SK7342000A3 - Formulations comprising dissolved paroxetine - Google Patents

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

Oral ingestion capsule containing paroxetine, process for its manufacture and use

Technical field

The invention relates to capsules and solid dosage forms for oral administration for swallowing containing paroxetine and the use of these capsules in therapy. More particularly, the invention relates to paroxetine antidepressant capsules.

BACKGROUND OF THE INVENTION

Pharmaceutical products with antidepressant and anti-Parkinsonian properties are described in US-A-3 912 743 and US-A-4 007 196. Among the disclosed compounds, paroxetine, (-) - trans isomer 4 (4 ^, -, fluorophenyl) -3- (3 ', ^{4-ethylenedioxy-phenoxymethyl)} -piperidine. Paroxetine hydrochloride hemihydrate is used in therapy for the treatment and prophylaxis of inter alia depression, obsessive compulsive disorders (OCD) and panic conditions.

Paroxetine hydrochloride hemihydrate is disclosed in EP-A-0 223 403 of the Beecham Group and non-hydrate forms A, B and C of paroxetine hydrochloride are described in WO 96/24 595 to SmithKline Beecham plc. All of the solid oral dosage forms of paroxetine hydrochloride marketed hitherto are in the form of oral swallow tablets containing hemihydrate. WO 95/16448 discloses that paroxetine appears to cause a pink coloration to the formulation; discoloration is not observed when paroxetine is formulated into tablets in a manner in which water is not present in the formulation; it may be, for example, a process for direct paroxetine compression or dry granulation of paroxetine and subsequent compression of tablets.

From the point of view of patient comfort and satisfaction with the dosage regimen, there is still a need for the preparation of new, alternative dosage forms to the prior art tablets for swallowing. Because of the low solubility of paroxetine hydrochloride in many solvents, this requirement is difficult to achieve.

For example, it is difficult to satisfy the requirement to prepare a capsule for swallowing

Of a sufficiently small size to allow the patient to swallow it comfortably, containing a sufficient effective amount of paroxetine in solution and using physiologically acceptable solvents capable of encapsulation. The present inventors have overcome these difficulties.

SUMMARY OF THE INVENTION

The present invention provides an oral capsule for ingestion containing paroxetine dissolved in a carrier.

An oral capsule for swallowing typically consists of a capsule-forming shell in which paroxetine as the free base or a pharmaceutically acceptable salt thereof or a solvate thereof is in solution in a carrier. The carrier may be liquid or solid.

The liquid carrier may be a solvent which is present in the capsule in the form of a flowable liquid, in the form of a viscous liquid, in the form of a semi-solid, or as a gel. The carrier can also be solid or semi-solid solvents such as fats and waxes, or film-forming thermoplastic polymers. Preference is given to solvents in which supersaturated solutions are formed, as the proportion of active ingredient can be increased by supersaturation.

When the carrier is a solid, semi-solid or gel, such carrier together with paroxetine may be self-supporting, without encapsulation. The self-supporting formulation may also be encapsulated by other means, such as by inserting it into a preformed capsule shell, for example by coating the encapsulating material. A self-supporting formulation without encapsulation may also be used as a dosage form.

In another aspect, the invention relates to a solid oral dosage form for swallowing comprising paroxetine dissolved in a solid, semi-solid or gel carrier.

The solid dosage form typically comprises tablets, pellets, spheroids, granules, lozenges or gels in which paroxetine is present as a solid solution in the polymeric carrier.

The capsules and solid dosage forms of the invention may be coated, for example, by the use of an active ingredient to the target part of the body

-3enterosolubile (acid resistant) coating materials to prevent paroxetine release in the stomach; the coatings may further serve to delay or control the release of paroxetine, and the coatings may further comprise an unpleasant taste masking agent. Optionally, the materials can be formulated into a carrier to achieve the above effects.

Paroxetine is preferably used in the form of the hydrochloride; it can be used as the monohydrate or as the anhydrous form A, B, C or D; or the paroxetine or paroxetine hydrochloride may be used in any other form, for example in the form of pharmaceutically acceptable salts other than the hydrochloride. Other suitable forms of paroxetine include the free base, amorphous and non-crystalline forms of paroxetine, and pharmaceutically acceptable paroxetine derivatives.

In one embodiment, paroxetine hydrochloride in a form other than the hemihydrate is used in the capsules or solid dosage forms of the invention; wherein said forms of paroxetine are formulated under conditions such that no detectable conversion to the hemihydrate occurs during the manufacturing process.

This overcomes the unexpected problem that even in relatively dry conditions, paroxetine hydrochloride anhydride tends to convert, at least in part, to hemihydrate during tabletting. Although this partial conversion is not dangerous, it creates difficulties in establishing and maintaining benchmarks in terms of legal requirements and quality control.

For example, paroxetine hydrochloride may be present in amorphous form or as an anhydride in crystalline form and dissolved in a carrier, or may be present in constitutive excipients which are substantially hydrophobic or substantially anhydrous, containing typically less than 2% water, more preferably less % of water and preferably less than 1% of water.

The amount of paroxetine used in each capsule is preferably adjusted so that a therapeutically effective amount of paroxetine is in a single unit dose. The unit dose preferably contains from 5 to 100 mg of paroxetine (expressed as free base). More preferably, the amount of paroxetine per unit dose is 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. The most preferred amount of paroxetine per unit dose is 20 mg.

In order to achieve the required unit dose in a capsule in which paroxetine is a solution in the carrier, the paroxetine must be dissolved in the carrier to an extent sufficient to allow the active ingredient to be of sufficient concentration to contain the required unit dose. In addition to the ability to dissolve paroxetine, the solvent must also be compatible with the capsule material and physiologically acceptable for administration to the patient.

Since solid forms of paroxetine are generally only slightly soluble in conventional solvents, the solvent suitable for use in the capsule and for administration to the patient should be subjected to conventional solubility tests to verify that the solvent makes it possible to achieve and maintain an appropriate concentration of paroxetine. Further, higher levels of the paroxetine form in a suitable solvent may be achieved using conventional physical techniques such as heating, shaking or ultrasonic sounding. Optionally, it can be used in small amounts of solvent that dissolve paroxetine well as co-solvents (solubilizers), thereby also achieving dissolution of paroxetine in liquids that are suitable for capsule material but in which paroxetine is poorly soluble. Polysorbates, poloxamers, cyclodextrins, as well as ionic and nonionic surfactants such as Pluronic F60 and sorbitan esters can be used as solubilizers; these increase the solubility of paroxetine hydrochloride in solvents suitable for capsule materials, but in which paroxetine is poorly soluble.

The term capsule for oral ingestion most preferably refers to a capsule having a volume of not more than 0.86 ml. Preferred capsules according to the invention have a volume of at most about 0.45 ml and in particular in the range of 0.2 to 0.4 ml, although according to the invention small capsules with a volume of 0.14 ml are also included. A typical capsule at the upper limit of the stated size range allowed for pharmaceutical use (soft gel elongated capsule, size 14) has a volume of 0.86 ml. At the 10 mg dose of paroxetine (calculated as free base) to be 11.1 mg of paroxetine required in the volume of 0.86 ml concentration of 12.9 mg.ml ^"1 and 1.29% (w / v). Therefore, the preferred such solvent to be dissolved using a minimum of 10 mg.ml ^"1 paroxetine hydrochloride and more preferably the solubility should be at least 25 mg.ml ^'first For larger doses of the drug with the same formulation, larger ones may be used where necessary

-5capsules, for example 0.95 ml (size 00 hard capsules), Supro A capsules (0.68 ml) or size 12 soft elongated capsules (1.01 ml volume).

The solubility level of paroxetine excludes the use of many solvents commonly used as liquid carriers for encapsulated drugs such as vegetable oils sunflower oil, safflower oil, peanut oil, soybean oil, cottonseed oil, corn oil, castor oil, apricot oil, olive oil, oil wheat germ, sesame oil, evening primrose oil, rapeseed oil as well as mineral oil and liquid paraffin. Other well known liquid carriers such as Miglyol (810 and 812), oleic acid, ethyl oleate, Span 80 and 85, lipophilic Labrafac, Plurol Oleique and Peceol (glycerol oleate) also do not have the ability to dissolve paroxetine to concentrations above 10 mg / ml. ¹ .

The present inventors have identified some solvents and solvent systems in which paroxetine dissolves to the extent desired. Such solvents include propylene carbonate, triacetin, glycerol, lauroglycol, propylene glycol, PEG 300, glycofurol, PEG 400, IPA, Span 20, Transkutol, Labrasol, Labrafil, Olepal, glycerol linoleate (Maisine 35-1) and Pharmasolve. When using the solvents mentioned, a cosolvent such as ethanol may be required for physiological suitability. The present invention includes said solvents and solvent systems as well as functional equivalents thereof, which can be identified by the methods set forth below.

The inventors have found that a particularly effective means for dissolving paroxetine, more particularly paroxetine hydrochloride, in particular hemihydrate, in a liquid, semi-solid or solid carrier, especially in oils and fats, is the use of a solubilizer such as N-methyl-2-pyrrolidone (Pharmasolve, International). Specialty Products, Texas, USA) as cosolvents.

According to a preferred embodiment of the invention, paroxetine, optionally as the free base or more typically than its pharmaceutically acceptable salt, for example the hydrochloride, is dissolved in a solubilizer and mixed with an oily or fat carrier before being filled into capsules.

The invention also encompasses a new formulation of a paroxetine solution, optionally as a free base or more typically than a pharmaceutically acceptable salt thereof, for example the hydrochloride in a mixture of a solubilizer and a fat and / or oil.

When using a solubilizer, paroxetine can also be dissolved in oils and fats previously assessed as unsuitable solvents, such as soybean oil, sunflower oil, and peanut oil.

In the same way, paroxetine can also be dissolved in lipids, especially those derived from natural sources such as coconut oil glycerides, Cithrol 4DL (PEG-8 dilaurate). Examples of coconut oil glycerides include Labrasol and Labrafac CM10 (Gattefosse, France) which are Ca / C 10 polyglycolized coconut oil glycerides with a hydrophilic: lipophilic portion ratio of 14 to 10.

Formulations based on the use of solubilizer and oils / lipids are preferably formulated with at least one antioxidant to maintain storage stability of the solution. If the above solutions are required to be filled into capsules, then the compatibility of the solution with the capsule material should be tested.

The invention further encompasses the use of supersaturated solutions, for example in solid or semi-solid solvents such as fats and waxes. The supersaturated solutions can be easily prepared by heating and have a high stability for their inter alia very high viscosity.

The solvents used in a preferred embodiment of the invention contain less than 2%, more particularly less than 1.5%, preferably less than 1% water, or are substantially hydrophobic.

The solution may optionally contain one or more antioxidants such as tocopherol, ascorbic acid, ascorbic palmitate, thiodipropionic acid, bis-hydroxytoluene (BHT), bis-hydroxyanisole (BHA), gallic acid, propyl / octyl / dodecyl gallate, benzyl alcohol and nordihydroguaiaretic acid 1,4, bis [3,4-dihydroxyphenyl] -2,3-dimethylbutane) with or without the addition of pH modifiers and chelating agents such as citric acid and EDTA.

The capsule shell itself may be of any material commonly used for capsules, for example hard or soft gelatin capsules or starch capsules. In addition to taking into account the dissolving effect of the liquid carrier, further attention should be paid to the pH of the liquid in the capsule. For example, soft gels have limits of use at pH 2.5 to 7.5. Since the addition of paroxetine hydrochloride to the solvent system tends to reduce the pH of the system by at least one unit, solvent systems with a pH of less than 3.5 are generally not preferred.

The invention further includes capsules having an acid-resistant coating or incorporated acid-resistant material into the shell of the capsule; this is to prevent paroxetine from being released in the acidic environment of the stomach. The aim is not to allow unwanted uncontrolled precipitation of paroxetine from its solution in the acidic environment of the stomach and to allow its absorption properties from the non-aqueous solution to be applied only in the intestinal mucosal environment.

The liquid carrier may be present in the capsule as a flowable liquid, as a viscous liquid, as a semi-solid or as a gel. The viscosity properties may vary depending on the nature of the starting solvent or the particular cosolvents or thickeners used.

The liquid carrier or solid carrier or semi-solid carrier which has been liquefied or allowed to soften by heating can be filled together with dissolved paroxetine into capsules by conventional capsule technology.

Paroxetine hydrochloride may be required to be used in a form other than hemihydrate; another form is formulated into capsules or solid dosage forms under conditions that do not allow conversion to the hemihydrate during the preparation process to an extent that can be determined. Paroxetine hydrochloride may be present, for example, in amorphous form or as a crystalline anhydride.

This may be achieved, for example, by the use of excipients or carriers which are substantially anhydrous (containing, for example, less than 2%, preferably less than 1.5%, preferably less than 1% water), or which are substantially hydrophobic. The capsules and solid dosage forms are then preferably packaged with a desiccant to prevent conversion of the anhydride to the hemihydrate upon storage.

The invention further relates to a process for the preparation of paroxetine hydrochloride anhydride capsules, or solid dosage forms thereof, with no detectable amount of hemihydrate; said process being characterized by the use of conditions in which no detectable conversion of the anhydride to the hemihydrate occurs during the preparation process. Said conditions can be achieved by using substantially anhydrous / hydrophobic excipients and / or carriers under conditions of low relative humidity.

Examples of excipients with the necessary low moisture content include substances such as anhydrous dibasic calcium phosphate, anhydrous lactose, mono-

Carbohydrates such as mannitol, disaccharides such as lactitol, powdered cellulose, pregelatinized starch and the like. Anhydrous dibasic calcium phosphate is also commercially available in a pharmaceutically required purity, for example, A-TAB (Rhône Poulenc).

Examples of liquid and semi-solid excipients with the necessary hydrophobicity include substances such as polyglycolized glycerides, for example Gelucire 44/14; composite fatty materials of vegetable origin, for example theobromine oil, carnauba wax; vegetable oils such as peanut oil, olive oil, palm kernel fat, cottonseed oil, corn oil, soybean oil; hydrogenated vegetable oils such as hydrogenated peanut oil, hydrogenated palm kernel fat, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated coconut oil; natural fatty materials of animal origin such as beeswax, lanolin, fatty alcohols such as cetyl, stearyl, lauryl, myristyl, palmityl alcohol; esters such as glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate; solid interesterified semisynthetic glycerides such as Suppocire, Witepsol; liquid interesterified semisynthetic glycerides, for example Miglyol 810/812; fatty acid amides or alkolamides, for example, ethanol stearyl amide, coconut fatty acid diethanolamide; polyoxyethylene glycols, for example PEG 600, PEG 4000.

Liquid and semisolids with suitable solubility characteristics to perform the role of dissolved paroxetine carriers and with similar hydrophobicity to the above-mentioned liquid excipients include Labraphil, a liquid interesterified semi-synthetic glyceride, and PEG 400, polyoxyethylene glycol.

In order to obtain solutions of paroxetine with anhydrous / hydrophobic properties, the solid and liquid excipients can be mixed with the carriers described above with suitable solubility for paroxetine and, if necessary, with cosolvents. Carriers that already have suitable anhydrous / hydrophobic properties can be mixed directly with paroxetine, again if it is necessary to promote dissolution as well as with cosolvents. Said formulations may be filled into capsules, for example, gelatin shells of the capsules, or into cellulosic shells with a truly low moisture content (for example, Shionogi Qualicaps capsules, <3% water).

Liquid interesterified semisynthetic commercially available glycerides with pharmaceutically required purity include Labrafil M 2125CS (Grattfosse). In one embodiment of the method of the invention, paroxetine hydrochloride anhydride is admixed with Labrafil M 2125CS (Gattfosse) to form a formulation suitable for encapsulation into hard or soft gelatin capsules.

Paroxetine hydrochloride anhydride can be prepared as disclosed in WO 96/24 595. Suitable processes for preparing paroxetine include those disclosed in U.S. Patents 4,009,196, 4,902,801, 4,861,893 and 5,039,803, and PCT / GB 93/00721.

The invention further encompasses solid dosage forms of paroxetine for oral ingestion in which the paroxetine is dissolved in a polymeric carrier. These forms include tablets, pellets, spheroids, granulates, lozenges and gels containing paroxetine in solid solution.

In order to achieve a unit dose, for example, in a melt-extruded tablet in which paroxetine is in solution in the polymeric carrier, the paroxetine must be soluble in the polymeric carrier or in a solvent / cosolvent soluble in the polymeric carrier to achieve a sufficient concentration thereof. so that the tablet can contain a unit dose at the selected size and volume. In addition to being able to dissolve paroxetine sufficiently, the solvent / cosolvent must be compatible with the polymeric carrier material and be pharmaceutically acceptable to the patient.

If the solid dosage form is a granulate or pellet, then more granules or pellets must be pooled together in a unit dose. The granules or pellets may be used for filling capsules or for compression into tablets, optionally with a binder and / or other excipients.

Since solid paroxetine forms are generally sparingly soluble in conventional solvents, solvent / co-solvent and carriers suitable for use in said solid forms and for administration to a patient are subjected to conventional dissolution tests to verify that the solvent allows the appropriate concentration of paroxetine to be maintained. Further, higher levels of the paroxetine form in a suitable solvent can be achieved using conventional physical techniques such as heating, shaking, and ultrasonic sounding. Optionally small

-10-amounts of solvents that dissolve paroxetine well as co-solvents (solubilizers) to dissolve paroxetine in polymers that are suitable for melt extrusion, melt granulation, gel formulation but in which paroxetine is poorly soluble. Polysorbates, poloxamers, cyclodextrins, ionic and nonionic surfactants such as Pluronic F60 and sorbitan esters can be used as solubilizers; these substances increase the solubility of paroxetine hydrochloride in solvents in which paroxetine is poorly soluble, but are suitable for the polymers used to prepare solid solvent systems in the form of tablets, pellets, granules, or spheroids.

Preferably, the polymer used and / or solvents are capable of dissolving at least 10 mg.ml ^"1 paroxetine hydrochloride and more preferably, the solubility of paroxetine in the solvent is at least 25 mg ml ^1st

The use of polymers to prepare semi-solid / solid solution systems in the present invention generally offers a wide flexibility in the preparation process. In addition to filling in hard / soft gelatin capsules, the polymers used can be processed by melt extrusion to form tablets, pellets, spheroids or other shapes, depending on the shape of the mouth of the extruder; or the polymers can be injection molded and / or melted to form pellets or granules. Optionally, the granulate may be milled and the tablet stock compressed into tablets or other shapes, depending on the shape and design of the mold.

Examples of pharmaceutical polymers used in the methods are film forming and thermoplastic polymers which are generally on the International Pharmacopoeias List of Approved Substances, for example polyethylene oxide, water-soluble resins, ethoxylated glycerides and triglycerides, cetyl esters, glycerol palmitate polyvinyl acetate, cellulose, lanolin-based products, latex products, carbocarbon polyethylene glycols, gelatin (protein), ethylene oxide / glycol such as ethylene glycol, glycol ethers and ethanolamines, unipolar polymers, polypropylene resins, silicone products, saturated polyglycol glycerate glycerate glycerates, glycerides and vinyl acetate monomers. These polymers perform the function (s) of the drug carrier and / or solubilizer and / or binder and / or permeability enhancers.

-11 Solvents in which paroxetine is sufficiently soluble, such as propylene carbonate, triacetin, glycerol, lauryl glycol, propylene glycol, PEG 300, glycofurol, PEG 400, IPA, Span 20, Transkutol, Labrasol, Labrafil, Olepal, glyceryl linoleate (Maisine 35 and Pharmasolve mentioned above can be used as co-solvents to promote solubilization of paroxetine in said solid, semi-solid and polymeric carriers. For reasons of physiological suitability, it may be desirable to use said solvents together with another cosolvent such as ethanol. The present invention encompasses the use of these solvents and solvent systems as well as functional equivalents thereof, which can be identified by the following methods.

The corresponding lanolin derivative, for example ethoxy-75 lanolin, is also commercially available in a pharmaceutically required purity such as Solan E (C rod a). In one embodiment of the present invention, paroxetine hydrochloride hemihydrate is dissolved in Pharmasolve and mixed in a suitable mixer with molten Solan E; Upon cooling, a granulate is formed from the mixture which is compressed into tablets after drying the solid solution and sieving.

Polyglycolized glyceride is also commercially available in a pharmaceutically required purity, for example, as Gelurice 44/14 (Gattfosse). In one embodiment of the invention, paroxetine hydrochloride hemihydrate is dissolved in Pharmasolve and blended in a suitable mixer with melted Gelucire 44/14 to form a melt extrudate which is shaped into tablets and / or pellets with cooling.

Polyethylene glycols of different molecular weights and in the required pharmaceutical purity are also commercially available, for example PEG 4000 (Union Carbide Corp. and BASF). In one embodiment of the invention, paroxetine hydrochloride hemihydrate is dissolved in PEG 300 and then mixed with molten PEG 4000 to provide a melt extrudable material; this material forms a solid solution upon cooling and can be shaped as tablets and / or pellets.

The solid solution may optionally contain one or more antioxidants, for example tocopherol, ascorbic acid, ascorbic palmitate, thiodipropionic acid, bis-hydroxytoluene (BHT), bis-hydroxyanisole (BHA), gallic acid, propyl / octyl / dodecyl gallate, benzyl alcohol, and nordihydroguine

-12 (1,1'-bis-4'-dihydroxyphenyl-6'-dimethylbutane) with or without the addition of pH modifiers and chelating agents such as citric acid and EDTA.

The invention further encompasses a solid dosage form which may have an acid-resistant coating; this is to prevent paroxetine from being released in the acidic environment of the stomach. The aim is not to allow unwanted uncontrolled precipitation of paroxetine from its solution in an acidic environment and to allow its absorption properties from the solution to be applied only in the aqueous environment of the intestinal mucosa.

The solid solution / semi-solid material systems of the present invention may be coated with a suitable polymer, which may also be used for melt granulation or hot melt coating such as Precirol ATO 5 (glyceryl palmitostearate), for masking the taste of paroxetine and / or the system may be coated with acid-resistant (enterosoluble) coating of methacrylic acid copolymer C (e.g. Eudragit L 30 D-55).

Semi-solid or gel formulations may optionally be encapsulated. The viscosity characteristics of semi-solids and gels can be varied by the choice and amount of solvent or by the appropriate use of cosolvents or thickeners.

The semi-solid or gelled paroxetine carrier can be filled into capsules by a conventional capsule technique.

The self-supporting solid paroxetine solutions can be successfully prepared in the form of tablets, pellets, spheroids, granules using Solan E, Gelucir, higher molecular weight polyethylene glycols and gelatin-based gels and various co-solvents.

For example, paroxetine is first dissolved in a co-solvent constitutive excipient such as PEG 300, Pharmasolve and water / ethanol (using efficient mixing to ensure complete wetting and solubilization). The resulting mixture is then preheated and added to a suitable amount of melted polymer, for example Gelucir 44/14 (m.p. 42-46 ° C, Solan E (mp 45-50 ° C), PEG 6000 (mp 55-63 ° C). C), PEG 4000 (melting point 50-58 ° C) or Gelatin (gelatin in liquid co-solvents; melting point between 50-55 ° C) The samples can then be left at ambient temperature until the polymer solidifies. The molds can then be molded into tablets, pellets, spheroids and gels.

- 13 dissolved in the polymer during the melting phase remains dissolved in the solid solution also in the final product. Transparent solid solutions containing dissolved drug can be made using gelatin-based formulations.

It has already been mentioned that paroxetine hydrochloride may be required to be used in a form other than its hemihydrate to formulate self-supporting solid dosage forms and under conditions where conversion to hemihydrate cannot be detected during processing. The paroxetine hydrochloride may then be present, for example, in amorphous form or as a crystalline anhydride.

It has already been stated that such conditions can be achieved, for example, by the use of excipients or polymeric carriers which are substantially anhydrous (i.e., contain less than 2%, more preferably less than 1.5%, preferably less than 1% water), or which are essentially hydrophobic.

The therapeutic use of the paroxetine formulations of the invention includes the treatment of alcoholism, anxiety, depression, obsessive compulsive disorder, panic, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression , dysthymia and substance abuse; hereinafter referred to as malfunctions.

According to the present invention further comprises:

The use of paroxetine dissolved in a carrier for the manufacture of capsules for oral administration for swallowing or for the manufacture of solid dosage forms for the treatment or prophylaxis of one or more disorders;

A method of treating disorders; said method comprising administering an effective or prophylactic amount of paroxetine in solution in a carrier in an oral capsule for swallowing, or in a solid dosage form, to a person suffering from one or more disorders;

A method of treating disorders; said method comprising administering to a person suffering from one or more disorders an effective or prophylactic amount of paroxetine as a solution in the liquid formulation of the invention.

The formulations of the invention may also be used for veterinary treatment of animals when such treatment is useful.

The invention is illustrated by the following examples.

Example 14 (Note: 10 mg of anhydrous paroxetine free base is equivalent to 11.38 mg of paroxetine hydrochloride - the conversion factor from paroxetine hydrochloride to anhydrous paroxetine base is 0.8787).

In Examples 1 to 10, paroxetine is dissolved in a carrier, optionally with a cosolvent, and filled into capsules.

Example 1

component mg per capsule paroxetine hydrochloride 22,22 polyethylene glycol 400 450.0 Capsule, size 11, soft gel, elongated

Example 2

component mg per capsule paroxetine hydrochloride 22,22 polyethylene glycol 400 400.0 ethanol 45.0 Capsule, size 0, hard shell, bandaged

-15Example 3

component mg per capsule paroxetine hydrochloride 22,22 propylene glycol 350.0 Capsule, size Ô, soft gel, num lhovastá acid resistant coating methacrylic acid 32.0 copolymer type C propylene glycol 8.0

Example 4

component mg per capsule paroxetine hydrochloride 22,22 polyethylene glycol 400 150.0 fractionated coconut oil 300.0 polysorbate 80 50.0 Capsule, size 11, soft gel, elongated

Example 5

component mg per capsule paroxetine hydrochloride 22,22 glycerol 100.0 propylene glycol 100.0 propyl gallate 0.3 Capsule, size 5, soft gel, etc. lhovastá

- 16Example 6

component 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, soft gel, etc. lhovastá

Example 7

component mg per capsule paroxetine hydrochloride 22,22 Pharmasolve 50.0 high purity cottonseed oil 150.0 propyigalát 0.2 Capsule, size 4, soft gel, etc. lhovastá

Example 8

component mg per capsule paroxetine hydrochloride 22,22 polyethylene glycol 400 50.0 Pharmasolve 10,0 citric acid 2.0 Capsule, size 3, soft gel, oval

- 17Example 9

component mg per capsule paroxetine hydrochloride 22,22 lauroglycol 400 100.0 Pharmasolve 10,0 citric acid 2.0 Capsule, size 3, hard shell, bandaged

Example 10

component mg per capsule paroxetine hydrochloride 22,22 polyethylene glycol 400 50.0 Pharmasolve 10,0 citric acid 2.0 starch capsule

Example 11

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

paroxetine hydrochloride 22.22 mg Labrafil M 2125CS 227.78 mg Capsule weight 250.0 mg

In Examples 12 to 30, paroxetine was dissolved in a co-solvent and then blended into the molten polymer. A clear solution of paroxetine was obtained before solidification of the polymer.

-18Example 12

component mg paroxetine hydrochloride 22.76 PEG 300 200.00 PEG 4000 300.00 dl-a-tocopherol 0.1% (w / w) ascorbyl 0.1% (w / w) tablet

Example 13

component mg paroxetine hydrochloride 45,52 Gelucire 44/14 227.78 Pharmasolve 100.00 tablet

Example 14

component mg paroxetine hydrochloride 22.76 mg Gelucire 44/14 227.78 mg tablet

Example 15

component mg paroxetine hydrochloride 68.28 Solan E (ethoxy 75 lanolin) 350.00 Pharmasolve 150.00 tablet

-19Example 16

Example 17

Example 18

Example 19

component mg paroxetine hydrochloride 22.76 mg PEG 1,450 227.78 mg tablet

component mg paroxetine hydrochloride 22.76 mg PEG 4000 227.78 mg tablet

component mg paroxetine hydrochloride 19.91 PEG 300 200.00 PEG 1,450 300.00 dl-a-tocopherol 0.1% (w / w) ascorbyl 0.1% (w / w) tablet

component mg paroxetine hydrochloride 22.76 Suppocire DM 227.78 tablet

-20Example 20

component mg paroxetine hydrochloride 73,96 Gelatine 100.00 purified water 350.00 Pharmasolve 150.00 polysorbate 80 1 drop metalparabén 0.2% (w / w) gel

Example 21

component mg paroxetine hydrochloride 42.67 Gelatine 50.00 purified water 200.00 propylene glycol 400.00 propyl gallate 0.1% (w / w) ascorbic acid 0.1% (w / w) polysorbate 80 1 drop gel

Example 22

component mg paroxetine hydrochloride 113.79 Gelatine 50.00 purified water 200.00 propylene glycol 200.00 Pharmasolve 200.00 methylparaben 0.2% (w / w) polysorbate 80 1 drop gel

-21 Example 23

component mg paroxetine hydrochloride 102.41 Gelatine 50.00 purified water 200.00 Pharmasolve 200.00 ethanol 200.00 polysorbate 80 1 drop methylparaben 0.2% (w / w) gel

Example 24

component mg paroxetine hydrochloride 28.45 Gelatine 50.00 purified water 200.00 propylene glycol 200.00 ethanol 200.00 polysorbate 80 1 drop gel

Example 25

component mg paroxetine hydrochloride 45,52 Gelatine 50.00 purified water 200.00 propylene glycol 400.00 PEG 300 50.00 polysorbate 80 1 drop gel

-22Example 26

component mg paroxetine hydrochloride 11.38 Gelatine 50.00 purified water 500.00 propylene glycol 100.00 polysorbate 80 1 drop gel

Example 27

component mg paroxetine hydrochloride 28.45 Gelatine 50.00 purified water 300.00 propylene glycol 300.00 polysorbate 80 1 drop gel

Example 28

component mg paroxetine hydrochloride 68.28 Gelatine 50.00 purified water 300.00 propylene glycol 150.00 Pharmasolve 150.00 polysorbate 80 1 drop gel

-23Example 29

component mg paroxetine hydrochloride 79,65 Gelatine 50.00 purified water 300.00 Pharmasolve 150.00 polysorbate 80 1 drop methylparaben 0.22% (w / w) ethanol 150.00 gel

Example 30

component mg paroxetine hydrochloride 17.07 Gelatine 50.00 purified water 300.00 propylene glycol 150.00 ethanol 150.00 polysorbate 80 1 drop gel

In Examples 31-44, paroxetine was first dissolved in Pharmasolve and the obtained solution was mixed with an oily and lipid carrier such that the dissolved paroxetine in the carrier provides a liquid formulation that can be filled into capsules (Examples 32-42) as well as an enterosoluble coating formulation. (Examples 43-45).

Example composition System / solution appearance * Pxt solution stability Example 31 Labrasol 2.25 ml clear, light yellow solution clear very light pink solution Example 32 Cithrol 4 DL Pharmasolve drug 2.25 ml 0.25 ml 125 mg clear, light yellow solution clear, light pink solution Example 34 sunflower oil Pharmasolve drug 2.25 ml 0.25 ml 125 mg clear, light yellow solution unchanged, clear, very pale yellow solution Example 35 soybean oil Pharmasolve drug 2.25 ml 0.25 ml 125 mg clear, light yellow solution unchanged, clear, very pale yellow solution Example 36 peanut oil Pharmasolve drug 2.25 ml 0.25 ml 125 mg clear, light yellow solution unchanged, clear, very light yellow solution

Note: stored for 25 days at room temperature (visual observation) ** at the time of preparation (fresh samples)

Example composition appearance system / solution " stability Pxt solution * Licaps Capsule Compatibility * Example 36 Labrafac CM10 4.50 ml Pharmasolve 0.50 ml Tween 80 1 drop drug 250 mg clear, light yellow solution clear, light yellow solution Yes Example 37 Labrafil M1994Cs 4.50 ml Pharmasolve 0.50 ml Tween 80 1 drop drug 250 mg clear, light yellow solution yellow viscous / semi-solid Yes

Example 38 Labrasol 4.50 ml Pharmasolve 0.50 ml Tween 80 1 drop drug 250 mg clear, light yellow solution clear, light yellow solution Yes Example 39 Cithrol 4DL 4.50 ml Phar.asolve 0.50 ml Tween 80 1 drop drug 250 mg clear, light yellow solution clear very light yellow solution Yes

Note: stored for 10 days at room temperature (visual observation) ** at the time of preparation (fresh samples)

Example composition appearance ** system / solution Pxt solution stability * Licaps Capsule Compatibility * Example 40 Labrafac CMIO 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg drug 500 mg clear, light yellow solution clear, light yellow solution Yes Example 41 Labrasol 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg drug 500 mg clear, light yellow solution yellow viscous / semi-solid Yes Example 42 Cithrol 4DL 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg drug 500 mg clear, light yellow solution clear, light yellow / white solution Yes

-26Note: ‘stored for 10 days at room temperature / visual observation) ** at the time of preparation (fresh samples)

Example 43 Labrasol Pharmasolve Tween 80 ascorbic acid propyl gallate Sureteric drug 9.0 ml 1.0 ml 2 drops 1.0 mg 1.0 mg 32.0 mg 500 mg Capsule: Licaps, size 1 (cartridge for 12 capsules)

Example 44 Labrasol 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg Eudragit L30D55 42.0 mg drug 500 mg Capsule: size 11, elongated from soft gel (refill for 15 soft gel capsules)

Example 45 Labrafac CM 10 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops ascorbic acid 1.0 mg propyl gallate 1.0 mg Aquateric 52.0 mg drug 500 mg Capsule: size 0, with hard cover, (refill for 12 capsules)

Claims (18)

PATENT CLAIMS An oral capsule for swallowing comprising paroxetine dissolved in a carrier. An oral swallowing capsule having a coating comprising paroxetine in the form of the free base or in the form of a pharmaceutically acceptable salt or solvate in solution in a liquid or solid carrier. Capsule according to claim 2, characterized in that the carrier is a liquid solvent present in the capsule as a flowable substance or as a viscous substance or as a semi-solid substance or as a gel. Capsule according to claim 2, characterized in that the carrier is a solid or semi-solid solvent. Capsule according to claim 4, characterized in that the solid or semi-solid solvent is selected from natural or synthetic fats and waxes or from film-forming and thermoplastic polymers. A solid dosage form for oral administration for swallowing, comprising paroxetine dissolved in a solid, semi-solid or gel carrier. 7. A solid dosage form comprising tablets, pellets, spheroids, granulates, lozenges or gels in which paroxetine is present as a solid solution in a polymeric carrier. Capsules and solid dosage forms according to any one of claims 1 to 7, characterized in that they have a coating on the surface to aid the administration of the active ingredient. Capsules and solid dosage forms according to claim 8, characterized in that they are coated with coatings for delaying or controlling the release rate of paroxetine and / or coatings for masking the taste of paroxetine. Capsules and solid dosage forms according to any one of claims 1 to 9, characterized in that the paroxetine is used in the form of the hydrochloride or anhydride hemihydrate. Capsules and solid dosage forms according to any one of claims 1 to 10, characterized in that paroxetine is used as paroxetine hydrochloride in a form other than hemihydrate and which is formulated under conditions such that no detectable conversion to paroxetine occurs during the manufacturing process. hemihydrate. Capsules and solid dosage forms according to claim 11, characterized in that the paroxetine hydrochloride is used in amorphous form or as a crystalline anhydride. Capsules and solid dosage forms according to claim 12, characterized in that the paroxetine hydrochloride is dissolved in a carrier which is substantially hydrophobic or anhydrous. Capsules or solid dosage forms according to claim 12 or 13, characterized in that the paroxetine hydrochloride is dissolved in the carrier in the presence of one or more excipients which are substantially hydrophobic or anhydrous. A pharmaceutical formulation comprising a solution of paroxetine in a mixture of a solubilizing agent and a lipid and / or oil. Process for preparing a formulation according to claim 15, characterized in that it comprises dissolving paroxetine in a solubilizing agent and mixing the obtained solution with a lipid and / or oil. The use of paroxetine dissolved in a carrier for the manufacture of capsules or solid dosage forms for oral administration according to any one of claims 1 to 14 for the treatment or prophylaxis of one or more disorders selected from the group consisting of alcoholism, anxiety, depression, obsessive compulsive disorder, panic conditions. , chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome - PMS, adolescent depression, trichothilomania, dysthymia and substance habits. Use of paroxetine as a solution for the manufacture of a pharmaceutical formulation according to claim 15 for the treatment or prophylaxis of one or more of the disorders selected from the group consisting of alcoholism, anxiety, depression, obsessive compulsive disorder, panic, chronic pain, obesity, senile dementia, migraine. bulimia, anorexia, social phobia, premenstrual PMS syndrome, adolescent depression, trichothilomania, dysthymia and substance abuse.