HUP0100580A2 - Formulations comprising dissolved paroxetine - Google Patents

Abstract

The finding refers to pharmaceutical preparations containing paroxetine, in which paroxetine is present in the form of a solution formed with a solid, semi-solid or liquid carrier. The solutions can be put into capsules, and the carrier solid solutions can be converted into solid dosage forms, e.g. tablets or pellets. New, liquid preparations in which solubilizing agents are used for the dissolution of paroxetine in oils and/or lipids are also part of the subject matter. The subject matter also includes procedures in which unlike paroxetine hemihydrate, anhydrous or hydrophobic carriers or carriers are used to prevent the breakdown of the hemihydrate. HE

Description

to .

70.387/DE

International

M.ΙΛίο ^Szat,adain,i office Budapest, Andrássy út IP 34 -24 PREPARATIONS CONTAINING DISSOLVED PAROXETINE

PUBLICATION COPY

The invention relates to novel formulations of pharmaceutically active compounds. More particularly, the invention relates to novel formulations of the antidepressant paroxetine.

Antidepressant and antiparkinsonian pharmaceutical products are described in U.S. Patents 3,912,743 and 4,007,196. Of particular note among the compounds described therein is (-)-trans-4-(4-fluorophenyl)-3-{[3,4-(methylenedioxy)phenoxy]methyl}-piperidine, known as paroxetine. Paroxetine hydrochloride hemihydrate is used in medicine to treat, among other things, depression, obsessive compulsive disorder (OCD), and panic disorder.

Paroxetine hydrochloride hemihydrate is described in European Patent Application No. 0 223 403. International Patent Application No. WO 96/24595 describes paroxetine hydrochloride anhydrate forms A, B, C and D. All solid oral dosage forms of paroxetine hydrochloride sold to date have been oral swallowable tablets containing the hemihydrate. International Patent Application No. WO 95/16448 describes that paroxetine is prone to purple discoloration unless the active ingredient is formulated into tablets using formulation processes that exclude water, such as when paroxetine is directly dry-pressed into tablets or when paroxetine is compressed into tablets after dry granulation.

There is a continuing need for alternative dosage forms to swallowable tablets to facilitate easier administration of dosage regimens. However, this goal is significantly hindered by the low solubility of paroxetine hydrochloride in many solvents. It has not previously been feasible to produce swallowable capsules using pharmaceutically acceptable encapsulation solvents that are small enough to be easily swallowed while still containing an effective dose of paroxetine in solution. The present invention has solved this problem.

One aspect of the invention relates to oral, ingestible capsules containing paroxetine dissolved in a carrier.

Typically, oral, swallowable capsules consist of capsule shells containing paroxetine, either as the free base or as a pharmaceutically acceptable salt, in solution with a carrier. The carrier may be a liquid or solid.

Liquid carriers can be, for example, solvents that are present in the capsule in the form of a free-flowing liquid, a viscous liquid, a semi-solid or a gel. The carrier can also be a solid or semi-solid solvent, such as fats and waxes, or a film-forming or thermoplastic polymer. Solvents in which supersaturated solutions can be formed are particularly preferred, since such solvents allow for an increase in the active ingredient content.

If the carrier is a solid or semi-solid material or a gel, the paroxetine-containing carrier can be used alone without encapsulation (hereinafter referred to as self-supporting). Self-supporting compositions can be encapsulated in other ways than by filling into preformed capsule shells, for example by coating with an encapsulating material. Self-supporting compositions can also be used as dosage forms without encapsulation.

Accordingly, a further aspect of the invention is oral, ingestible, solid dosage forms comprising paroxetine dissolved in a solid, semi-solid or gel carrier.

Solid dosage forms are typically tablets, pellets, spheroids, granules, lozenges or gels in which paroxetine is present as a solid solution with a polymeric carrier.

To facilitate the administration of the active ingredient, the capsules and solid dosage forms of the invention may be coated, for example, by using an enteric coating material to prevent the release of paroxetine in the stomach, coatings to provide delayed or controlled release of paroxetine, or coatings containing taste masking agents. Alternatively, the aforementioned materials may be incorporated into the carrier to achieve the same effect.

Paroxetine is preferably used in the form of its hydrochloride salt, or the active ingredient may be used as its hemihydrate, or as anhydrate forms A, B, C or D, or as paroxetine hydrochloride or any other form of paroxetine, for example as a pharmaceutically acceptable salt other than the hydrochloride salt. Other suitable forms of paroxetine include, for example, paroxetine free base, amorphous or non-crystalline forms of paroxetine, and pharmaceutically acceptable derivatives of paroxetine.

In one particular embodiment, the capsules or solid dosage forms of the invention employ paroxetine hydrochloride in a form other than the hemihydrate, and the formulation is carried out under conditions such that no detectable conversion to the hemihydrate occurs during the manufacturing process.

This solves the unexpectedly recognized problem that paroxetine hydrochloride anhydrate tends to at least partially convert to the hemihydrate during tableting, even under relatively dry conditions. Although this is not particularly dangerous, it makes it difficult to produce and maintain a reference standard for regulatory and quality control purposes.

Paroxetine hydrochloride may be in amorphous form or crystalline anhydrate form, for example, and may be dissolved in a carrier or carriers which are substantially hydrophobic or substantially anhydrous, typically containing less than 2% by weight, more preferably less than 1.5% by weight, and preferably less than 1% by weight, of water.

The amount of paroxetine used in each capsule is preferably selected so that a therapeutically effective amount of paroxetine is present in a single dosage unit. The dosage unit (measured as the free base) preferably contains 5 to 100 mg of paroxetine. More preferably, the amount of paroxetine in a dosage unit is 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. Most preferably, the amount of paroxetine in a dosage unit is 20 mg.

To achieve the desired dosage unit in a capsule containing paroxetine dissolved in a vehicle, the paroxetine must be soluble in the vehicle to a degree that allows a concentration to be achieved that will fit the desired dosage unit in the volume of the selected capsule. The solvent (in addition to dissolving the paroxetine) must be compatible with the capsule material and physiologically acceptable for administration to patients.

Since solid forms of paroxetine are generally only sparingly soluble in common solvents, solvents suitable for use in capsules and for administration to patients should be tested in conventional solubility tests to determine their ability to maintain adequate concentrations of paroxetine. Solutions of a given form of paroxetine in a suitable solvent with higher drug content can be prepared by conventional physical methods such as heating, shaking and sonication. Alternatively, good solvents for paroxetine can be used in small amounts as co-solvents to dissolve paroxetine in liquids which are suitable for encapsulation but in which paroxetine is only poorly soluble. Solubilizers in solvents suitable for encapsulation but which are only poorly soluble in paroxetine, .1 . ·.:.:... : —.

·· · · · ··♦··· For example, polysorbates, poloxamers, cyclodextrins, ionic and nonionic surfactants such as Pluronic F60 and sorbitan esters can be used to enhance the solubility of paroxetine hydrochloride.

The term oral, swallowable capsule is most appropriately used to refer to a capsule having a volume of up to 0.86 ml. Preferred capsules of the invention have a maximum volume of about 0.45 ml, more preferably 0.2-0.4 ml, although capsules as small as 0.14 ml may be used in the present invention. The upper limit of the size range of typical capsules acceptable for pharmaceutical use is a volume of 0.86 ml (Soft Gel Size 14 Oblong). A 10 mg dose of paroxetine (free base) requires 11.11 mg of paroxetine hydrochloride, which, given the 0.86 ml capsule volume, requires a concentration of 12.9 mg/ml or 1.29% w/v. Accordingly, the solvent is considered preferable, which in the case of paroxetine hydrochloride provides a solubility of at least 10 mg/ml, more preferably allows a concentration of at least 25 mg/ml of paroxetine hydrochloride to be achieved. However, in order to provide higher doses of active ingredient in the same formulations, larger capsules can be used in certain cases, such as the Hard Shell Size with a volume of 0.96 ml, the Supro A with a volume of 0.68 ml and the Softgel Size 12 Oblong with a capacity of 1.01 ml.

These solubility requirements preclude the use of a number of solvents traditionally used as liquid carriers for encapsulated active ingredients, including, but not limited to, vegetable oils such as sunflower, safflower, peanut, soybean, cottonseed, corn, castor, apricot kernel, olive, wheat germ, sesame, evening primrose and rapeseed oils, as well as mineral oils and liquid paraffin. Due to solubility below 10 mg/ml, other well-known liquid carriers are also not suitable, including, but not limited to: Miglyol (810 and 812), oleic acid, ethyl oleate, Span 80 and 85, Labrafac lipophil, Plurol Oleique and Peceol (glyceryl oleate).

During our studies, we have identified some solvents and solvent systems that meet the necessary solubility requirements. Solvents that provide adequate solubility include, but are not limited to, the following: propylene carbonate, triacetin, glycerin, leuroglycol, propylene glycol, polyethylene glycol (PEG) 300, glycofurol, polyethylene glycol 400, isopropyl alcohol (IPA), Span 20, transcutol, Labrasol, Labrafil, Olepal, glyceryl linoleate (Maisine 35-1), and Pharmasolve. For physiological applicability, the aforementioned solvents are optionally used together with a cosolvent, such as ethanol. Such solvents and solvent systems that can be used in the present invention, as well as their functional equivalents, can be identified by the methods described below.

We have found that the use of a solubilizing agent, such as N-methyl-2-pyrrolidone (Pharmasolve, International Specialty Products, Texas, USA) as a co-solvent can be extremely effective in dissolving paroxetine, especially the hydrochloride, and even more so the hemihydrate, in a liquid, semi-solid or solid carrier, especially oils and lipids.

Accordingly, in one preferred embodiment of the invention, paroxetine, optionally in the form of the free base, or more preferably in the form of a pharmaceutically acceptable salt thereof, such as the hydrochloride salt, is dissolved in a solubilizing agent, the solution is then mixed with an oil or lipid carrier, and the resulting mixture is then filled into capsules.

The invention also provides a novel composition comprising a solution of paroxetine, optionally in the form of the free base, or more preferably in the form of a pharmaceutically acceptable salt thereof, such as the hydrochloride salt, in a mixture of a solubilizing agent and a lipid and/or oil.

The use of solubilizers also makes it possible to dissolve paroxetine in oils and lipids that were previously considered unsuitable solvents, such as soybean oil, sunflower oil, and peanut oil.

With similar assistance, paroxetine can also be dissolved in lipids, especially lipids derived from natural sources, such as coconut-derived glycerides, Cuthrol 4DL (PEG-8 dilaurate). Coconut-derived glycerides include, among others, Labrasol and Labrafac CM10 (Gattefosse, France), which are Cg/Cio polyglycosylated glycerides derived from coconut oil with a hydrophilic/lipophilic balance of 14 and 10, respectively.

In order to maintain the stability of the solution during storage, formulations based on solubilizers and oils/lipids are preferably formulated with at least one antioxidant. If necessary, the compatibility of the solutions to be filled into capsules and the capsule material should be tested.

The invention also relates to the use of supersaturated solutions prepared with solid or semi-solid solvents, such as fats and waxes. Such supersaturated solutions can be easily prepared by heating; among other things, due to their extremely high viscosity, these supersaturated solutions are particularly stable.

The solvents used in the solutions according to the invention preferably contain less than 2% by weight, more preferably less than 1.5% by weight, particularly preferably less than 1% by weight of water, and are essentially hydrophobic in nature.

The solution may optionally contain one or more antioxidants, such as tocopherols, ascorbic acid, ascorbic palmitate, thiodipropionic acid, bis(hydroxytoluene) (BHT), bis(hydroxyanisole) (BEA), gallic acid, gallic acid propyl/octyl/dodecyl ester, benzyl alcohol and nordihydroguaiaretic acid, and optionally pH modifiers and chelating agents, such as citric acid and EDTA.

The capsule shell material can be any material that is stable to the liquid carrier and the solute;

for example, capsules can be hard or soft gelatin capsules, as well as starch capsules. In addition to the resistance to the solvent effect of the liquid carrier, attention must also be paid to the pH of the liquid contained in the capsule. For example, in the case of soft gels, the pH range is 2.5-7.5. Since the addition of paroxetine hydrochloride to the solvent system reduces the pH value by at least 1 unit, the use of solvent systems with a pH of less than 3.5 is not advantageous.

The invention also provides capsules which are provided with an enteric coating or which contain enteric coating materials incorporated into the capsule shell, so that paroxetine is not released in the acidic environment of the stomach. The purpose of this is to prevent unwanted, uncontrolled precipitation of paroxetine from solution, and to allow the delivery of paroxetine in a non-aqueous solution to the intestinal mucosa, if desired, to modify the absorption characteristics of the active ingredient.

In the capsule, the liquid carrier may be present in the form of a free-flowing liquid, a viscous liquid, a semi-solid, or a gel. The viscosity characteristics can be modified by the choice of solvent and by the appropriate use of co-solvents or thickeners.

The liquid carrier containing dissolved paroxetine, or the solid or semi-solid carrier previously softened or liquefied by heating, can be filled into capsules using conventional encapsulation methods.

Paroxetine hydrochloride is preferably used in a form other than the hemihydrate, which is formulated into capsules or solid dosage forms under conditions under which no detectable conversion to the hemihydrate occurs during the manufacturing process. Paroxetine hydrochloride may be, for example, in an amorphous form or in a crystalline anhydrate form.

The former object can be achieved, for example, by using carriers or vehicles which are essentially anhydrous (i.e., containing less than 2% by weight, more preferably less than 1.5% by weight, and preferably less than 1% by weight of water) or which are essentially hydrophobic. In order to prevent the conversion of the anhydrate to the hemihydrate during storage, the capsules and solid dosage forms are subsequently packaged in the presence of a desiccant.

Accordingly, a further object of the invention is to provide a process for preparing paroxetine hydrochloride anhydrate capsules or solid dosage forms free of detectable hemihydrate, wherein conditions are employed under which no detectable conversion from anhydrate to hemihydrate occurs during the manufacturing process. Such conditions can be achieved by using substantially anhydrous/hydrophobic carriers and/or excipients under conditions of low relative humidity.

Examples of suitable low moisture carriers include, but are not limited to, the following: anhydrous calcium dihydrogen phosphate, anhydrous lactose, monosaccharide sugars such as mannitol, disaccharide sugars such as lactitol, powdered cellulose, pregelatinized starch, and the like. Anhydrous calcium dihydrogen phosphate is also commercially available in pharmaceutically acceptable purity (e.g., A-TAB, Rhome Poulenc).

Examples of liquid and semi-solid carriers with the necessary hydrophobicity include, but are not limited to, the following: polyglycosylated glycerides, such as Gelucire 44/14; complex fats of vegetable origin, such as theobroma oil, carnauba oil; vegetable oils, such as peanut, olive, palm kernel, cottonseed, corn, soybean oil; hydrogenated vegetable oils, such as hydrogenated peanut, palm kernel, cottonseed, soybean, castor, coconut oil; natural fats of animal origin, such as beeswax, lanolin; fatty alcohols, such as cetyl, stearyl, leuryl, myristyl, palmityl, stearyl alcohol; esters, such as glyceryl stearate, glycol stearate, ethyl oleate, isopropyl myristate; solid, transesterified, semi-synthetic glycerides, for example Suppocire, Witepsol; liquid, transesterified, semi-synthetic glycerides, for example Miglyol 810/812; amides or fatty acid alkanolamides, for example stearamide ethanol, diethanol amides of coconut fatty acids; poly(oxyethylene) glycols, for example PEG 600, PEG 4000.

Liquids and semi-solids that function as carriers for dissolved paroxetine, have suitable dissolution characteristics, and have hydrophobicity similar to that of the liquid carriers described above, for example, include Labraphil, which is a liquid, transesterified, semi-synthetic glyceride, and PEG 400 of the poly(oxyethylene) glycol type.

The above solid and liquid carriers can be mixed with the above-described carriers capable of adequately dissolving paroxetine, and optionally with co-solvents to obtain anhydrous/hydrophobic paroxetine solutions. Carriers that already have suitable anhydrous/hydrophobic properties can also be mixed directly with paroxetine, in which case co-solvents can also be used to aid dissolution. The formulations can be filled into capsules, such as gelatin capsule shells or cellulose capsule shells with a low internal moisture content (e.g. Shionogi Qualicap, <3%).

Liquid, transesterified, semi-synthetic glycerides available in pharmaceutically acceptable grades include, but are not limited to, Labrafil M 2125CS (Gattefosse, France). In one specific process of the invention, paroxetine hydrochloride anhydrate is mixed with Labrafil M 2125CS (Gattefosse) to prepare a formulation for encapsulation in hard or soft gelatin capsules.

Paroxetine in the form of hydrochloride anhydrate can be prepared according to the methods described in International Patent Application WO 96/24595. Suitable processes for the preparation of paroxetine are described in, among others, the following patent documents: U.S. Patent Nos. 4,009,196, 4,902,801, 4,861,893 and 5,039,803, and International Patent Application PCT/GB93/00721.

The invention also provides oral, ingestible, solid dosage forms of paroxetine in which paroxetine is dissolved in a polymeric carrier. These forms may include, for example, tablets, pellets, spheroids, granules, lozenges or gels containing paroxetine in solid solution.

In order to achieve the desired unit dosage form, for example in the form of a melt-extruded tablet in which paroxetine is present in solution with the polymer carrier, the paroxetine must be soluble in the polymer carrier or in a solvent/co-solvent soluble in the polymer carrier to a degree that allows a sufficiently high concentration to be achieved so that the chosen tablet size and volume can contain the desired unit dosage. The solvent/co-solvent, in addition to dissolving the paroxetine, must be compatible with the polymer carrier material and physiologically acceptable for administration to patients.

If the solid dosage form consists of granules or pellets, an agglomerate of a large number of granules or pellets may be formed to form a unit dose. The granules or pellets may be filled into capsules or compressed into tablets, optionally with binders or excipients.

Since solid forms of paroxetine are generally only sparingly soluble in conventional solvents, suitable solvents/cosolvents and carriers for use in the above dosage forms and for administration to patients should be tested in conventional solubility tests for their ability to maintain adequate paroxetine concentrations. Solutions of higher active ingredient content in a suitable solvent can be prepared from a given form of paroxetine using conventional physical methods such as heating, shaking and sonication. Alternatively, good solvents for paroxetine can be used as cosolvents in small amounts to dissolve paroxetine in polymers suitable for melt extrusion, melt granulation, gel formation, but in which paroxetine is only poorly soluble. Solubilizers such as polysorbates, poloxamers, cyclodextrins, ionic and nonionic surfactants such as Pluronic F60 and sorbitan esters can be used to enhance the solubility of paroxetine hydrochloride in solvents that are suitable for polymers used to prepare solid solution systems in the form of tablets, pellets, granules, spheroids, but only poorly soluble in paroxetine.

The polymer and/or solvent used preferably provides a solubility of at least 10 mg/ml for paroxetine hydrochloride, more preferably allowing a concentration of at least 25 mg/ml of paroxetine hydrochloride to be achieved.

The use of polymers in the present invention to produce semi-solid/solid solution systems allows for very flexible use. In addition to filling hard/soft gelatin capsules, such systems can be used to produce melt-extruded systems such as tablets, pellets, spheroids and other shapes depending on the shape of the extruder die, or to produce pellets or granules by injection molding and/or melt granulation into various shapes. Alternatively, the granules can be milled and compressed into tablets or other shapes depending on the shape and design of the die.

Examples of pharmaceutical polymers used in the above applications include, but are not limited to, the following: film-forming and thermoplastic polymers, such as those generally accepted materials listed in international pharmacopoeias, such as poly(ethylene oxide) water-soluble resins, ethoxylated glycerides and triglycerides, cetyl esters, cetyl palmitate, glyceryl esters, poly(vinyl acetate), cellulose, lanolin-based products, vinyl resins, latex products, carbowax polyethylene glycols, gelatin (protein), ethylene oxide/glycol, such as ethylene glycol, glycol ethers and ethanolamines, unipol polymers, polypropylene resins, silicone products, saturated polyglycosylated glycerides, glyceryl behenate, glyceryl palmitostearate, semi-synthetic glycerides and vinyl acetate monomers. These polymers can perform the following functions: active ingredient carrier and/or solubilizer and/or binder and/or permeability enhancer.

In order to facilitate the solubilization of paroxetine in the above-mentioned solid, semi-solid and polymeric carriers, solvents that adequately dissolve paroxetine can be used as co-solvents, such as — among others — the following solvents already mentioned above: propylene carbonate, triacetin, glycerin, leuroglycol, propylene glycol, «·*** -- * ·♦ * • » w * V* *

- 17 - <·-··< λ:** polyethylene glycol (PEG) 300, glycofurol, polyethylene glycol 400, isopropyl alcohol (IPA), Span 20, transcutol, Labrasol, Labrafil, Olepal, glyceryl linoleate (Maisine 35-1) and Pharmasolve. For physiological suitability, the aforementioned solvents are optionally used together with a co-solvent, such as ethanol. Such solvents and solvent systems that can be used in the present invention, as well as their functional equivalents, can be identified by the methods described below.

A suitable lanolin derivative, namely ethoxy-75 lanolin, is also available in pharmaceutically acceptable grades [Solan E (Croda)]. In one particular process of the invention, paroxetine hydrochloride hemihydrate is dissolved in Pharmasolve, then mixed with molten Solan E in a suitable mixer, followed by cooling, drying and sieving to form granules which are compressed into solid solution tablets.

One of the polyglycosylated glycerides is also available in pharmaceutically acceptable grades [Gelucire 44/14 (Gattefosse)]. In one specific process of the invention, paroxetine hydrochloride hemihydrate is dissolved in Pharmasolve, then mixed with molten Gelucire 44/14, and the mixture is then formed into a melt extrudate in the form of tablets and/or pellets after cooling.

Polyethylene glycols of various molecular weights are also available in pharmaceutically acceptable grades, such as PEG 400 (Union Carbide Corp., BASF). In one specific process of the invention, paroxetine hydrochloride hemihydrate is dissolved in PEG 300 and the solution is mixed with molten PEG 4000 to form melt-extruded materials which, upon cooling, can be formed into tablets and/or pellets as solid solutions.

The solid solution may optionally contain one or more antioxidants, such as tocopherols, ascorbic acid, ascorbic palmitate, thiodipropionic acid, bis(hydroxytoluene) (BHT), bis(hydroxyanisole) (BHA), gallic acid, gallic acid propyl/octyl/dodecyl ester, benzyl alcohol and nordihydroguaiaretic acid, and optionally pH modifiers and chelating agents, such as citric acid and EDTA.

A further object of the invention is to provide solid dosage forms which are coated with an enteric coating to prevent the release of paroxetine in the acidic environment of the stomach. This is to prevent unwanted, uncontrolled precipitation of paroxetine from solution and to allow the delivery of paroxetine in a non-aqueous solution to the intestinal mucosa, if desired, to modify the absorption characteristics of the active ingredient.

The solid solution/semi-solid systems of the invention can be coated with a suitable polymer using melt granulation or hot melt coating, for example with Precirol ATO 5 (glyceryl palmitostearate) to mask the taste of paroxetine and/or with methacrylic acid copolymer C (for example Eudragit L 30 D-55) to form an enteric coating.

Semi-solid or gel formulations may optionally be encapsulated. The viscosity characteristics of semi-solid or gel formulations may be modified by the choice of initial solvent and the amount of solvent, or by the appropriate use of co-solvents or thickeners.

The semi-solid or gel carrier containing dissolved paroxetine can be filled into capsules using conventional encapsulation techniques.

Self-supporting, solid paroxetine solutions in the form of tablets, pellets, spheroids or granules can be successfully prepared by using Solan E, Gelucire, higher molecular weight polyethylene glycols (PEGs) and gelatin-based gels, as well as various co-solvent components.

For example, paroxetine is first dissolved in co-solvent components such as PEG 300, Pharmasolve and a water/ethanol mixture (with adequate mixing to ensure complete wetting/solubilization). The resulting mixture is preheated and then added to appropriate portions of a molten polymer such as Gelucire 44/14 (melting point: 42-46 °C), Solan E (melting point: 45-50 °C), PEG 6000 (melting point: 55-63 °C), PEG 4000 (melting point: 50-58 °C) or gelatin (gelatin melted at 50-55 °C in liquid co-solvents). The samples are then left at ambient conditions to allow the polymer to resolidify. Solid dosage forms such as tablets, pellets, spheroids and gels can then be prepared using suitable forming tools. During the melt phase, the active ingredient molecules dissolved in the polymer remain dissolved in the final product, in the form of a solid solution. Transparent solid solutions containing dissolved active ingredient can be prepared with gelatin-based formulations.

As mentioned above, paroxetine hydrochloride is preferably used in a form other than the hemihydrate, and the formulation of the self-supporting solid dosage forms is carried out under conditions under which no detectable conversion to the hemihydrate occurs during the manufacturing process. Paroxetine hydrochloride may be, for example, in an amorphous form or in a crystalline anhydrate form.

As also mentioned above, the former object can be achieved, for example, by using carriers or supports which are essentially anhydrous (i.e. contain less than 2% by weight, more preferably less than 1.5% by weight, preferably less than 1% by weight of water) or which are essentially hydrophobic.

The therapeutic uses of the paroxetine compositions of the invention include, but are not limited to, the treatment of the following disorders: alcoholism, anxiety, depression, obsessive-compulsive disorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and drug addiction (collectively referred to hereinafter as "Disorders ^" ).

Further objects of the invention include: the use of paroxetine dissolved in a carrier to prepare oral, ingestible capsules or solid dosage forms for the treatment or prevention of one or more disorders;

A method for treating Disorders comprising administering to a patient suffering from one or more Disorders an effective or prophylactic amount of a solution of paroxetine with a carrier in an oral, ingestible capsule or solid dosage form;

A method for treating Disorders comprising administering to a patient suffering from one or more Disorders an effective or prophylactic amount of a solution of paroxetine with a carrier in the form of a liquid composition according to the invention.

The compositions of the invention can also be used for veterinary treatment of animals.

The invention is illustrated by the following examples.

(10.0 mg of anhydrous paroxetine free base is equivalent to 11.8 mg of paroxetine hydrochloride; the conversion factor from paroxetine hydrochloride to anhydrous paroxetine base is 0.8787).

In Examples 1-10, paroxetine is dissolved in a vehicle, optionally assisted by a cosolvent, and the solution is then filled into capsules.

Example 1

Excipient mg/capsule paroxetine hydrochloride 22.22 polyethylene glycol 400 450.0 capsule Size 11 Oblong Soft Gel

Example 2

Excipient mg/capsule paroxetine hydrochloride 22.22 polyethylene glycol 400 400.0 ethanol 45.0 capsule

Size 0 Hard Shell, layered capsule enteric capsule

Example 3

Carrier material paroxetine hydrochloride propylene glycol Size 8 Oblong Soft Gel mg/capsule 22.22 350.0 coating methacrylic acid type C copolymer 32, 0 propylene glycol Example 4 8.0 Carrier mg/capsule paroxetine—hydrochloride 22, 22 fractionated coconut oil 300, 0 polyethylene glycol 400 150, 0 polysorbate 80 Size 11 Oblong Soft Gel 50.0

Example 5

Excipient paroxetine hydrochloride mg/capsule

22.22

glycerin 100, 0 propylene glycol 100.0 ptopyl gallate 0, 3 capsule Size 5 Oblong Soft Gel Example 6 Carrier mg/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 Carrier mg/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 Carrier mg/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 Carrier mg/capsule paroxetine—hydrochloride 22.22 lauroglycol 400 100, 0 Pharmasolve 10, 0 citric acid 2.0 capsule Size 3 Hard Shell, layered

Example 10

Carrier mg/capsule paroxetine—hydrochloride 22.22 polyethylene glycol 400 50, 0 Pharmasolve 10, 0

citric acid 2.0 capsules

Starch Capil

In Example 11, paroxetine is dissolved in a hydrophobic carrier.

Example 11 mg paroxetine hydrochloride t

22.22

Labrafil M 2125CS

227.78 capsule weight

250.00

In Examples 12-30, paroxetine was dissolved in a co-solvent and the solution was then mixed with a molten polymer. Clear solutions of paroxetine were obtained before the polymers solidified.

Example 12 Paroxetine hydrochloride 22.76 mg PEG 300 200.00 mg PEG 4000 300.00 mg d, L-α-tocopherol 0.1% w/w pill ascorbyl palmitate 0.1% by weight Example 13 paroxetine hydrochloride 45.52 mg Gelucire 44/14 227.78 mg pill Pharmasolva 100.00 mg Example 14 paroxetine hydrochloride 22.76 mg pill Gelucire 44/14 227.78 mg Example 15 paroxetine hydrochloride 68.28 mg Solan E (ethoxy-75 lanolin) 350.00 mg pill Pharmasolve 150.00 mg

Example 16

pill paroxetine hydrochloride PEG 1450 22.76 mg 227.78 mg Example 17 paroxetine hydrochloride 22.76 mg pill PEG 4000 227.78 mg Example 18 paroxetine hydrochloride 19.91 mg PEG 300 200.00 mg PEG 1450 300.00 mg d,L-a-tokoferői 0.1% by weight pill as sorbyl palmitate 0.1% by weight Example 19 paroxetine hydrochloride 22.76 mg tablet Suppocire DM 227.78 mg Example 20 paroxetine hydrochloride 72.96 mg gelatin 100.00 mg purified water 350.00 mg Pharmasolve 150.00 mg polysorbate 80 1 drop gel methylparaben 0.2% by weight

Example 21 gel

paroxetine—hydrochloride 42.67 mg gelatin 50.00 mg purified water 200.00 mg propylene glycol 400.00 mg propyl gallate 0.1% by weight ascorbic acid 0.1% by weight polysorbate 80 1 drop

Example 22

paroxetine—hydrochloride 113.79 mg gelatin 50.00 mg purified water 200.00 mg Pharmasolve 200.00 mg propylene glycol 200.00 mg polysorbate 80 1 drop gel methylparaben 0.2% by weight Example 23 paroxetine—hydrochloride 102.41 mg gelatin 50.00 mg purified water 200.00 mg Pharmasolve 200.00 mg ethanol 200.00 mg polysorbate 80 1 drop gel methylparaben 0.2% by weight

Example 24

paroxetine—hydrochloride 28.45 mg gelatin 50.00 mg purified water 200.00 mg ethanol 200.00 mg propylene glycol 200.00 mg gel polysorbate 80 1 drop Example 25 paroxetine—hydrochloride 45.52 mg gelatin 50.00 mg purified water 200.00 mg propylene glycol 400.00 mg PEG 300 50.00 mg gel polysorbate 80 1 drop Example 26 paroxetine—hydrochloride 11.38 mg gelatin 50.00 mg purified water 500.00 mg propylene glycol 100.00 mg gel polysorbate 80 1 drop Example 27 paroxetine—hydrochloride 28.45 mg gelatin 50.00 mg purified water 500.00 mg propylene glycol 300.00 mg

gel polysorbate 80 1 drop Example 28 paroxetine—hydrochloride 68.28 mg gelatin 50.00 mg purified water 300.00 mg Pharmasolve 150.00 mg propylene glycol 150.00 mg gel polysorbate 80 1 drop Example 29 paroxetine—hydrochloride 79.65 mg gelatin 50.00 mg purified water 300.00 mg Pharmasolve 150.00 mg ethanol 150.00 mg polysorbate 80 1 drop gel methylparaben 0.2% by weight Example 30 paroxetine—hydrochloride 17.07 mg gelatin 50.00 mg purified water 300.00 mg propylene glycol 150.00 mg ethanol 150.00 mg gel polysorbate 80 1 drop

In Examples 31-44, paroxetine is first dissolved in Pharmasolve, then the resulting solution is mixed with oil and lipid carriers, and the paroxetine is thus dissolved in the carrier to obtain liquid formulations that can be encapsulated (Examples 36-42) and enteric coated (Examples 43-45).

Composition System/solution appearance ^A Paroxetine solution stability* Example 31 Labrasol 2.25 ml Pharmasolve 0.25 ml active ingredient 125 mg clear, pale yellow solution clear, very pale pink solution Example 32 Cithrol 4D1 2.25 ml Pharmasolve 0.25 ml active ingredient 125 mg clear, pale yellow solution clear, pale pink solution Example 34 sunflower oil 2.25 ml Pharmasolve 0.25 ml active ingredient 125 mg clear, pale yellow solution no change clear, very pale yellow solution Example 35 soybean oil 2.25 ml Pharmasolve 0.25 ml active ingredient 125 mg clear, pale yellow solution no change clear, pale yellow solution Example 36 peanut oil 2.25 ml Pharmasolve 0.25 ml active ingredient 125 mg clear, pale yellow solution no change clear, very pale yellow solution

*: storage for 25 days at room temperature (visual observation) at the time of production (fresh sample)

For example: Composition System/solution appearance* Paroxetine solution stability* Compatibility with Locaps capsules 36. Labrafac CM10 4.50 ml Pharmasolve 0.50 ml Tween 80 1 drop active ingredient 250 mg clear, pale yellow solution clear, pale yellow solution yes 37. Labrafil M 1994CS 4.50 ml Pharmasolve 0.50 ml Tween 80 1 drop active ingredient 250 mg clear, pale yellow solution yellow, viscous/semi-solid yes 38. Labrasol 4.50 ml Pharmasolve 0.50 ml Tween 80 1 drop active ingredient 250 mg clear, pale yellow solution clear, pale yellow solution yes 39. Cithrol 4DL 4.50 ml Pharmasolve 0.50 ml Tween 80 1 drop active ingredient 250 mg clear, pale yellow solution clear, very pale pink solution yes

*: storage for 10 days at room temperature (visual observation) ^A : at the time of production (fresh sample)

For example: Composition System/solution appearance ^A Paroxetine solution stability* Compatibility with Locaps capsules 40. Labrafac CM10 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg active ingredient 500 mg clear, pale yellow solution clear, pale yellow solution yes 41. Labrasol 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg active ingredient 500 mg clear, pale yellow solution clear, pale yellow solution yes 42. Cithrol 4DL 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg active ingredient 500 mg clear, pale yellow solution clear, pale yellow solution yes

*: storage for 10 days at room temperature (visual observation) at the time of production (fresh sample)

Example 43

Labrasol 9.0 ml Pharmasolve 1.0ml Tween 90 2 drops ascorbic acid 1.0 mg

propyl gallate

1.0 mg .Λ

Sureteric 32.0 mg active ingredient 500 mg

Capsule: Licaps size 1 (fills 20 capsules)

Example 44

Labrasol 9.0 ml Pharmasolve 1.0 ml Tween 90 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg Eudragit L30D55 42.0 mg active ingredient 500mg Capsule: Size 11 Oblonge Soft Gel (For filling 15 capsules)

Example 45 Labrafac CM10 9.0 ml Pharmasolve 1, 0 ml Tween 90 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg Aquatic 52, 0 mg active ingredient 500 mg

Capsule: Size 0 Hard Shell, laminated (fills 15 capsules)

Claims (19)

PATENT CLAIMS 1. An oral, swallowable capsule containing paroxetine dissolved in a carrier. 2. An oral, ingestible capsule comprising a capsule shell containing paroxetine as the free base or a pharmaceutically acceptable salt or solvate thereof in solution with a liquid or solid carrier. 3. A capsule according to claim 2, wherein the carrier is a liquid solvent in the form of a free-flowing liquid, viscous liquid, semi-solid or gel in the capsule. A capsule according to claim 2, wherein the carrier is a solid or semi-solid solvent. A capsule according to claim 4, wherein the solid or semi-solid solvent is selected from the group consisting of natural and synthetic fats and waxes, and film-forming and thermoplastic polymers. 6. An oral, ingestible, solid dosage form comprising paroxetine dissolved in a solid, semi-solid or gel carrier. 7. A solid dosage form comprising tablets, pellets, spheroids, granules, lozenges or gels, wherein paroxetine is present in the form of a solid solution with a polymeric carrier. 8. Capsules and solid dosage forms according to any one of claims 1-7, which are coated to facilitate the administration of the active ingredient* 9. Capsules and solid dosage forms according to claim 8. tablets coated with coatings providing delayed or controlled release of paroxetine and/or taste-masking coatings. 10. Capsules and solid dosage forms according to any one of claims 1-9, wherein the paroxetine is used in the form of the hydrochloride hemihydrate or anhydrate. 11. Capsules and solid dosage forms according to any one of claims 1-9, wherein the paroxetine hydrochloride is used in a form other than the hemihydrate and the formulation is carried out under conditions under which no detectable conversion to the hemihydrate occurs during the manufacturing process. 12. Capsules and solid dosage forms according to claim 11, wherein the paroxetine hydrochloride is used in an amorphous form or in a crystalline anhydrate form. 13. Capsules and solid dosage forms according to claim 12, wherein the paroxetine hydrochloride is dissolved in a substantially hydrophobic or anhydrous carrier. 14. Capsules and solid dosage forms according to claim 12 or 13, wherein the paroxetine hydrochloride is dissolved in a carrier in the presence of substantially hydrophobic or anhydrous excipients. 15. A pharmaceutical composition comprising a solution of paroxetine in a mixture of a solubilizing agent and a lipid and/or oil. 16. A method for preparing a composition according to claim 15, characterized in that paroxetine is dissolved in a »·**· .··, .t S Z . ·* * ··· ···:··.-· u,.. * in a solubilizing agent, and then the resulting solution is mixed with an oil and/or lipid. 17. Use of paroxetine dissolved in a carrier for the preparation of oral, ingestible capsules or solid dosage forms according to any one of claims 1-14 for the treatment or prevention of one or more Disorders. 18. A method for treating Disorders comprising administering to a mammal suffering from one or more Disorders an effective or prophylactic amount of a solution of paroxetine in a carrier in an oral, ingestible capsule or solid dosage form according to any one of claims 1-14. 19. A method for treating Disorders, comprising administering to a mammal suffering from one or more Disorders an effective or prophylactic amount of a paroxetine solution in the form of a composition according to claim 15. The authorized person: Member of the International Patent Office R-b¥i2 Budapest, úí Π ' Tops·.»: 34-24-950. Fax: 34-24-32?·