Background of the Invention

[0001] The present invention relates to an improved pharmaceutical dosage form of duloxetine and its use as a medicament.

[0002] Duloxetine is a pharmaceutically active compound useful as an antidepressant. See, for example, Wong et al., Neuropsychopharmacology, 8, 23-33 (1993), where the compound is named by its research number LY248686.

[0003] Duloxetine is (+)-N-methyl-3-(l-naphthalenyloxy)-2-thiophenepropanamine, and is commonly used in pharmaceutical compositions as its hydrochloride salt, hi this document, the word "duloxetine" will refer to the specific enantiomer just named.

[0004] The marketed pharmaceutical dosage form of duloxetine sold in the US by EH Lilly &Co. under the brand name Cymbalta ^® is a capsule comprising a plurality of enteric coated pellets containing duloxetine hydrochloride.

[0005] Enteric pharmaceutical formulations are manufactured in such a way that the product passes unchanged through the stomach of the patient, but dissolves and releases the active ingredient after it leaves the stomach and enters the small intestine. Such formulations conventionally are in tablet or pellet form, where the active ingredient is in the inner part of the tablet or pellet and is enclosed in a film or envelope, i.e., the "enteric coating", which is insoluble in acid environments, such as the stomach, but is soluble in near-neutral environments such as the small intestine. [0006] The need to formulate duloxetine in an enteric formulation is due to the poor stability characteristics of duloxetine in acidic solutions. The duloxetine molecule decomposes easily in an acidic environment upon formation of a highly toxic naphthol moiety.

[0007] When a pharmaceutical dosage form has been orally taken and before it reaches the intestines it normally resides in the stomach for a period of 0.2-2 hours. According to "Innovations in drug delivery" (ISBN 90-73520-06-1) by CG. Wilson and N. Washington, pg 42-56, typically the resting gastric pH of a normal healthy subject is around 1.8. Meals markedly alter the pH which can increase to 3-5 after eating, where after the resting gastric pH is obtained again. As can be seen in the same chapter gastric emptying of pellets from the stomach to the intestines can take up to 3 hours for pellets and up to 9 hours for large non-disintegrating tablets, depending on the content of the stomach.

[0008] The EP 693282 (and corresponding US 5,508,276) teaches that an enteric coated pellet formulation of duloxetine was more desirable than an enteric coated tablet, based on bioavailability studies which showed that more consistent plasma profiles were obtained after pellet administration.

[0009] Furthermore, the EP 693282 teaches that certain difficulties arose in preparing conventional enteric coated formulations. Most importantly, duloxetine was found to react with many enteric coatings forming a slowly- or even insoluble coating in some cases . Because of this unexpected cross-reactivity, formulations using an enteric coated pellet were found to have a disadvantageous drug-release profile and low bioavailability.

[0010] Further, it was found to be particularly difficult to prepare an enteric formulation with higher levels of drug loading which did not allow some release of duloxetine in the acid environment, thus creating a danger that some drug would be released in the stomach, contrary to the desired safe method of administration.

[0011] As a solution of the above problems, the EP 693282 offers an enteric coated pellet comprising (a) a core consisting of duloxetine [hydrochloride] and a pharmaceutically acceptable excipient; (b) an optional separating layer; (c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; and (d) an optional finishing layer.

[0012] The HMPCAS polymer was selected, in part, for use in the enteric coating because of its small number of carboxylic acid groups per unit weight or repeating unit of the polymer. The HPMCAS has been defined as containing not less than 4% and not more than 28% of succinoyl groups, which are the only free carboxylic groups in the compound. It is commercially available (under brand name AQO AT™ made by Shin-Etsu) in two particle size grades and three molecular weight ranges.

[0013] In the case of coating HPMCAS from a water-based system, the dissolution of the polymer in the aqueous solvent can be obtained by neutralizing the polymer, preferably with ammonia. For example, operation with from about 25% to about 100% neutralization has been preferred in the above document. The coating process is, however, somewhat difficult.

[0014] In an article of P.J.Jansen et al. ( J. Pharm. Sci., vol.87 (1) p.81-85, (1998)) it is explained that duloxetine reacts with polymer degradation products or residual free acids in hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) in dosage formulations to form succinamide and phthalamide duloxetine derivatives, respectively, as impurities. [0015] It has been proposed that polymer-bound succinic and phthalic substituents can be cleaved from the polymer resulting in the formation of either the corresponding free acids or the anhydrides. These can react with duloxetine to form the succinamide and phthalamide impurities.

[0016] It has been postulated that the reaction between duloxetine and the enteric coating material is enabled by the migration of either (1) the free acid or (2) the parent drug through the formulation. The formation of impurities was minimized by increasing the thickness of the physical barrier (subcoat) separating the enteric coating from the drug.

[0017] It has been furthermore stated that the succinamide and phthalamide impurities were actually detected in enteric coated products upon storage in pharmaceutically relevant storage conditions.

[0018] The danger of forming the succinamide and phthalamide impurities is pharmaceutically relevant and forms, in general, a serious disadvantage of the HMPCAS coating.

[0019] In practice, the use of the HPMCAS as a coating material also faces several technological problems. As seen from the Examples in EP 693282, the coating by HPMCAS must be performed upon cooling and the HMPCAS must be neutralized by ammonia to provide an aqueous solution. In addition, the use of a special dual channel nozzle is suggested to avoid clogging (gelation) of the HPMCAS in the tubing of the coater.

[0020] WO 2005/108386 describes duloxetine free base and novel polymorphic forms thereof. Also some pellet formulations containing duloxetine base or duloxetine HCl are described in examples 6-9. The disclosed formulations all have a seal coating between the duloxetine containing layer and an enteric coating layer. The enteric coating shown in these examples comprises approximately 7-14 wt% based on the total weight of the bead/pellet and contains the polymer Eudragit L 100-55. However, these formulations do not exhibit the desired release rate of duloxetine. Similar formulations have been disclosed in WO 2007/ 139886.

[0021] It would be advantageous to find a duloxetine dosage form with an effective enteric coating that avoided or minimized any of the above-noted disadvantages.

Summary of the Invention.

[0022] The present invention relates to pharmaceutical dosage forms of duloxetine hydrochloride. A first aspect of the invention relates to a pharmaceutical dosage form comprising a plurality of pellets, wherein each pellet comprises: i) a water soluble pellet core with a diameter of 600-1000 micrometer; ii) a drug layer covering the core, comprising duloxetine or a pharmaceutically acceptable salt thereof, especially duloxetine hydrochloride, and a binder, which preferably is methyl cellulose, which layer typically constitutes 25-40 wt% of the total weight of the pellet; iii) a separating layer covering the drug layer, comprising a binder and a pore forming component, which layer typically constitutes 3-10 wt% of the total weight of the pellet; and iv) an enteric coating layer covering the separating layer, comprising hydroxypropylmethylcellulose acetate succinate polymer and/ or hydroxypropyl methylcellulose phthalate polymer, which layer typically constitutes 10-40 wt% of the total weight of the pellet, wherein the enteric coating layer composition has been preferably applied onto the separating layer by using a non-aqueous solvent.

It has been found that the mass of the enteric coat applied to the pharmaceutical dosage form of the invention and the coating technique using preferably a non-aqueous solvent are two important parameters that affect the dissolution rate of duloxetine in dissolution media of different pH. From pharmaceutical and safety reasons, two aspects are important:

1. low duloxetine release and low naphtol origination in gastric fluid

2. complete and immediate release of duloxetine in intestinal fluid

In combination of the above parameters with the proper composition of the core , and/or of the drug layer, and/or of the separating layer, a medicament may be made , which exhibits the therapeutically desirable release rate of the drug.

[0023] A second aspect of the invention relates to the use of the pharmaceutical dosage form defined above as a medicament, preferably for the treatment of stress urinary incontinence, major depressive disorder, general anxiety disorder or neuropathic pain.

[0024] Another aspect of the invention relates to a process, which comprises: coating a pellet core having a diameter of 600-1000 micrometer, with a drug layer, comprising duloxetine or a pharmaceutical acceptable salt thereof and a binder; coating said drug layer with a separating layer, comprising a binder and a pore forming component, wherein said separating layer constitutes 3-10 wt% of the total weight of the pellet; and coating said separating layer with an enteric coating layer, comprising hydroxypropylmethylcellulose acetate succinate and/ or hydroxypropyl methylcellulose phthalate; wherein said enteric coating layer constitutes 10-40 wt% of the total weight of the pellet and , preferably, it is coated as a solution in a non-aqueous solvent onto said separating layer.

Detailed Description of the Invention. [0025] The present invention relates to pharmaceutical formulations of duloxetine having a defined enteric coating. Unless otherwise stated the expressions of percentage will be in weight percentage.

[0026] The pharmaceutical dosage forms of the invention comprise a plurality of pellets wherein each pellet comprises a water soluble pellet core, said core being successively layered by a drug layer, a separating layer and an enteric coating layer. Additional layers are possible, such as a finish layer over the enteric coating.

[0027] The pellet core of the formulation of the invention is a spherical core (spherical bead) that may be made by pelletizing of pharmaceutically acceptable water soluble materials such as sugars or starches or mixtures thereof in a manner know by a skilled person in the art. Preferably the pellet core may be sugar spheres on which the drug layer of duloxetine hydrochloride may be applied on a manner known by a skilled person in the art. The diameter of the spheres is typically 600-1000 micrometers, preferably the diameter of the spheres is 600-710 or 710-850 micrometers for to obtain the optimal dissolution profile. Typically the pellet core constitutes 30-50 wt% of the total weight of the pellet.

[0028] The pellet core is surrounded by a drug layer. The drug layer comprises duloxetine hydrochloride or another water soluble salt of duloxetine, together with a pharmaceutically acceptable binder.

[0029] Typically the binder is a hydrophilic polymer and most preferably it is methyl cellulose . Alternately or in addition to, also other polymers such as PVP, starch, hydrophilic cellulose derivatives (such as HPMC) , and hydrophilic acrylate or methacrylate polymers may be used. The drug layer typically constitutes 25-40 wt% of the total weight of the pellet, wherein the relative amount of the hydrophilic polymer, particularly methyl cellulose, may be 20-40% of the drug layer.

[0030] The pellet core comprising the drug layer is surrounded by a separating layer that separates the drug layer from the enteric coating layer. The functions of the separating layer are to provide a smooth base for the application of the enteric coating layer, to prolong the pellet's resistance to the acidic conditions, to improve the drug stability by inhibiting any interaction between the drug and the enteric polymer in the enteric layer, and to improve stability by protecting the drug from light exposure.

[0031] It is advantageous that the separating layer constitutes 3-10 wt% of the total pellet weight.

[0032] Typically such separating layer comprises a binder and a pore forming agent. Preferably the binder has gel-forming properties after contact with water. A useful binder is, for instance, HPMC such as the commercially available Methocel E5 or a methyl cellulose. Generally the binder constitutes 40-60 wt% of the total weight of the separating layer.

[0033] The pore forming agent is a component which is well soluble in water. Preferably such a pore forming agent is a sugar such as sucrose or a polyvinylpyrrolidone and preferably constitutes 10-40 wt% of the total weight of the separating layer. To counteract the tackiness of such substances, an inert anti-tacking agent may be added to the separating layer, e.g. talc.

[0034] The pellet comprising the core, drug layer and separating layer is surrounded with an enteric coating layer. The function of the enteric coating layer is to obtain a release of the active ingredient in the intestines instead of the stomach. [0035] The enteric coating layer in the pellets of the present invention comprises the acid resistant hydroxypropylmethylcellulose acetate succinate (HPMCAS) and/ or hydroxypropyl methylcellulose phthalate (HPMCP). Generally these pharmaceutically acceptable acid resistant polymers constitute, in total, 40-75 wt% of the total weight of the enteric coating layer.

[0036] Preferably, a plasticizing agent may be added to the enteric coating layer composition prior to the coating such as for instance a triethylcitrate or dibutylsebacate in an amount as known by a skilled person in the art.

[0037] Furthermore, the enteric coating layer composition may comprise inert anti- tacking agent(s), e.g. talc, and/or an antifoaming agent.

[0038] The coating composition may be , in general, applied on the preceded layer in an aqueous or in a non-aqueous solvent. In an advantageous , but not limiting aspect, the enteric coat composition is coated onto the separating layer surface by spraying thereof in a solution or suspension in a non-aqueous solvent. Suitable non-aqueous solvent is ,e.g., an C1-C4 aliphatic alcohol, e.g. isopropanol or ethanol . Water may be added to the non-aqueous solvent in certain extent, e.g. in an amount of less than 50% of the total volume of the solvent, whereby still the solvent should be understood as "non-aqueous" . It has been found that the coating technique/conditions affects the performance of the enteric coating layer, in respect to the overall release, and also to the amount of impurities that may be formed by a reaction of the coating polymer with the duloxetine. Accordingly, it is preferred that the enteric coating layer be one that was formed using a non-aqueous liquid in the coating process. Moreover, dissolving the polymer in the non-aqueous liquid to form a solution, as opposed to a suspension, is a further preferred technique. An enteric coating layer made by such a non-aqueous liquid can provide reduced lag time and improved total drug release, even though the liquid is removed from the pellet, and is thus a preferred enteric coating layer. Furthermore, no basic agent recommended in the prior art compositions is required in the composition of the enteric coating layer.

[0039] In the case of duloxetine, a strong (i.e. low permeable) enteric coating layer is of crucial importance as the duloxetine easily hydrolyses in an acidic environment upon releasing the toxic naphthol. Therefore, it is generally required for duloxetine-containing formulations that any release of the naphthol in the gastric phase of dissolution testing (2 hrs in 0.1 N HCl) be below 1%.

[0040] It has now been found that the relative mass of the HPMCAS / HPMCP enteric coating layer is of importance in determining the dissolution rate of duloxetine in intestinal fluid. From the administrative and therapy point of view, it is desired that at least 70% of duloxetine is released within 45 minutes in the intestinal fluid (which fluid may be simulated by in vitro tests in simulated intestinal fluid dissolution medium pH 6.8 as known from the Pharmacopeias), after prior contact with a stomach fluid (which fluid may be simulated by in vitro tests in 0.1 N HCl [for fasted state of stomach] or by a buffer pH 4.5 [for fed state of stomach]).

[0041] If the mass of the enteric coating of the pharmaceutical dosage form of the invention is too high, the release rate of the duloxetine in the (simulated) intestinal fluid is decreased.

[0042] When the mass of the enteric coating layer according to the invention is too low, the release in the stomach fluid is too high and a formation of the undesirable naphthol impurity is observed .

[0043] As a result, the proper amount of the enteric coating layer of the pellet of the invention comprising a HPMCAS / HPMCP polymer may be from about 10 to 40, and preferably it is from 12 to about 35 wt% of the total weight of the pellet. The weight percentages are intended to be calculated on a dry pellet basis.

[0044] Separately from the basic components disclosed above, the pellets of the present invention may also comprise a finishing layer. A finishing layer over the enteric layer is basically not necessary from the functional point of view, but it may be used particularly for to improve the elegance of the product and its handling, storage and machinability properties.

[0045] For example, a thin layer of a wax or a polymeric material such as hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like, in an amount such as from a few tenths of % up to about 3%, may be applied. The polymeric material may also carry a suspension of an opacifier, a bulking agent such as talc, or a coloring material, particularly an opaque finely divided color agent such as red or yellow iron oxide. Such a layer quickly dissolves away in the stomach, leaving the enteric layer to protect the duloxetine, but provides an added measure of pharmaceutical elegance and protection from mechanical damage to the product.

[0046] Finishing layers to be applied to the present product are of essentially the same types commonly used in pharmaceutical science to smooth, seal and color enteric products, and may be formulated and applied in the usual manners.

[0047] The pellets of the present invention are made by sequential coating of the respective , above specified, layers with the aid of a coating liquid followed by drying to remove the liquid. A typical process comprises coating a pellet core having a diameter of 600-1000 micrometer, with a drug layer, comprising duloxetine or a pharmaceutical acceptable salt thereof and a binder; coating the drug layer with a separating layer, comprising a binder and a pore forming component; and coating the separating layer with an enteric coating layer, comprising a pharmaceutically acceptable acid resistant HPMCAS and/or HPMCP polymer dissolved or suspended , preferably, in a non-aqueous liquid and more preferably as a solution in a nonaqueous solvent, typically in C1-C4 aliphatic alcohol. The amount of water in the non-aqueous liquid or solvent is typically less than 50%, more typically less than 25 %. The non-aqueous liquid or solvent, e.g., an alcohol or alcohol/water mixture, can provide a more advantageous enteric coating layer in terms of total release or lag time and formation of impurities.

[0048] The pellets can be filled into a capsule or compressed into a tablet to obtain a pharmaceutical dosage form comprising a plurality of pellets which contains an amount of 0.1- 100 mg of duloxetine calculated as the free base, per dosage form. Preferably the pharmaceutical dosage form is a capsule and contains 20, 30 or 60 mg duloxetine calculated as the free base.

[0049] The pharmaceutical dosage form comprising the plurality of pellets according to the invention desirably exhibits a dissolution release profile of duloxetine of at least 70 % within 45 minutes in simulated intestinal fluid (buffer pH 6.8) using USP (711), Apparatus 1 method at 100 rpm after having been contacted for 2 hours in simulated gastric fluid (0.1 N HCl) using USP <711>, Apparatus 1 method at 100 rpm.

[0050] The pharmaceutical dosage form with the plurality of pellets of the present invention also desirably exhibits a dissolution release profile of duloxetine of at least 70 % within 45 minutes in simulated intestinal fluid using USP <711>, Apparatus 1 method at 100 rpm after having been contacted for 3 hours in a buffer of pH 4.5 using USP (711), Apparatus 1 method at 100 rpm.

[0051] The dosage form of the present invention should have sufficient gastric resistance. During the dissolution test of the pharmaceutical dosage form in simulated gastric fluid under the above conditions, preferably less than 1% of the naphthol impurity is formed and released. More preferably less than 0.2% of naphthol is released and most preferably less than 0.1% of naphthol is released.

[0052] Furthermore, during the dissolution test of the pharmaceutical dosage form of the present invention in the buffer with a pH of 4.5 under the above conditions, less than 10% of duloxetine is generally released. Preferably less than 5% of duloxetine is released and most preferably less than 1% of duloxetine is released.

[0053] The buffer with a pH of 4.5 is understood by a person skilled in the art to be simulating a fed state of the stomach.

[0054] In conclusion, the dissolution release profile of the dosage form of the invention in the simulated intestinal fluid described above is maintained independently of the nature of the simulated gastric fluid media in which the dosage form was kept prior to the dissolution testing in the simulated intestinal fluid. The pharmaceutical dosage form of the invention thus has no food effect, i.e. the dissolution release profile of the pharmaceutical dosage form is independent if the stomach is fasted or fed. The dosage form of the invention has also sufficient gastric residence both in the fasted and in the fed state of stomach.

[0055] The composition and the dosage form of the invention may be used in any duloxetine-treatable disease. Typically the dosage form of the invention may be used for the treatment of stress urinary incontinence, major depressive disorder, general anxiety disorder or neuropathic pain.

[0056] The following examples illustrate the invention. Example 1 - organic HPMCAS coating Composition

Drug layer:

Methylcellulose was dispersed in purified water and allowed to hydrate overnight under stirring.

The coating fluid was made by dispersing duloxetine HCl in water, and subsequent addition of the methylcellulose dispersion.

Thereafter, sugar spheres were placed in Glatt GPCGl or Glatt GPCG2 fluid bed apparatus and coated by conventional bottom spray with Wurster insert at a product temperature of 40-45 ⁰ C.

Pellets were dried after coating for approximately 5 minutes in the fluid bed apparatus

Separating layer: Hydroxypropyl methylcellulose was dispersed in purified water and allowed to hydrate overnight under stirring. The coating fluid was made by adding sucrose, talc and the Hydroxypropyl methylcellulose dispersion to purified water under stirring. Thereafter, pellets were coated and dried as described above for the drug layer.

Enteric layer:

HPMCAS was gradually added to ethanol under stirring. Water was added under stirring (ratio ethanol-water 80:20). Stirring continued until a clear solution was obtained. Triethylcitrate and talc were added subsequently under stirring.

Thereafter, pellets were coated by conventional bottom spray with Wurster insert with a product temperature of 34-36°C. Pellets were dried after coating for approximately 5 minutes in the fluid bed apparatus and for 12 hours in a ventilating oven at 50 ⁰ C.

Testing conditions :

Dissolution test was performed in USP apparatus 1 (baskets) at 100 RPM with 1000 ml dissolution medium. The pellet formulations were submitted to dissolution testing in 0.1 N HCl (pH 1.0; simulated gastric fluid)) for 2 hours, followed by dissolution testing in phosphate buffer pH 6.8 USP (simulated intestinal fluid) for 1 hour.

Criteria of acceptability : Dissolution in simulated gastric fluid:

- duloxetine < 5% in 2 hours

- naphtol < 1% in 2 hours Dissolution in simulated intestinal fluid: - duloxetine > 70% in 45 minutes

Table 1 : Duloxetine and naphtol release after 2 hours in simulated gastric fluid.

Com osition

Drug layer and separating layer: Equal to Example 1.

Enteric layer: HPMCP was gradually added to ethanol under stirring. Water was added under stirring (ratio ethanol-water 80:20). Stirring continued until a clear solution was obtained. Triethylcitrate and talc were added subsequently under stirring.

Testing conditions and criteria of acceptability: See Example 1

Table 2: Duloxetine and naphtol release after 2 hours in simulated gastric fluid.

[0057] Each of the patents, patent applications, and journal articles mentioned above are incorporated herein by reference. The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.