OA11385A

OA11385A - Formulations comprising dissolved paroxetine.

Info

Publication number: OA11385A
Application number: OA1200000153A
Authority: OA
Inventors: Ahmad Ghazawi; Graham Stanley Leonard
Original assignee: Smithkline Beecham Plc
Priority date: 1997-11-21
Filing date: 2000-05-19
Publication date: 2004-01-27
Also published as: AU1168099A; NO20002590L; PE20000381A1; SK7342000A3; EA200000552A1; KR20010032320A; EP1033986A1; CN1279608A; MA24704A1; JP2001523718A; DZ2658A1; PL340555A1; IL136106A0; AR015485A1; CO4970832A1; HUP0100580A2; AP2000001821A0; WO1999026625A1; HUP0100580A3; NO20002590D0

Abstract

Pharmaceutical formulations of paroxetine are provided in which the paroxetine is in solution in a solid, semi-solid or liquid carrier. The solutions are used to fill capsules, or self-supporting solid solutions are shaped into solid dosage forms such as tablets or pellets. Also disclosed are novel liquid formulations in which a solubilising agent is used to solubilise paroxetine in oils and/or lipids, and methods of avoiding other paroxetine forms converting to the hemihydrate, by use of anhydrous or hydrophobic carriers or excipients.

Description

P31926WO 1 NOVEL FORMULATIONS 011385

The présent invention relates to novel formulations of a pharmaceutically activecompound, and to the use of the formulations in therapy. In particular this invention is5 concemed with new formulations of the anti-depressant paroxetine.

Pharmaceutical products with antidepressant and anti-Parkinson properties are describedin US-A-3912743 and US-A-4007196. An especially important compound amongthose disclosed is paroxetine, the {-}trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-10 methylenedioxy-phenoxymethyl)-piperidine. Paroxetine hydrochloride hemihydrate isused in therapy for the treatment and prophylaxis of inter alia dépréssion, obsessivecompulsive disorder (OCD) and panic.

Paroxetine hydrochloride hemihydrate is described in EP-A-0223403 of Beecham15 Group and paroxetine hydrochloride anhydrate Forms A, B, C and D are described in WO 96/24595 of SmithKline Beecham pic. Ail solid oral dosage forms of paroxetinehydrochloride sold to date hâve been in the form of oral swallow tablets, containing thehemihydrate. WO 95/16448 discloses that paroxetine is likely to develop a pink colourunless it is formulated into tablets using a formulation process in which water is absent, 20 such as dry direct compression of paroxetine or dry granulation of paroxetine followedby compression into tablets.

To assist in patient compliance with dosage régimes, there remains a need for alternativedosage forms to the swallow tablet. However, the low solubility of paroxetine25 hydrochloride in many solvents has made this difficult to achieve. In particular, it wasnot believed feasible to devise an oral swallow capsule of sufficiently small size to bereadily swallowed and containing sufficient paroxetine in solution for an effective dose,using physiologically acceptable solvents capable of encapsulation. The présentinventors hâve now overcome this problem. 30

In one aspect, the présent invention provides an oral swallow capsule containingparoxetine dissolved in a carrier.

Typically the oral swallow capsule comprises a capsule shell containing paroxetine as35 the free base or a pharmaceutically acceptable sait or solvaté thereof in solution in a carrier. The carrier may be liquid or solid.

P31926WO 2 011385 A liquid carrier may be a solvent présent in the capsule as a flowable liquid, as a viscousliquid or semi-solid or as a gel. The carrier may also be a solid or semi-soüd solventsuch as fats and waxes, or film-forming or thermoplastic polymers. Solvents in whichsupersaturated solutions can be formed are advantageous because of the possibility toincrease the loading of active ingrédient.

When the camer is a solid or semi-solid or a gel, the paroxetine containing carrier maybe self-supporting without encapsulation. Accordingly a self-supporting formulationmay be encapsulated by other means than loading into a preformed capsule shell, forexample by coating with an encapsulating material. Also the self-supportingformulation may be used as a dosage form without encapsulation.

Accordingly in another aspect the présent invention provides an oral swallow soliddosage form containing paroxetine dissolved in a solid, semi-solid or gel carrier.

Typically the solid dosage form comprises tablets, pellets, spheroids, granules, lozengesor gels in which paroxetine is présent as a solid solution in a polymeric carrier.

Capsules and solid dosage forms of this invention may be coated to assist inadministration of the active ingrédient, for example using an enteric coating material toprevent release of paroxetine in the stomach, coatings to delay or control release ofparoxetine and coatings of taste-masking agents. Altematively such materials can beincorporated in the carrier to achieve the same effect.

The paroxetine is preferably used as the hydrochloride, and as such may be used as thehemihydrate, or as the anhydrate Form A, B, C or D, or as any other form of paroxetinehydrochloride or paroxetine, such as pharmaceutically acceptable salts other than thehydrochloride. Other suitable paroxetine forms include paroxetine free base, andamorphous and non-crystalline forms of paroxetine and pharmaceutically acceptabledérivatives of paroxetine.

In a particular embodiment, the capsules or solid dosage forms of présent invention useparoxetine hydrochloride in a form other than the hemihydrate, and are formulatedunder conditions such there is no détectable conversion to hemihydrate during themanufacturing process.

This overcomes the surprisingly discovered problem that, even under relatively dryconditions, paroxetine hydrochloride anhydrate has a tendency to convert at least

P31926WO 3 011385 partially to the hemihydrate during tabletting. Although not dangerous, this créâtesdifïïculties in establishing and maintaining a référencé standard for reguîatory andquality control purposes. 5 The paroxetine hydrochloride may, for example, be présent in an amorphous form or asa crystalline anhydrate, and dissolved in a carrier, or in the presence of excipients,which are essentially hydrophobie, or essentially anhydrous, typically containing lessthan 2%, more especially less than 1.5%, preferably less than 1% by wt., water. 10 The amount of paroxetine used in each capsule is preferably adjusted such that in a single unit dose there is a therapeutically effective amount of paroxetine. Preferably theunit dose contains from 5 to 100 mg paroxetine (as measured in terms of the free base).More preferably the amount of paroxetine in a unit dose is lOmg, 20mg, 30mg, 40mg or50mg. The most preferred amount of paroxetine in a unit dose is 20mg. 15

To achieve the desired unit dose in a capsule where the paroxetine is in solution in thecarrier, the paroxetine needs to be soluble in the carrier to an extent that allows asufficient concentration so that the selected capsule volume can contain the desired unitdose. In addition to being able to dissolve paroxetine, the solvent must be compatible 20 with the capsule material and physiologically acceptable for administration to apatient.

Since solid paroxetine forms are in general only sparingly soluble in common solvents,the solvents which are acceptable for use in capsules and for administration to patientsneed to be subjected to routine solubility testing to confirm that they can maintain an 25 appropriate concentration of paroxetine. In addition, higher loadings of a paroxetineform in a suitable solvent may be achieved by using conventional physical techniquessuch as heating, shaking and sonication. Altematively good solvents for paroxetine maybe used in small amounts as cosolvents to solubilize paroxetine in liquids that areacceptable for capsule use but in which paroxetine is poorly soluble. Solubilising 30 agents such as the polysorbates, the poloxamers, cyclodextrins, ionic and non-ionic surface active agents, for example Pluronic F60 and Sorbitan esters may also be used toenhance the solubility of paroxetine hydrochloride in solvents acceptable for capsule usebut in which paroxetine is poorly soluble. 35 The term "oral swallow capsule" most suitably dénotés a capsule having a maximumvolume of 0.86 ml. Preferred capsules according to the présent invention hâve amaximum volume of about 0.45 ml and more especially may lie in the range 0.2 to 0.4ml, although capsules as small as 0.14 ml are also provided by the invention. A typical

P31926WO 4 011385 capsule at the upper end of the size range acceptable for pharmaceutical use (Soft GelSize 14 Oblong) has a volume of 0.86 ml. For a 10 mg dose of paroxetine (as ffee base)11.11 mg of paroxetine hydrochloride is needed, which in a volume of 0.86 ml requiresa concentration of 12.9 mg/ml or 1.29 % w/v. Therefore it is preferred that the solvent5 which is used has a solubility of at least 10 mg/ml for paroxetine hydrochloride andmore preferably the solubility should be at least 25 mg/ml. However larger capsulesizes such as Hard Shell Size 00 (0.95 ml capacity), Supro A (0.68 ml) and Softgel Size12 Oblong (1.01 ml) may be used when appropriate to provide higher drug dose withthe same formulation. 10

This level of solubility rules out many solvents conventionally used as liquid carriers forencapsulated drugs, such as the plant oils Sunflower, Safflower, Peanut, Soybean,Cottonseed, Corn, Castor, Apricot seed, Olive, Wheat germ, Sesame, Evening Primroseand Canola (Rapeseed) oil, and also Minerai oil and liquid paraffin. Other well known15 liquid carriers such as Miglyol (810 and 812), Oleic acid, Ethyl Oleate, Span 80 and 85,Labrafac lipophile, Plurol Oleique and Peceol (Glyceryl oleate) also show less thanlOmg/ml solubility.

The présent inventors hâve now identified certain solvents and solvent Systems which20 exhibit the required levels of solubility. Solvents that show a useful solubility include

Propylene Carbonate, Triacetin, Glycerol, Lauroglycol, Propylene glycol, PEG 300,Glycofurol, PEG 400, IPA, Span 20, Transcutol, Labrasol, Labrafil, Olepal, GlycerylLinoleate (Maisine 35-1) and Pharmasolve. For physiological suitability it may bedésirable to use such solvents with a cosolvent such as éthanol. The présent invention25 makes use of these solvents and solvent Systems as well as of functional équivalents thereof which can be identified using the techniques taught herein.

The présent inventors hâve found that an especially effective means to solubiliseparoxetine, particularly the hydrochloride, especially as the hemihydrate, in a liquid, 30 semi-solid or solid carrier, in particular oils and lipids, is to use a solubilising agent, such as N-methyl-2-pyrrolidone (Pharmasolve, International Speciality Products, Texas,USA) as a cosolvent.

Accordingly in a preferred embodiment of this invention, paroxetine, optionally as the35 free base but more typically as a pharmaceutically acceptable sait such as the hydrochloride is dissolved in a solubilising agent and then blended with an oil or lipidcarrier before filling capsules.

P31926WO 5 011385

The invention also provides as a novel formulation a solution of paroxetine, optionallyas the free base but more typically as a pharmaceutically acceptable sait such as thehydrochloride in a blend of a solubilising agent and a lipid and/or oil. 5 By use of a solubilising agent it is possible to solubilise paroxetine in oils and lipidspreviously regarded as unsuitable solvents, such as soybean oil, sunflower oil, andarachis oil.

Also by the same means paroxetine may dissolved in lipids, especially lipids derivedfrom natural materials, such coconut oil-derived glycerides, Cithrol 4DL (PEG-8 10 dilaurate). Examples of coconut oil-derived glycerides include Labrasol and LabrafacCM10(Gattefosse, France) which are C%/C\q polyglycolised glycerides from coconutoil having a hydrophilicdipophilic balance of 14 and 10 respectively.

Formulations based on a solubilising agent and oils/lipids are preferably formulated 15 with at least one antioxidant to maintain stability of the solution on storage. If it desiredto use the solutions for filling capsules then the compatibility of the solution with thecapsule material must be investigated.

The présent invention in a further aspect makes use of supersaturated solutions, for 20 example in solid or semi-solid solvents such as fats and waxes. These may readily beprepared by heating and exhibit high stability because of inter alia their very highviscosity.

Preferably, the solvents used in carrying out the invention contain less than 2%, more 25 especially less than 1.5%, preferably less than 1%, water, or are essentiallyhydrophobie.

The solution may optionally contain one or more antioxidants such as the tocopherols,ascorbic acid, ascorbic palmitate, thiodipropionic acid, bis hydroxy toluene (BHT), bis 30 hydroxy anisole (BHA), gallic acid, propyl/octyl/dodecyl gallate, benzyl alcohol andnordihydroguaiaretic acid with or without the addition of pH modifiers and chelatingagents such as citric acid and EDTA.

The capsule shell may be of any conventional material that is stable to the liquid carrier 35 and soluté, for example hard and soft gelatin capsules and starch capsules. In addition toresisting the solvent action of the liquid carrier attention must be paid to the pH of theliquid within the capsule. For example soft gels hâve a pH limit of 2.5-7.5. Since the

P31926WO 6 011385 addition of paroxetine hydrochloride to a solvent System tends to lower the pH by atleast 1 unit, then in general solvent Systems with a pH of below 3.5 are not preferred.

According to a further aspect of the invention, the capsules hâve an enteric résistant 5 coating or incorporate enteric résistant materials in the capsule shell, such that theparoxetine is not discharged in the acidic conditions of the stomach. The object of thisis to prevent any undesired uncontrolled précipitation of the paroxetine from solution,and to enable its absorption characteristics to be modified if desired by presenting it tothe intestinal mucosa in non-aqueous solution. 10

The liquid carrier may be présent in the capsule as a flowable liquid, as a viscous liquidor semi-solid or as a gel. The viscosity characteristics may be varied by initial choice ofsolvent or by appropriate use of cosolvents or thickening agents. 15 A liquid carrier, or a solid or semi-solid carrier that has been softened or made flowableby heating·, with dissolved paroxetine may be filled into capsules using conventionalcapsulation technology.

It may be désirable to use paroxetine hydrochloride in a form other than the 20 hemihydrate, which is formulated into capsules or solid dosage forms under conditionssuch there is no détectable conversion to hemihydrate during the manufacturing process.The paroxetine hydrochloride may, for example, be présent in an amorphous form or asa crystalline anhydrate. 25 This may be achieved for example by the use of either excipients or carriers which areessentially anhydrous (that is to say, they contain less than 2%, more especially lessthan 1.5%, preferably less than 1% water) or which are essentially hydrophobie. Thecapsules and solid dosage forms are then preferably packaged with a desiccant in orderto prevent conversion of anhydrate to hemihydrate on storage. 30

Accordingly, the présent invention also provides a process for the préparation ofparoxetine hydrochloride anhydrate capsules or solid dosage forms free of détectablehemihydrate which is characterised by the use of conditions such there is no détectableconversion of the anhydrate to hemihydrate during the manufacturing process. Such35 conditions can be achieved by the use of essentially anhydrous/hydrophobic excipientsand/or carriers under conditions of low relative humidity

P31926WO 7 011385

Examples of excipients with the necessary low moisture content include materials suchas dibasic calcium phosphate anhydrous, anhydrous lactose, monosaccharide sugars egmannitol, disaccharide sugars eg lactitol, powdered cellulose, pregelatinised starch andsimilar materials. Dibasic calcium phosphate anhydrous is commercially available in apharmaceutically acceptable grade, eg A-TAB (Rhône Poulenc).

Examples of liquid and semi-solid excipients with the necessary hydrophobicity includematerials such as polyglycolised glycerides eg Gelucire 44/14; complex fatty materialsof plant origin eg theobroma oil, camauba wax; plant oils eg peanut, olive, palmkernels, cotton, corn, soya; hydrogenated plant oils eg peanut, palm kernels, cotton,soya, castor, coconut; natural fatty materials of animal origin eg beeswax, lanolin, fattyalcohols eg cetyl, stearyl, lauric, myristic, palmitic, stearic; esters eg glycerol stéarate,glycol stéarate, ethyl oleate, isopropyl myristate; solid interesterified semi-syntheticglycerides eg Suppocire, Witepsol; liquid interesterified semi-synthetic glycerides egMiglyol 810/812,; amide or fatty acid alcolamides eg stearamide éthanol,diethanolamide of fatty coconut acids; polyoxyethylene glycols eg PEG 600, PEG4000.

Liquids and semi-solids having suitable solubility characteristics to act as carriers fordissolved paroxetine, and having similar hydrophobicity to the above liquid excipients,include Labraphil, a liquid interesterified semi-synthetic glyceride, and PEG 400, apolyoxyethylene glycol.

The above solid and liquid excipients may be blended with carriers of suitable solubilityfùr paroxetine disclosed above and if necessary cosolvents to obtain solutions ofparoxetine with anhydrous/hydrophobic properties. Carriers already having suitableanhydrous/hydrophobic properties may be blended directly with paroxetine, again usingcosolvents where neccessary to promote dissolution. The formulations may be filledinto capsules, such as gelatin capsule shells, or cellulose capsule shells of intrinsicallylow moisture content (eg Shionogi Qualicaps, < 3%).

Liquid interesterified semi-synthetic glycerides commercially available in apharmaceutically acceptable grade include Labrafil M 2125CS (Gattfosse). In aparticular process of the invention, paroxetine hydrochloride anhydrate is mixed withLabrafil M 2125CS (Gatfosse) to produce a formulation for encapsulation in a hard orsoft gelatin capsule.

P31926WO 8 011385

Paroxetine in the form of the hydrochloride anhydrate may be prepared according to theprocedures outlined in WO 96/24595. Suitabie procedures for preparing paroxetineinclude those mentioned in US Patents 4,009,196,4,902,801, 4,861,893 and 5,039,803and PCT/GB 93/00721. 5

The présent invention also provides solid dosage forms of paroxetine for oral swallowuse in which paroxetine is dissolved in a polymeric carrier. These forms include tablets,pellets, spheroids, granules, lozenges and gels containing paroxetine in solid solution. 10 To achieve the desired unit dose in for example a melt extruded tablet where the paroxetine is in solution in the polymer carrier, the paroxetine needs to be soluble in thepolymer carrier or a solvent/cosolvent that is soluble in the polymer carrier to an extentthat allows a sufficient concentration so that the selected tablet size and volume cancontain the desired unit dose. In addition to being able to dissolve paroxetine, the 15 solvent/cosolvent must be compatible with the polymer carrier material andphysiologically acceptable for administration to a patient.

When the solid dosage form is granules or pellets then a plurality of granules or pelletsmay be collected in an aggregation that as a whole constitutes a unit dose. The granules20 or pellets may be used as a fxll for capsules or pressed, optionally with binders orexcipients, into tablet form.

Since solid paroxetine forms are in general only sparingly soluble in common solvents,the solvents/co-solvents and carriers which are acceptable for use in the above dosage25 forms and for administration to patients need to be subjected to routine solubility testingto confirm that they can maintain an appropriate concentration of paroxetine. Inaddition, higher loadings of a paroxetine form in a suitabie solvent may be achieved byusing conventional physical techniques such as heating, shaking and sonication.Altematively good solvents for paroxetine may be used in small amounts as cosolvents30 to solubilize paroxetine in polymers that are acceptable for melt extrusion, melt granulation, gel formulation use but in which paroxetine is poorly soluble. Solubilisingagents such as the polysorbates, the poloxamers, cyclodextrins, ionic and non-ionicsurface active agents, for example Pluronic F60 and Sorbitan esters may also be used toenhance the solubility of paroxetine hydrochloride in solvents acceptable for polymers35 used to produce solid solution Systems in forms of tablet, pellet, granule, spheroid usebut in which paroxetine is poorly soluble.

P31926WO 9 011385

It is preferred that the polymer and/or solvent which are used hâve a solubility of at least10 mg/ml for paroxetine hydrochloride and more preferably the solubility should be atleast 25 mg/ml. 5 In general the use of polymers in this invention to produce semi-solid/solid solutionSystem offer a broad flexibility of use. Beside filling into hard/soft gelatin capsules theymay be used to make melt extruded System such as tablets, pellets, spheroid and anyother shape depending on the shape of the extruder die, can be injection moulded intodifferent shapes and /or melt granulated to produce pellets or granules. Altematively the10 granules can be milled and pressed into tablets and other shapes depending on the shapeand design of the press die.

Examples of the pharmaceutical polymers used for the above applications are filmforming and thermoplastic polymers that are generally approved substances listed in15 international Pharmacopoeias such as polyethylene oxide water soluble resins, ethoxylated glycerides and triglycérides, cetyl esters, cetyl palmitate, glyceryl esters,polyvinyl acetate, cellulose, lanolin based product, vinyl resins, latex product, carbowaxpolyethylene glycols, gelatin (protein), ethylene oxide/glycol such as ethylene glycol,glycol ethers and ethanolamines, unipol polymers, polypropylene resins, silicone20 products, saturated polyglycolysed glycerides, glyceryl behenate, glyceryl palmitostearate, semisynthetic glycerides and vinyl acetate monomers. The function(s)of these polymers will be as a drug carrier and/or solubiliser and/or binder and/orpermeability enhancers. 25 Solvents that show a useful solubility for paroxetine, such as Propylene Carbonate,Triacetin, Glycerol, Lauroglycol, Propylene glycol, PEG 300, Glycofurol, PEG 400, IP A, Span 20, Transcutol, Labrasol, Labrafil, Olepal, Glyceryl Linoleate (Maisine 35-1)and Pharmasolve mentioned previously, may be used as cosolvents to assistsolubilisation of paroxetine in the solide, semi-solid and polymeric carriers mentioned 30 above. For physiological suitability it may be désirable to use such solvents with another cosolvent such as éthanol. The présent invention makes use of these solventsand solvent Systems as well as of functional équivalents thereof which can be identifiedusing the techniques taught herein. 35 An appropriate lanolin dérivative e.g. ethoxy-75 lanolin is commercially available in apharmaceutical grade e.g. Solan E (Croda). In a particular process of the invention,paroxetine hydrochloride hemihydrate is dissolved in Pharmasolve and mixed with

P31926WO 10 011385 molten Solan E in a suitable blender to form granules on cooling, drying, sifting thensolid solution tablet upon compression. A polyglycolised glyceride is commercially available in a pharmaceutically acceptable 5 grade .e.g. Gelucire 44/14 (Gattfosse). In a particular process of the paroxetine invention, paroxetine hydrochloride hemihydrate is dissolved in Pharmasolve and thenmixed with molten Gelucire 44/14 to form a melt extrudate in forms of a tablet and/orpellet on cooling. 10 Polyethylene glycols of different molecular weights are commercially available in apharmaceutically acceptable grade e.g. PEG 4000 (Union Carbide Corp & BASF). In aparticular process of the invention, Paroxetine hydrochloride hemihydrate is dissolvedin PEG 300 and then mixed with molten PEG 4000 to form melt extruded materialswhich on cooling as solid solution may be converted into forms of tablets and/or pellets. 15

The solid solution may optionally contain one or more antioxidants such as thetocopherols, ascorbic acid, ascorbyl palmitate, thiodipropionic acid, bis hydroxy toluene(BHT), bis hydroxy anisole (BHA), gallic acid, propyl/octyl/dodecyl gallate, benzylalcohol and nordihydroguaiaretic acid with or without the addition of pH modifiers and20 chelating agents such as citric acid and EDTA.

According to a further aspect of the invention, the solid dosage form may hâve anenteric résistant coating such that paroxetine is not discharged in the acidic conditions ofthe stomach. The object of this is to prevent any undesired uncontrolled précipitation of25 the paroxetine from solution, and to enable its absorption characteristics to be modifiedif desired by presenting it to the intestinal mucosa in an aqueous solution.

The solid solution/semi-solid Systems presented in this invention can be coated withsuitable polymer that can be used with melt granulation or hot melt coating such as30 Precirol ATO 5 (Glyceryl palmito stéarate) for taste-masking paroxetine and/orenterically coated with methacrylic acid copolymer C (e.g. Eudragit L 30 D-55).

The semi-solid or gel formulation can also be optionally capsulated. The viscositycharacteristics of the semi-solid or gel may be varied by initial choice and amount of35 solvent or by appropriate use of cosolvents or thickening agents.

The semi-solid or gel carrier with dissolved paroxetine may be filled into capsules usingconventional capsulation technology.

P31926WO 11 011385

Self-supporting solid of paroxetine solution can be successfully prepared in forms oftablet, pellets, spheroid, granules using Solan E, Gelucire, higher molecular weights ofPEG's and gel based on gelatin with different cosolvents constituents. 5

For example, the paroxetine is first dissolved in co-solvent constituents, such as PEG300, Pharmasolve and water/ethanol (using sufficient mixing to assure complétéwetting/solubilisation). The résultant mixture is then preheated and added to a suitableportions of a melted polymer such as Gelucire 44/14 (melting point 42-46 C), Solan E10 (melting point 45-50 C), PEG 6000 (melting point 55-63 C), PEG 4000 (melting point50-58 C) or Gelatin (gelatin in liquid co-solvents melted between 50-55 C). Thesamples may then be left at ambient condition for resolidification of the polymer tooccur. A shaping device may then be used to produce solid dosage forms as tablets,pellets, spheroids and gels. The drug molécule dissolved in the polymer during the15 melting phase will remain dissolved in the finished product as a solid solution. Withgelatin based formulations, transparent solid solutions containing dissolved drug areproduced.

As mentioned above, itt may be désirable to use paroxetine hydrochloride in a form 20 other than the hemihydrate, which is formulated into self-supporting solid dosage formsunder conditions such there is no détectable conversion to hemihydrate during themanufacturing process. The paroxetine hydrochloride may, for example, be présent inan amorphous form or as a crystalline anhydrate. 25 As already described, this may be achieved for example by the use of either excipientsor polymeric carriers which are essentially anhydrous (that is to say, they contain lessthan 2%, more especially less than 1.5%, preferably less than 1% water) or which areessentially hydrophobie. 30 Therapeutic uses of the paroxetine formulations of this invention include treatment of:alcoholism, anxiety, dépréssion, obsessive compulsive disorder, panic disorder, chronicpain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrualsyndrome (PMS), adolescent dépréssion, trichotillomania, dysthymia, and substanceabuse, referred to below as "the disorders". 35

Accordingly, the présent invention also provides:

P31926WO 12 011385 the use of paroxetine dissolved in a carrier to manufacture oral swallow capsules orsolid dosage forms for the treatment or prophylaxis of one or more of the disorders; a method of treating the disorders which comprises administering an effective or5 prophylactic amount of paroxetine as a solution in a carrier in an oral swallow capsule or solid dosage form to a person suffering from one or more of the disorders;a method of treating the disorders which comprises administering an effective orprophylactic amount of paroxetine as a solution in a liquid formulation of the inventionto a person suffering from one or more of the disorders. 10

The formulations of this invention may also be used where appropriate for veterinarytreatment of animais.

The invention is illustrated by the foliowing Examples: 15 (Paroxetine anhydrous ffee base 10.0 mg is équivalent to 11.38 mg paroxetine HCl conversion factor from paroxetine HCl to paroxetine anhydrous base is 0.8787).

In Examples 1-10, paroxetine is dissolved in a carrier, optionally assisted by acosolvent, and filled into capsules.

Example 1. Capsule Excipient Paroxetine hydrochloridePolyethylene Glycol 400 Size 11 Oblong Soft Gel mg per capsule 22.22 450.0 Example 2. Excipient mg per capsule Paroxetine hydrochloride 22.22 Polyethylene Glycol 400 400.0 Ethanol 45.0 Capsule Size 0 Hard Shell, banded Example 3. Excipient mg per capsule Paroxetine hydrochloride 22.22 Propylene Glycol 350.0 Capsule: Size 8 Oblong Soft gel Enteric Coat Methacrylic Acid Copolymer Type C 32.0 Propylene Glycol 8.0

P31926WO 13 011385

Example 4. Excipient mg per capsule Paroxetine hydrochloride 22.22 Fractionated coconut oil 300.0 Polyethylene Glycol 400 150.0 Polysorbate 80 50.0 Capsule: Size 11 Oblong Soft gel Example 5. Excipient mg per capsule Paroxetine hydrochloride 22.22 Glycerol 100.0 Propylene Glycol 100.0 Propyl gallate 0.3 Capsule: Size 5 Oblong Soft gel Example 6. Excipient mg per capsule Paroxetine hydrochloride 22.22 Glycofurol 100.0 Polyethylene glycol 300 50.0 Citric acid 1.5 BHT 0.02 Capsule: Size 4 Oblong Soft gel Example 7. Excipient mg per capsule Paroxetine hydrochloride 22.22 Pharmasolve 50.0 High Purity CottonSeed Oil 150.0 Propyl gallate 0.2 Capsule: Size 4 Oblong Soft gel Example 8. Excipient mg per capsule Paroxetine hydrochloride 22.22 Polyethylene Glycol 400 50.0 Pharmasolve 10.0 Citric Acid 2.0 Capsule Size 3 Oval Soft Gel Example 9. Excipient mg per capsule

P31926WO 14 011385

Capsule Paroxetine hydrochlorideLauroglycol 400 Pharmasolve Citric Acid Size 3 Hard Shell, banded 22.22 100.0 10.0 2.0 Example 10. Excipient mg per capsule Paroxetine hydrochloride 22.22 Polyethylene Glycol 400 50.0 Pharmasolve 10.0 Citric Acid 2.0 Capsule Starch Capil

In Example 11, paroxetine is dissolved in a hydrophobie carrier. mg 22.22 227.78 250.00

Example 11

Paroxetine hydrochloride fLabrafil M 2125CS

Capsule weight5

In Examples 12-30, paroxetine was dissolved in a cosolvent, and then blended with amolten polymer. Clear paroxetine solutions were obtained before solidification of thepolymers. 10

Example 12 Paroxetine HCL PEG 300 PEG 4000dl alfa tocopherol 22.76 mg200.00 mg300.00 mg0.1% w/w Tablet Ascorbyl Palmitate 0.1% w/w Example 13 Paroxetine Hydrochloride 45.52 mg Gelucire 44/14 227.78 mg Tablet Pharmasolve lOO.OOmg Example 14 Paroxetine Hydrochloride 22.76 mg Tablet Gelucire 44/14 227.78 mg Example 15 Paroxetine Hydrochloride 68.28 mg Solan E (ethoxy 75 lanolin) 350.00 mg Tablet Pharmasolve 150.00mg

P31926WO 15 011385 5 Example 16Tabiet Example 17Tabiet Paroxetine Hydrochloride PEG 1450 Paroxetine Hydrochloride PEG 4000 22.76 mg227.78 mg 22.76 mg227.78 mg Example 18 Paroxetine HCL 19.91 mg 10 PEG 300 PEG 1450dl alfa tocopherol 200.00 mg300.00 mg0.1% w/w Tabiet Ascorbyl Palmitate 0.1% w/w 15 Example 19 Paroxetine Hydrochloride 22.76 mg Tabiet Suppocire DM 227.78 mg Example 20 Paroxetine HCL 73.96 mg 20 Gélatine Purified water Pharmasolve Polysorbate 80 100.00 mg350.00 mg150.00 mg 1 drop 25 Gel Methyl Paraben 0.2% w/w Example 21 Paroxetine HCL Gélatine Purified water Propylene Glycol 42.67 mg50.00 mg200.00 mg400.00 mg 30 Propyl Gallate Ascorbic Acid 0.1 % w/w0.1% w/w Gel Polysorbate 80 1 drop Example 22 Paroxetine HCL 113.79 mg 35 Gélatine Purified water Pharmasolve Propylene Glycol Polysorbate 80 50.00 mg200.00 mg200.00 mg200.00 mg 1 drop 40 Gel Methyl Paraben 0.2% w/w

Example 23 Paroxetine HCL 102.41 mg Gélatine 50.00 mg 45 Purified water 200.00 mg Pharmasolve 200.00 mg Ethanol 200.00 mg Polysorbate 80 1 drop

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Gel Methyl Paraben 0.2% w/w Example 24 Paroxetine HCL Gélatine 28.45 mg50.00 mg 5 Purified water Ethanol Propylene Glycol 200.00 mg200.00 mg200.00 mg Gel Polysorbate 80 1 drop 10 Example 25 Paroxetine HCL Gélatine Purified water Propylene Glycol PEG 300 45.52 mg50.00 mg200.00 mg400.00 mg50.00 mg 15 Gel Polysorbate 80 1 drop Example 26 Paroxetine HCL Gélatine Purified water 11.38 mg50.00 mg500.00 mg 20 Propylene Glycol 100.00 mg Gel Polysorbate 80 1 drop Example 27 Paroxetine HCL Gélatine 28.45 mg50.00 mg 25 Purified water Propylene Glycol 300.00 mg300.00 mg Gel Polysorbate 80 1 drop Example 28 Paroxetine HCL 68.28 mg 30 Gélatine Purified water Pharmasolve Propylene Glycol 50.00 mg300.00 mg150.00 mg150.00mg 35 Gel Polysorbate 80 1 drop Example 29 Paroxetine HCL Gélatine Purified water Pharmasolve 79.65 mg50.00 mg300.00 mg150.00 mg 40 Ethanol Polysorbate 80 150.00 mg 1 drop Gel Methyl Paraben 0.2% w/w Example 30 Paroxetine HCL 17.07 mg 45 Gélatine Purified water Propylene Glycol Ethanol 50.00 mg300.00 mg150.00 mg150.00 mg

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Gel Polysorbate 80 ï drop

In Examples 31 -44, paroxetine is initially dissolved in Pharmasolve and the résultantsolution is blended with oil and lipid carriers, so that the paroxetine is dissolved in the5 carrier to give liquid formulations that may be capsulated (36 - 42) and also providedwith an enteric coating (43 - 45)

Composition Appearance of System/Solu tionA Stability of Pxtsolution * Example 31 Labrasol........2.25mL Pharmasolve... .0.25mLDrug............125mg clear paleyellowsolution clear very pale pink solution Example 32 Cithrol 4DL.....2.25mL Pharmasolve... .0.25mLDrug............125mg clear paleyellowsolution clear pale pink solution Example 34 Sunfloweroil....2.25mLPharmasolve... .0.25mLDrug..............125mg clear paleyellowsolution no change clear v. pale yellow solution Example 35 Soybean oil......2.25mL Pharmasolve... .0.25mLDrug.............125mg clear paleyellowsolution no change clear pale yellow solution Example 36 Arachis oil......2.25mL Pharmasolve... .0.25mLDrug..............125mg clear paleyellowsolution no change clear v, pale yellow solution * stored at RT for 25 days (visual observation) Λ at the time of préparation (fresh samples)

Exam pie Composition Appearance of System/Solutio ηΛ Stability of Pxt solution* Compatabili ty with Licaps Capsule* 36 Labrafac CM10......4.50mL Pharmasolve...........0.50mL clear pale clear pale Yes

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Tween 80....... .......1 drop yellow solution yellow Drug............... ......250me solution

P31926WO 19 011385 37 Labrafil 1994Cs.....4.50mL Pharmasolve......... Tween 80............. Drug.................... M ...0.50mL ....1 drop ...250mg clear pale yellow solution yellow viscous/semi solid Yes 38 Labrasol.............. Pharmasolve........ Tween 80............. Drug.................... ...4.50mL ....0.50mL ...1 drop ..250mg clear pale yellow solution clear pale yellow solution Yes 39 Cithrol 4DL.......... Pharmasolve......... Tween 80............. Drug..................... .4.50mL 0.50mL .1 drop .250mg clear pale yellow solution clear v. pale pink solution Yes * stored at RT for 10 days (visual observation)Λ at the time of préparation (ffesh samples)

Exam pie Composition Appearance of System/Solu tionA Stability of Pxtsolution* Compat ability with Licaps Capsul e* 40 Labrafac CM 10.. Pharmasolve....... Tween 80........... Ascorbic acid..... Propyl Gallate....Drug.................. ....9.0mL ....l.OmL ..2 drops ..l.Omg ...l.Omg ...500mg clear paleyellowsolution clear pale yellowsolution Yes 41 Labrasol............ Pharmasolve....... Tween 80........... Ascorbic acid..... Propyl Gallate....Drug.................. ,.9.0mL ....l.OmL ..2 drops ..l.Omg ...l.Omg ...500mg clear paleyellowsolution clear pale yellowsolution Yes 42 Cithrol 4DL....... Pharmasolve....... Tween 80........... Ascorbic acid..... Propyl Gallate.... ....9.0mL....l.OmL..2 drops...l.Omg...l.Omg clear paleyellowsolution clear paleyellow/whitesolution Yes

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Drug.....................500mg | * stored at RT for 10 days (visual observation), Λ at the time of préparation (fresh samples)

Example Labrasol............. .9.0mL 43 Pharmasolve....... ...l.OmL Tween 80............ .2 drops Ascorbic acid...... ..l.Omg Propyl Gallate..... ..l.Omg Sureteric.......... ...32.0mg Drug................... ..500mg Capsule: Licaps size 1(fill 20 capsules)

Example Labrasol................ ....9.0mL 44 Pharmasolve........... ....l.OmL Tween 80.............. ....2 drops Ascorbic acid......... .....l.Omg Propyl Gallate........ ....l.Omg Eudragit L30D55... ....42.0mg Drug................... ....500mg Capsule: size 11 oblonge softgel(fill 15 softgel capsules)

Example 45 Labrafac CM 10..... Pharmasolve.......... Tween 80.............. Ascorbic acid........ Propyl Gallate....... Aquateric............ ...9.0mL ..l.OmL ...2 drops ...l.Omg ...l.Omg ..52.0mg Drug................. ..500mg Capsule: size 0 Hard Shell,Banded (fill 15 capsules)

Claims

P31926WO 21 011385 CLAIMS I. An oral swallow capsule containing paroxetine dissolved in a carrier.
2. An oral swallow capsule comprising a capsule shell containing paroxetine as the free base or a pharmaceutically acceptable sait or solvaté thereof in solution in a liquidor solid carrier.
3. A capsule according to claim 2 in which the carrier is a liquid solvent présent in 10 the capsule as a flowable liquid, as a viscous liquid or semi-solid or as a gel.
4. A capsule according to claim 2 in which the carrier is a solid or semi-solidsolvent. 15
5. A capsule according to claim 4 in which the solid or semi-solid solvent is selected from natural and synthetic fats and waxes, and film-forming and thermoplasticpolymers.
6. An oral swallow solid dosage form containing paroxetine dissolved in a solid, 20 semi-solid or gel carrier.
7. A solid dosage form comprising tablets, pellets, spheroids, granules, lozenges orgels in which paroxetine is présent as a solid solution in a polymeric carrier.
8. Capsules and solid dosage forms according to any one of daims 1 to 7 which are coated to assist in administration of the active ingrédient.
9. Capsules and solid dosage forms according to claim 8 which are coated withcoatings to delay or control release of paroxetine and/or coatings for taste-masking. 30
10. Capsules and solid dosage forms according to any one of daims 1 to 9 in whichparoxetine is used as the hydrochloride hemihydrate or anhydrate. II. Capsules and solid dosage forms according to any one of daims 1 to 10 in which 35 paroxetine is used as paroxetine hydrochloride in a form other than the hemihydrate, which is formulated under conditions such there is no détectable conversion tohemihydrate during the manufacturing process.
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12. Capsules and solid dosage forms according to claim 11 in which the paroxetinehydrochloride is used in an amorphous form or as a crystalline anhvdrate
13. Capsules and solid dosage forms according to claim 12 in which the paroxetine5 hydrochloride is dissolved in a carrier which is essentially hydrophobie or anhydrous.
14. Capsules and solid dosage forms according to claim 12 or 13 in which theparoxetine hydrochloride is dissolved in a carrier in the presence of excipients, whichare essentially hydrophobie or anhydrous. 10
15. A pharmaceutical formulation comprising a solution of paroxetine in a blend ofa solubilising agent and a lipid and/or oil.
16. A process for preparing a formulation acording to claim 15 which comprises 15 dissolving paroxetine in a solubilising agent and blending the résultant solution with alipid and/or oil.
17. The use of paroxetine dissolved in a carrier to manufacture oral swallowcapsules or solid dosage forms according to any one of daims 1 to 14 for the treatment 20 or prophylaxis of one or more of the disorders;
18. A method of treating the disorders which comprises administering an effectiveor prophylactic amount of paroxetine as a solution in a carrier in an oral swallowcapsule or solid dosage form according to any one of daims 1 to 14 to a mammal 25 suffering ffom one or more of the disorders.
19. A method of treating the disorders which comprises administering an effectiveor prophylactic amount of paroxetine as a solution in a formulation according to daim15 to a mammal suffering from one or more of the disorders.