as measured by USP Type II Apparatus (sinkers), with 750 ml of 0.08 N HCI for two hours and then 200ml of buffer concentrate added to adjust the solution to pH 6.0 for the next two hours, at 37°C, at a paddle speed of 50 rpm.

In a further aspect of the present invention there is provided a modified release pharmaceutical composition comprising pellets containing one or more active ingredients and at least one pharmaceutically acceptable excipient, wherein the modified enteric coating allows the active ingredient to be released in such a way that less than 50% of the active ingredient is released in the stomach and substantially the same amount of the remaining active ingredient is released in the intestine. Preferable, the pulsatile release provides a release of amphetamine salts from about 2 hours to about 4 hours after administration.

According to a further aspect of the present invention, there is provided a method of manufacturing a modified release pharmaceutical composition, wherein the method comprises the following steps:

1) Drug layering:

(a) loading a sugar spheres or optionally seal coated pellets in a coating equipment;

(b) dissolving the active ingredient;

(c) mixing the active ingredient with a hydrophilic binder and at least one pharmaceutically acceptable excipient;

(d) spraying solution comprising the active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the sugar spheres or seal coated pellets to obtain a drug layered pellet;

2) Protective coating:

(e) dissolving a hydrophilic polymer and at least one pharmaceutically acceptable excipient;

(f) loading the drug layered pellets in a fluid bed processor;

(g) coating drug layered pellets with solution of step (e) to obtain sub-coated pellets;

3) Modified enteric coating:

(h) dissolving a channeling agent;

(i) preparing a dispersion solution; adding enteric polymer to solution of step (h); (j) adding an enteric polymer and at least one pharmaceutically acceptable excipient to solution of step (i);

(k) loading sub-coated pellets in a fluid bed processor;

(I) applying a solution of step (j) onto the sub-coated pellets of step (2) to obtain modified enteric coated pellets; and ) Optionally color coating:

(m) preparing a dispersion solution of Opadry beige; (n) loading enteric coated pellets from step (3) in a fluid bed processor; and (o) spraying color solution onto the enteric coated pellets to obtain a color coated pellets.

Preferably, the layers were applied as a solution/dispersion of coating ingredients. The modified release pharmaceutical composition preferably is in the form of a capsule.

The present invention is directed to be used in the treatment or prevention of narcolepsy and Attention-Deficit/Hyperactivity Disorder (ADHD). BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution profile for the modified release composition prepared according to Example 1 as compared to Adderall XR ^® . FIG. 2 shows the dissolution profile for the modified release composition prepared according to Example 2 as compared to Adderall XR ^® .

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an orally administrable modified release pharmaceutical composition comprising pellets containing one or more active ingredients, wherein the pellets comprise an inert core, a first layer disposed over the inert core, and a modified enteric coating disposed over the first layer. The composition provides:

- continuous release of the pharmaceutically active ingredient at a pH of less than 5.5, and

- pulsatile release of the pharmaceutically active ingredient at a pH of 6.0 or more.

More particularly, the present invention provides a modified release pharmaceutical composition comprising pellets containing one or more active ingredients, said pellets comprising:

(a) an inert core; (b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and

(c) a modified enteric coating disposed over the first layer, said modified enteric coating comprising an enteric polymer and a channeling agent,

wherein said composition provides: a continuous release of the pharmaceutically active ingredient once the dosage form is exposed to a media of pH less than 5.5 and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.

A controlled release pharmaceutical composition means a pharmaceutical composition including at least one active pharmaceutical ingredient which is formulated with at least one pharmaceutically acceptable film forming polymer and optionally with at least one pharmaceutically acceptable excipient, where the pharmaceutical composition shows a pH-dependent or a pH-independent reproducible release profile. The term "controlled release pharmaceutical composition", as referred to herein, is defined to mean oral pharmaceutical compositions which, when administered, releases the active ingredient at a relatively constant rate and provide plasma concentrations of the active ingredient that remain substantially invariant over time within the therapeutic range of the active ingredient over a 24-hour period and encompasses the terms "prolonged release", "extended release", "delayed release" and "sustained release" compositions.

The term "modified release" as referred to herein, means that the release of the drug from the tablet has been modified in some manner (including "controlled release" as discussed above). Usually this is to slow the release of the drug so that the medicine doesn't have to be taken too often and therefore improves patient compliance. The other benefit from modifying release is that the drug release is controlled and there are smaller peaks and troughs in blood levels therefore reducing the chance of peak effects and increasing the likelihood of therapeutic effectiveness for longer periods of time.

The term "continuous release" means a drug formulation that is designed to deliver a dose of a medication over an extended period. The most common device for this purpose is a soft, soluble capsule containing minute pellets of the drug for release at different rates in the gastrointestinal tract, depending on the thickness and nature of the oil, fat, wax, or resin coating on the pellets. Another system consists of a porous plastic carrier impregnated with the drug and a surfactant to facilitate the entry of gastrointestinal fluids that slowly leach out of the drug. Ion exchange resins that bind to drugs and liquids containing suspensions of slow-release drug granules are also used to provide medication over an extended period.

The term "pulsatile release" means that a drug is delivered in one or more doses that fluctuate between a maximum and minimum dose over predetermined time intervals. This can be represented by a dose release profile having one or more distinct peaks or valleys. However, two or more pulsed releases may produce an overlapping, overall, or composite release profile that appears or effectively is constant. The need for pulsatile release may include the desire to avoid drug degradation in the stomach or first pass metabolism. Pulsatile release can be achieved via coating of multiparticulates with pH dependent and/or barrier membrane coating systems, followed by blending of the multiparticulates to achieve desired release profiles.

The terms "immediate release" and "delayed release" refer to the onset of release in relationship to administration of the drug. "Immediate" means that the release of drug begins very soon, within a relatively short time after administration, e.g. a few minutes or less. "Delayed" means that the release of drug is postponed, and begins or is triggered some period of time after administration (e.g., the lag time), typically a relatively long period of time, e.g. more than one hour.

The terms "pellet" refer to a discrete component of a dosage form. For example, a capsule shell is filled with a plurality of beads or pellets. As used herein, pellet means any discrete component of a dosage form.

The drug delivery system of the present invention typically comprises an inert core (e.g., core seed or matrix), which may or may not be loaded with drug, and one or more coating layers comprising drug, and/or comprising a layer have release characteristics which control the onset and release characteristics of the drug.

The inert core comprises at least one pharmaceutically acceptable excipient selected from the group consisting of: inert water soluble, inert water insoluble, swellable material and mixtures thereof. Preferably, the inert core is made of sugar spheres and more preferably the pellet further comprises a seal coat disposed between the inert core and the first layer. Preferably the first layer disposed over the inert core comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder, which is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof. More preferably, the hydrophilic binder is hypromellose (i.e. hydroxypropylmethyl cellulose).

The terms "drug", "medicinal ingredient", "active ingredient", "pharmaceutically active ingredient" and "active agent" refers to an active pharmaceutical ingredients (API) which are active chemicals used in the manufacturing of drugs. The active agent can be a therapeutic, a prophylactic, or a diagnostic agent.

According to the present invention the pharmaceutically active ingredient is selected from the group consisting of amphetamine salts, wherein the amphetamine salts are preferably selected from the group consisting of: amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.

In addition to the pharmaceutically active ingredient(s), the pharmaceutical composition according to the present invention contains at least one enteric polymer, at least one channeling agent, at least one hydrophilic polymer and at least one pharmaceutically acceptable excipient.

A protective coating layer may be disposed on the inert core before and/or after coating of the active agent. The inert core may be coated with a protective layer comprising a second binder (sub-coat) and/or an active agent-coated core may be coated with a protective layer comprising a third binder (outer-coat), by coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. The pellet further comprises a seal coat disposed between the inert core and the first layer.

Enteric polymers that may be used in the oral modified release pharmaceutical composition according to the present invention include, but are not limited to, ammonialkyl methacrylate copolymers, methacrylate copolymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, polymethacrylates containing carboxyl groups, amylose acetate phthalate, styrene maleic acid copolymer, and cellulose acetate succinate and a combination thereof. Examples of commercially available enteric material are available under the trade names EUDRAGIT ^® . Preferably, the enteric polymer is EUDRAGIT® L 30D-55 (methacrylic acid/ethyl acrylate copolymer), but similar enteric polymer may also be employed.

The present invention includes pharmaceutical composition producing a modified release having channels. The channels act as controlled transmission passages through the polymer. The channeling agent is selected from the group consisting, but not limited to: hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof. The preferred channeling agent is mannitol. Hydrophilic polymers that may be used in the oral modified release pharmaceutical composition are selected from the group, but are not limited to, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (i.e. hypromellose), carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, and combinations thereof.

In addition to the active ingredients and listed polymers the pharmaceutical composition of the present invention contains the pharmaceutically acceptable excipients added to the composition for a variety of purposes. One or more pharmaceutically acceptable excipients may be present in the composition of the present invention, including diluents, binders, lubricants, disintegrants, glidants, and acidifying agents. As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.

The hydrophilic binder is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose (i.e., hypromellose), carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, and a combination thereof. The preferred hydrophilic binder is hypromellose.

According to the present invention the plasticizer of the modified enteric coating is selected from the group consisting of: diethylphthalate, dibutylphthalate, dibutylsebacate, tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols, glyceryl monostearate, and a combination thereof. The preferred plasticizer is triethyl citrate.

Oral dosage forms which may be employed with the present invention include pellets in a capsule or in any other suitable solid form. During drug development, in vitro dissolution testing is an important tool in the evaluation of the formulations. Dissolution testing is also utilized to define the biopharmaceutical characteristics and to identify possible risks such as potential food effects on bioavailability or interaction with other drugs. The simulation of specific gastrointestinal conditions which may lead to potential therapeutic failure or adverse events seems to be another point of interest during drug development. At this stage various models and test conditions for in vitro dissolution studies are applied to learn about the biopharmaceutical characteristics of early formulations and about the discriminating power of the test system. Drug release and drug release profiles are measures or representations of the manner and timing by which a formulation releases or delivers active ingredients (drug) to a receiving environment (e.g. the stomach, intestines, etc.) upon administration. Various methods are known for evaluating drug release and producing release profiles, including in vitro tests which model the in vivo behavior of a formulation. These include USP dissolution testing for immediate release and controlled release solid dosage forms.

According to another aspect of the present invention, the method of manufacturing a modified release pharmaceutical composition comprising a single type of pellets containing one or more active ingredients which comprise: an inert core; a first layer; and a modified enteric coating; wherein said method comprises the following steps:

1 ) Drug layering:

a) loading sugar spheres or, optionally, seal coated pellets in a coating equipment; b) dissolving the active ingredient;

c) mixing the active ingredient with a hydrophilic binder and at least one pharmaceutically acceptable excipient;

d) spraying solution comprising the active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the sugar spheres or seal coated pellets to obtain a drug layered pellet;

2) Protective coating:

e) dissolving a hydrophilic polymer and at least one pharmaceutically acceptable excipient;

f) loading the drug layered pellets in a fluid bed processor;

g) coating drug layered pellets with solution of step (e) to obtain sub-coated pellets; 3) Modified enteric coating:

h) dissolving a channeling agent;

i) preparing a dispersion solution; adding enteric polymer to solution of step (h); j) adding an enteric polymer and at least one pharmaceutically acceptable excipient to solution of step (i);

k) loading sub-coated pellets in a fluid bed processor;

I) applying a solution of step (j) onto the sub-coated pellets of step (2) to obtain modified enteric coated pellets; and optionally

m) filing obtained pellets into a suitable sized capsule. In a preferred modified release pharmaceutical composition according to the present invention, the pellets comprise: from about 50 % w/w to about 90 % w/w of an inert core; about 2.0 % w/w to about 15.0 % w/w of each pharmaceutically active amphetamine salt; about 1 % w/w to about 12 % w/w of an enteric polymer; about 0.1 % w/w to about 3.0 % w/w of a channeling agent; about 0.1 % w/w to about 3 % w/w of a hydrophilic binder; about 0.1 % w/w to about 3.0 % w/w of Plasacryl®; about 0.1 % w/w to about 2.0 % w/w of a plasticizer; and optionally about 0.1 % w/w to about 5.0 % w/w of Opadry® beige. The w/w percentage is based on the total weight of the modified release pharmaceutical composition.

In a preferred embodiment of the present invention the modified release pharmaceutical composition exhibits the following dissolution profile:

- about 10% to about 40% of the mixed amphetamine salts is released after 60 min; - about 40% to about 50% of the mixed amphetamine salts is released after 120 min;

- about 80% to about 95% of the mixed amphetamine salts is released after 180 min;

- about 100% of the mixed amphetamine salts is released after 240 min, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0.08 N HCI for two hours and then 200ml of buffer concentrate is added to the solution to increase the pH to pH 6.0, at a paddle speed of 50 rpm.

A preferred modified release pharmaceutical composition of the present invention provides an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours, which is substantially the same as provided by an equivalent dose of Adderal ® XR, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0.08 N HCI for two hours and then 200ml of buffer concentrate added to make the solution have pH 6.0 for the next two hours, at 37°C, at a paddle speed of 50 rpm as illustrated in FIG. 1 and described below. Another illustrated embodiment is a modified release pharmaceutical composition having an in vitro dissolution profile of at least 97% of the active ingredient dissolved within 4 hours, which is substantially the same as provided by an equivalent dose of Adderal ® XR, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0.08 N HCI for two and then 200ml of buffer concentrate added to increase the pH of the solution to pH 6.0 for the next two hours, at 37°C, at a paddle speed of 50 rpm as illustrated in FIG. 2 and described below.

The following Examples illustrate the preferred embodiment but not limiting the present invention.

Example 1

Modified Release Pharmaceutical Composition of Amphetamine Mixed Salts

Example 1 includes the following amphetamine salts: amphetamine sulphate, dextroamphetamine sulfate, dextroamphetamine saccharate and amphetamine aspartate. These salts were dissolved in purified water to make 15.7% w/w solution (amphetamine salts mixture). The modified release composition comprised about 2.96 % w/w of each amphetamine salt.

The binder used in this example was h promellose. The modified release composition comprised about 2.36 % w/w of the binder.

The mixture comprising the pharmaceutically active amphetamine salts and the binder was sprayed over the sugar spheres or seal coated inert core in an amount sufficient to provide amphetamine drug layered pellets.

The required quantity of hypromellose was dissolved in purified water and to this solution colloidal silicon dioxide was dispersed to make 6.8% w/w protective coating solution. The modified release composition comprised about 7.9 %w/w of the hypromellose and about 1.2 % w/w of the colloidal silicon dioxide.

The amphetamine drug layered pellets were loaded into a bottom spray fluid bed processor. The protective coating solution was sprayed on the drug layered pellets to obtain the amphetamine sub-coated pellets.

The required quantity of mannitol was dissolved in purified water. The modified release composition comprises about 2.20 % w/w of mannitol. To this solution the Plasacryl® was dispersed and stirred for 45 minutes. The modified release composition comprised about 2.20 % w/w of Plasacryl®. Further to said dispersion the Eudragit L30D 55® was added. The modified release composition comprised about 11.1 % w/w of Eudragit L30D 55®. Further the triethyl citrate was added to make 15% w/w dispersion for the modified enteric coating. The modified release composition comprised about 1.1 %w/w of triethyl citrate. The modified enteric coating dispersion was stirred for 30 minutes before using. The amphetamine sub-coated pellets were loaded into a bottom spray fluid bed processor. The modified enteric coating dispersion was sprayed over the amphetamine drug layered pellets to obtain modified enteric coated pellets.

The modified enteric coated pellets were further incorporated into a capsule.

The formulation and manufacturing steps of Example 1 are set out in Table 1.

Table 1

FORMULATION AND MANUFACTURING OF AMPHETAMINE MIXED SALTS

I. Drug layering.

II. Sub Coating/ Protective Coating No. Ingredients % w/w Function

1. Drug layered pellets 90.9 Substrate for coating

Hypromellose 7.90 Protective coating

2.

polymer

3. Colloidal silicon dioxide 1.20 Anti adherent

Purified water Quantity sufficient Dispersing agent

to make 6.8%

4.

w/w

TOTAL 100.0

III. Modified enteric coatin

The in vitro dissolution rate of pharmaceutical composition obtained from Example 1 was subsequently tested, measured by Apparatus (USP Type II with sinkers), using the following parameters:

Media: 750 ml of 0.08N HCI for 2 hours and

200 ml of buffer concentrate added to make pH 6.0 for the next two hours (i.e. time points 2 to 4 hours);

Speed: 50 RPM

The dissolution results are set out in Table 2. Table 2

Dissolution rate of the amphetamine mixed salts pharmaceutical composition of Example 1.

Table 2 shows the dissolution rate of the pharmaceutical composition prepared according to Example 1 compared to Adderall XR® at several time points.

Example 2

Modified Release Pharmaceutical Composition of Amphetamine Mixed Salts

Example 2 includes the following amphetamine salts: amphetamine sulphate, dextroamphetamine sulfate, dextroamphetamine saccharate and amphetamine aspartate. These salts were dissolved in purified water to make 10.0% w/w solution (amphetamine salts mixture). The modified release composition comprised about 2.85 % w/w of each pharmaceutically active amphetamine salt.

The binder used in this example was hypromellose. The modified release composition comprised about 1.71 % w/w of the binder.

The mixture comprising the pharmaceutically active amphetamine salts and the binder was sprayed over the sugar spheres or seal coated inert core in an amount sufficient to provide an amphetamine drug layered pellets.

The required quantity of hypromellose was dissolved in purified water and to this solution colloidal silicon dioxide was dispersed to make 6.3% w/w protective coating solution. The modified release composition comprised about 7.9 %w/w of hypromellose and about 1.2% w/w of the colloidal silicon dioxide. The amphetamine drug layered pellets were loaded into a bottom spray fluid bed processor. The protective coating solution was sprayed on the drug layered pellets to obtain the amphetamine sub-coated pellets. The required quantity of mannitol was dissolved in purified water. The modified release composition comprises about 1.18 % w/w of mannitol. To this solution the Plasacryl®T20 was dispersed and stirred for 45 minutes. The modified release composition comprised about 2.38 % w/w of Plasacryl®T20. Further to said dispersion the Eudragit L30D 55® was added. The modified release composition comprised about 11.9 % w/w of Eudragit L30D 55®.

Further the triethyl citrate was added to make 15% w/w dispersion for the modified enteric coating. The modified release composition comprised about 1.18 % w/w of triethyl citrate. The modified enteric coating dispersion was stirred for 30 minutes before using. The amphetamine sub-coated pellets were loaded into a bottom spray fluid bed processor. The modified enteric coating dispersion was sprayed over the amphetamine drug layered pellets to obtain modified enteric coated pellets.

Opadry® beige was dispersed in purified water to obtain a 5.0% w/w dispersion. The color dispersion was stirred for 30 minutes before using. The modified release composition comprised about 4.76 % w/w of Opadry® beige. The modified enteric coating dispersion was stirred for 30 minutes before using. The amphetamine enteric coated pellets were loaded into a bottom spray fluid bed processor. The color coating dispersion was sprayed over the amphetamine drug layered pellets to obtain modified colored enteric coated pellets.

The modified enteric coated colored pellets were further encapsulated into a suitable size hard gelatin capsules to obtain 30 mg of mixed amphetamine salts per capsule. The formulation and manufacturing steps of Example 2 is set out in Table 3. Table 3

FORMULATION AND MANUFACTURING OF AMPHETAMINE MIXED SALTS

I. Drug layering

III. Modified enteric coatin

IV. Color Coating

The in vitro dissolution rate of the pharmaceutical composition obtained from Example 2 was subsequently tested, measured by Apparatus (USP Type II with sinkers), using the following parameters:

Media: 750 ml of 0.08N HCI for 2 hours and

200 ml of buffer concentrate added to make pH 6.0 for the next two hours (i. time points 2 to 4 hours);

Speed: 50 RPM

The dissolution results are set out in Table 4. Table 4

Dissolution rate of the amphetamine mixed salts pharmaceutical composition of Example

Table 4 shows the dissolution rate of the pharmaceutical composition of the present invention compared to Adderall XR® at several time points.