MXPA00005030A - 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

FORMULATIONS CONTAINING DISSOLVED PAROXETINE DESCRIPTIVE MEMORY The present invention relates to novel formulations of a pharmaceutically active compound and to the use of the formulations in therapy. In particular, this invention relates to new formulations of paroxetine antidepressant. In US-A-3912743 and US-A-4007196, pharmaceutical products with antidepressant and anti-Parkinson properties are described. Among the disclosed compounds, paroxetine is an especially important compound, the (-) trans isomer of 4- (4'-fluorophenyl) -3- (37 4'-methylenedioxy-phenoxymethyl) -piperidine. Paroxetine hydrochloride hemihydrate is used in therapy for the treatment and prophylaxis of depression, obsessive compulsive disorder (OCD) and panic, among others. Paroxetine hydrochloride hemihydrate is described in EP-A-0223403 of the Beecham Group and forms A, B, C and D of paroxetine hydrochloride dehydrate are described in WO 96/24595 of SmithKine Beecham foot. All the solid oral dosage forms of paroxetine hydrochloride sold to date have been in the form of swallowable tablets containing the hemihydrate. WO 95/16448 discloses that paroxetine tends to develop a pink color unless it is formulated into tablets using a formulation process in which there is no water, such as direct dry compression of paroxetine or dry granulation of paroxetine followed by compression in tablets. To help the patient comply with dosing regimens, the need for alternative dosage forms to the swallowable tablet prevails. However, the low solubility of paroxetine hydrochloride in many solvents has made this difficult to achieve. In particular, it was not believed feasible to devise a swallowable capsule of size small enough to be easily swallowed and containing sufficient paroxetine in solution for an effective dose, using physiologically acceptable solvents capable of encapsulation. Now the inventors of the present have overcome this problem. In one aspect, the present invention provides a swallowable capsule containing paroxetine dissolved in a carrier. Traditionally, the swallowable capsule comprises a capsule shell containing paroxetine as the free base or a pharmaceutically acceptable salt or solvate thereof in solution in a carrier. The vehicle can be liquid or solid. A liquid vehicle can be a solvent present in the capsule as a flowable liquid, as a viscous or semi-solid liquid or as a gel. The vehicle can also be a solid or semi-solid solvent such as fats and waxes, or thermoplastic polymers or film formers. Solvents in which supersaturated solutions can be formed are advantageous due to the possibility of increasing the loading of active ingredient.

When the vehicle is a solid or semi-solid or a gel, the paroxetine contained in the vehicle can be independent without encapsulation. Accordingly, an independent formulation can be encapsulated by means other than charging in a preformed capsule shell, for example by coating with an encapsulating material. In addition, the independent formulation can be used as a dosage form without encapsulation. In the same way, in another aspect, the present invention provides a solid swallowable dosage form containing paroxetine dissolved in a solid, semi-solid or gel carrier. Traditionally, the solid dosage form comprises tablets, pills, spheroids, granules, pellets or gels in which paroxetine is present as a solid solution in a polymer vehicle. Capsules and solid dosage forms of this invention can be coated to aid in the administration of the active ingredient, for example using an enteric coating material to prevent the release of paroxetine in the stomach, coatings to retard or control the release of paroxetine and coatings of flavor disguising agents. Alternatively, such materials can be incorporated into the vehicle to achieve the same effect. Preferably, paroxetine is used as the hydrochloride and as such can be used as the hemihydrate or as the dehydrated form A, B, C or D, or as any other form of paroxetine or paroxetine hydrochloride, such as different pharmaceutically acceptable salts to the hydrochloride. Other suitable forms of paroxetine include paroxetine free base and pharmaceutically acceptable amorphous and non-crystalline forms of paroxetine and paroxetine derivatives. In a particular embodiment, capsules or solid dosage forms of the present invention utilize paroxetine hydrochloride in a form other than the hemihydrate and are formulated under conditions such that there is no detectable conversion to hemihydrate during the manufacturing process. This overcomes the problem surprisingly discovered that even under relatively dry conditions, dehydrated paroxetine hydrochloride tends to become at least partially converted to the hemihydrate during tableting. Although not dangerous, this creates difficulties in establishing and maintaining a reference standard for regulatory purposes and quality control. For example, paroxetine hydrochloride can be present in an amorphous form or as a crystalline anhydrate and dissolved in a carrier, or in the presence of excipients, which are essentially hydrophobic or essentially anhydrous, usually containing less than 2%, especially less than 1.5%, preferably less than 1% by weight of water. The amount of paroxetine used in each capsule is preferably adjusted so that in a single unit dose there is a therapeutically effective amount of paroxetine. Preferably the unit dose contains from 5 to 100 mg paroxetine (as measured in terms of the free base). Preferably, the amount of paroxetine in a unit dose is 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. The preferred amount of paroxetine in a unit dose is 20 mg. To achieve the desired unit dose in a capsule in which the paroxetine is in solution in the vehicle, the paroxetine needs to be soluble in the vehicle to the extent that it allows a sufficient concentration so that the selected volume of capsules can contain the desired unit dose. In addition to being able to dissolve paroxetine, the solvent must be compatible with the capsule material and physiologically acceptable for administration to a patient. Because solid forms of paroxetine are generally poorly soluble in common solvents, solvents that are acceptable for use in capsules and for administration to patients need to undergo routine solubility tests to confirm that they can maintain an adequate concentration of paroxetine. . In addition, higher charges of a paroxetine form in a suitable solvent can be achieved using conventional physical techniques such as heat, agitation and sound treatment. Alternatively, good solvents for paroxetine can be used in small amounts as cosolvents to solubilize paroxetine in liquids that are acceptable for capsule use but in which paroxetine is sparingly soluble. Solubilizing agents such as polysorbates, poloxamers, cyclodextrins, ionic and nonionic surface active agents, for example Pluronic F60, and Sorbitan esters can also be used to increase the solubility of paroxetine hydrochloride in solvents acceptable for use in capsule but in which paroxetine is sparingly soluble. The term "swallowable capsule" refers more adequately to a capsule having a maximum volume of 0.86 ml. The preferred capsules according to the present invention have a maximum volume of about 0.45 ml and can especially be included in the 0.2 to 0.4 ml scale, although the invention also provides capsules as small as 0.14 ml. A traditional capsule at the upper end of the scale of acceptable size for pharmaceutical use (Soft Gel Size 14 Oblong) has a volume of 0.86 ml. For a dose of 10 mg of paroxetine (as a free base) 1 1.1 1 mg of paroxetine hydrochloride is required, which in a volume of 0.86 ml requires a concentration of 12.9 mg / ml or 1.29% w / v. Therefore, it is preferred that the solvent to be used have a solubility of at least 10 mg / ml for paroxetine hydrochloride and preferably the solubility should be at least 25 mg / ml. However, larger capsule sizes such as Hard Cover Size 00 (0.95 ml capacity), Supro A (0.68 ml) and Soft Gel Size 12 Oblong (1.01 ml) can be used when convenient to provide higher drug doses with the same formulation.

This level of solubility regulates many solvents conventionally used as liquid carriers for encapsulated drugs, such as sunflower, safflower, peanut, soybean, cottonseed, corn, castor oil, apricot seed, olive, wheat germ, sesame, vegetable oils. Oenothera sp, and Cañóla oil, and also 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, Plural Oleique and Peceol (glyceryl oleate) also show less than 10 mg / ml of solubility. Now the inventors of the present have identified certain solvents and solvent systems which present the required levels of solubility. Solvents showing a useful solubility include propylene carbonate, Triacetin, Glycerol, Lauroglycol, Propylene glycol, PEG 300, Glycofurol, PEG 400, IPA, Span 20, Transcutol, Labrasol, Labrafil, Olepal, Glyceryl Linoleate (Maisine 35-1) and Pharmasolve. For physiological convenience it would be advisable to use said solvents with a cosolvent such as ethanol. The present invention makes use of these solvents and solvent systems as well as functional equivalents thereof which can be identified using the techniques set forth herein. The inventors of the present have found that a particularly effective means to solubilize paroxetine, particularly the hydrochloride, especially as the hemihydrate, in a liquid, semi-solid or solid carrier, in particular oils and lipids, is to use a solubilizing agent, such as N- methyl-2-pyrrolidone (Pharmasolve, International Specialty Products, Texas, USA) as a cosolvent. Accordingly, in a preferred embodiment of this invention, paroxetine, optionally as the free base but more traditionally as a pharmaceutically acceptable salt such as the hydrochloride, is dissolved in a solubilizing agent and then mixed with an oil or lipid carrier before of filling in capsules. The invention also provides as a novel formulation a solution of paroxetine, optionally as the free base but more traditionally as a pharmaceutically acceptable salt such as the hydrochloride, in a mixture of a solubilizing agent and a lipid and / or oil. By the use of a solubilizing agent it is possible to solubilize paroxetine in oils and lipids previously considered as unsuitable solvents, such as soybean oil, sunflower oil and arachis oil. In addition, paroxetine can be dissolved in lipids, especially lipids derived from natural materials, such as glycerides derived from coconut oil, Cithorol 4DL (PEG-8 dilaurate). Examples of glycerides derived from coconut oil include Labrasol and Labrafac CM 10 (Gattefosse, France) which are polyglycolized glycerides of Cß / C-io of coconut oil having a hydrophilicliplophilic balance of 14 and 10 respectively. The formulations based on a solubilizing agent and oils / lipids are preferably formulated with at least one antioxidant to maintain the stability of the solution in storage. If you want to use the solutions to fill capsules, then you should investigate the compatibility of the solution with the capsule material. The present invention in a further aspect makes use of supersaturated solutions, for example, in solid or semi-solid solvents such as fats and waxes. These can be easily prepared by heat and show high stability due to among other things their very high viscosity. Preferably, the solvents used to carry out the invention contain less than 2%, especially less than 1.5%, preferably less than 1% water, or are essentially hydrophobic. Optionally, the solution may contain one or more antioxidants such as tocopherols, ascorbic acid, ascorbic palmitate, thiodipropionic acid, bishydroxytoluene (BHT), bishydroxianisol (BHA), gallic acid, propyl gallate / octyl / dodecyl, benzyl alcohol and nordihydroguaiaretic acid with or without the addition of pH modifiers and chelating agents such as citric acid and EDTA The capsule shell can be of any conventional material that is stable to the liquid and solute vehicle, for example hard and soft gelatin capsules and starch capsules. In addition to resisting the action of the liquid vehicle solvent, attention must be paid to the pH of the liquid inside the capsule. For example, soft gels have a pH limit of 2.5-7.5. Because the addition of paroxetine hydrochloride to a solvent system tends to lower the pH by at least one unit, solvent systems with a pH less than 3.5 are generally not preferred. According to another aspect of the invention, the capsules have an enteric resistant coating or incorporate enteric resistant materials in the capsule shell, so that the paroxetine is not discharged under the acidic conditions of the stomach. The objective is to avoid any undesired undesirable precipitation of paroxetine from the solution and allow its absorption characteristics to be modified if desired, by exposing it to the intestinal mucosa in non-aqueous solution. The liquid carrier may be present in the capsule as a flowable liquid, as a viscous or semi-solid liquid or as a gel. Viscosity characteristics may vary by initial solvent selection or by the proper use of co-solvents or thickening agents. A liquid vehicle, or a solid or semi-solid vehicle that has been softened or made flowable by heat with dissolved paroxetine, can be filled into capsules using conventional capsulation technology. It would be advisable to use paroxetine hydrochloride in a form other than the hemihydrate, which is formulated in capsules or solid dosage forms under conditions such that there is no detectable conversion to hemihydrate during the manufacturing process. For example, paroxetine hydrochloride may be present in an amorphous form or as a crystalline anhydrate.

This can be achieved, for example, by the use of either excipients or vehicles which are essentially anhydrous (ie containing less than 2%, especially less than 1.5%, preferably less than 1% water) or which are essentially hydrophobic. Capsules and solid dosage forms are preferably packaged with a desiccator in order to avoid conversion of anhydrate to hemihydrate in storage. Accordingly, the present invention also provides a process for the preparation of dehydrated paroxetine hydrochloride capsules or solid dosage forms free of detectable hemihydrate which is characterized by the use of conditions such that there is no detectable conversion of the anhydrate to hemihydrate during the manufacturing process. Such conditions can be achieved by the use of essentially anhydrous / hydrophobic excipients and / or vehicles under conditions of low relative humidity. Examples of excipients with the required low moisture content include materials such as anhydrous calcium dibasic phosphate, anhydrous lactose, monosaccharide sugars for example mannitol, disaccharide sugars for example lactitol, cellulose powder, pregelatinized starch and similar materials. Dibasic anhydrous calcium phosphate is commercially available to a pharmaceutically acceptable degree, for example A- (Rhone Poulenc).

Examples of liquid and semi-solid excipients with the necessary hydrophobic character include materials such as polyglycolized glycerides for example Gelucire 44/14; fatty materials in the form of a complex of animal origin, for example theobroma oil, carnauba wax; vegetable oils such as peanuts, olives, palm kernels, cotton, corn, soybeans; hydrogenated vegetable oils such as peanuts, palm kernels, cotton, soybeans, castor beans, coconut; natural fatty materials of animal origin, for example beeswax, lanolin, fatty alcohols, for example cetyl, stearyl, lauric, myristic, palmitic, stearic; esters for example glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate; solid interesterified semi-synthetic glycerides, for example Suppocire, Witepsol; semi-synthetic interesterified liquid glycerides eg Migliol 810/812; amide or fatty acid alcolamides for example stearamide-ethanol diethanolamide of fatty coconut acids; polyoxyethylene glycols for example PEG 600, PEG 4000. Liquids and semisolids having the solubility characteristics suitable to act as vehicles for dissolved paroxetine and having a hydrophobic character similar to the above liquid excipients include Labrafil, a semi-synthetic interesterified liquid glyceride, and PEG 400 , a polyoxyethylene glycol. The above solid and liquid excipients can be mixed with vehicles of adequate solubility for the paroxetine described above and if necessary cosolvents to obtain paroxetine solutions with anhydrous / hydrophobic properties. Vehicles that already have suitable anhydrous / hydrophobic properties can be mixed directly with paroxetine, again using cosolvents when necessary to promote dissolution. The formulations can be filled into capsules, such as gelatin capsules or cellulose capsules with intrinsically low moisture content (for example Shionogi Qualicaps, <3%). Commercially available liquid interesterified semisynthetic glycerides to a pharmaceutically acceptable degree include Labrafil M2125CS (Gattfosse). In a particular process of the invention, dehydrated paroxetine hydrochloride is mixed with Labrafil M2125CS (Gatfosse) to produce a formulation for encapsulation in a hard or soft gelatin capsule. Paroxetine in the form of dehydrated hydrochloride can be prepared according to the procedures outlined in WO 96/24595. Suitable methods for preparing paroxetine include those mentioned in the United States patents 4, 009.196, 4,902,801, 4,861, 893 and 5,039,803 and PCT / GB 93/00721. The present invention also provides solid dosage forms of paroxetine for swallowable use wherein the paroxetine is dissolved in a polymer carrier. These forms include tablets, pills, spheroids, granules, pills and gels containing paroxetine in solid solution.

To achieve the desired unit dose in a melt extruded tablet for example wherein the paroxetine is in solution in the polymer vehicle, the paroxetine needs to be soluble in the polymer vehicle or a solvent / cosolvent which is soluble in the polymer vehicle. to the extent that it allows sufficient concentration so that the selected size and volume of tablet can contain the desired unit dose. In addition to being able to dissolve paroxetine, the solvent / cosolvent must be compatible with the polymer carrier material and physiologically acceptable for administration to a patient. When the solid dosage forms are granules or pills, then a plurality of granules or pills can be put together in a set which as a whole constitutes a unit dose. The granules or pills can be used as a filling for capsules or tablets optionally with binders or excipients in the form of a tablet. Because solid forms of paroxetine are generally poorly soluble in common solvents, solvents / co-solvents and vehicles that are acceptable for use in the aforementioned dosage forms and for administration to patients need to undergo routine solubility tests for confirm that they can maintain an adequate concentration of paroxetine. In addition, higher charges of a paroxetine form in a suitable solvent can be achieved using conventional physical techniques such as heat, agitation and sound treatment. Alternatively, good solvents for paroxetine in small amounts as cosolvents can be used to solubilize paroxetine in polymers that are acceptable for melt extrusion, melt granulation, use of gel formulation but in which paroxetine is sparingly soluble. Solubilizing agents such as polysorbates, poloxamers, cyclodextrins, ionic and nonionic surface active agents, for example Pluronic F and Sorbitan esters can also be used to increase the solubility of paroxetine hydrochloride in acceptable solvents for polymers used to produce systems of solid solution in the form of a tablet, pill, granule, spheroid but in which paroxetine is sparingly soluble. It is preferred that the polymer and / or solvent used have a solubility of at least 10 mg / ml of paroxetine hydrochloride and preferably, the solubility should be at least 25 mg / ml. In general, the use of polymers in this invention to produce semi-solid / solid solution system offers a wide flexibility of use. In addition to filling hard / soft gelatin capsules, these can be used to make melt-extruded systems such as tablets, pills, spheroids and any other form depending on the shape of the extrusion die, it can be injection molded in different shapes and / or granulated fusion to produce pills or granules. Alternatively, the granules can be milled and compressed into tablets and other shapes depending on the shape and design of the pressure die.

Examples of pharmaceutical polymers used for the above applications are film-forming polymers and thermoplastics which are generally approved substances mentioned in international pharmacopoeias such as water-soluble resins of polyethylene oxide, glycerides and ethoxylated triglycerides, cetyl esters, cetyl palmitate, glyceryl esters , polyvinyl acetate, cellulose, lanolin-based product, vinyl resins, latex product, Carbowax polyethylene glycols, gelatin (paroxetine), ethylene / glycol oxide such as ethylene glycol, glycol ethers and ethanolamines, unipol polymers, polypropylene resins, products of silicon, saturated polyglycolized 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 solubilizer and / or binder and / or permeability enhancers. Solvents that show a useful solubility for paroxetine, such as propylene carbonate, Triacetin, Glycerol, Lauroglycol, Propylene glycol, PEG 300, Glycofurol, PEG 400, IPA, Span 20, Transcutol, Labrasol, Labrafil, Oleapal, glyceryl linoleate (Maisine 35-1) and Pharmasolve mentioned above, they can be used as cosolvents to assist in the solubilization of paroxetine in the aforementioned solid, semisolid and polymeric carriers. For physiological convenience it may be advisable to use said solvents with another cosolvent such as ethanol. The present invention makes use of these solvents and solvent systems as well as functional equivalents thereof which can be identified using the techniques set forth herein. A suitable lanolin derivative for example ethoxy-75 lanolin is commercially available in a pharmaceutical grade for example Solan E (Croda). In a particular process of the invention, the paroxetine hemihydrate hydrochloride is dissolved in Pharmasolve and mixed with molten Solan E in a suitable mixer to form granules upon cooling, drying, sifting the solid solution tablet during compression. A polyglycolized glyceride is commercially available to a pharmaceutically acceptable degree for example Gelucire 44/14 (Gattfosse). In a particular process of the invention of paroxetine, the paroxetine hemihydrate hydrochloride is dissolved in Pharmasolve and then mixed with melted Gelucire 44/14 to form a melt extrusion product in the form of a tablet and / or a pill upon cooling. Polyethylene glycols of different molecular weights are commercially available to a pharmaceutically acceptable degree for example PEG 4000 (Union Carbide Corp &; BASF). In a particular process of the invention, paroxetine hemihydrate hydrochloride is dissolved in PEG 300 and then mixed with molten PEG 4000 to form melt extrudates which upon cooling as a solid solution can be converted into tablet and / or pill forms . Optionally, the solution may contain one or more antioxidants such as tocopherols, ascorbic acid, ascorbic palmitate, thiodipropionic acid, bishydroxytoluene (BHT), bishydroxyanisole (BHA), gallic acid, propyl gallate / octyl / dodecyl, benzyl alcohol and nordihydroguaiarético acid with or without the addition of pH modifiers and chelating agents such as citric acid and EDTA. According to another aspect of the invention, the solid dosage form can have an enteric resistant coating so that paroxetine is not discharged under the acidic conditions of the stomach. The objective is to avoid any undesired, undesirable precipitation of paroxetine from the solution and allow its absorption characteristics to be modified if desired, by exposing it to the intestinal mucosa in aqueous solution. The solid / semisolid solution systems presented in this invention can be coated with a suitable polymer that can be used with melt-granulation or hot-melt coating such as Precirol ATO 5 (glyceryl palmito-stearate) to disguise the taste of paroxetine and / or enteric-coated with methacrylic acid copolymer C (for example Eudragit L 30 D-55). The semi-solid or gel formulation can also be optionally encapsulated. The viscosity characteristics of the semi-solid or gel may vary by initial selection of solvent or by the proper use of co-solvents or thickening agents. The semi-solid or gel vehicle with dissolved paroxetine can be filled into capsules using conventional capsulation technology.The independent solid paroxetine solution can be prepared successfully in the form of a tablet, pill, spheroid, granules, using Solan E, Gelucire, higher molecular weights of PEG and gelatin-based gel with different constituents of cosolvents. For example, paroxetine is first dissolved in cosolvent constituents, such as PEG 300, Pharmasolve and water / ethanol (using enough mixture to ensure complete wetting / solubilization). The resulting mixture is then preheated and added to suitable portions of a fused 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 (gelatine in liquid cosolvents fused between 50-55 C). The mixtures are then left at environmental condition for the polymerization to occur. A forming device can be used to produce solid dosage forms such as tablets, pills, spheroids and gels. The drug molecule dissolved in the polymer during the fusion phase will remain dissolved in the finished product as a solid solution. With gelatin-based formulations, transparent solid solutions containing dissolved drug are produced. As mentioned above, it would be advisable to use paroxetine hydrochloride in a form other than the hemihydrate, which is formulated in independent solid dosage forms under conditions such that there is no detectable conversion to hemihydrate during the manufacturing process. For example, paroxetine hydrochloride may be present in amorphous form or as a crystalline anhydrate. As described above, this can be achieved for example, by using either excipients or polymeric vehicles which are essentially anhydrous (i.e. containing less than 2%, especially less than 1.5%, preferably less than 1% of water) or which are essentially hydrophobic. Therapeutic uses of the paroxetine formulations of this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS) ), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the disorders". Therefore, the present invention also provides: the use of paroxetine dissolved in a vehicle for manufacturing swallowable capsules or solid dosage forms for the treatment or prophylaxis of one or more of the disorders; a method for treating disorders which comprises administering an effective or prophylactic amount of paroxetine as a solution in a vehicle in a swallowable capsule or solid dosage form to a person suffering from one or more of the disorders; a method for treating disorders which comprises administering an effective or prophylactic amount of paroxetine as a solution in a liquid formulation of the invention to a person suffering from one or more of the disorders. The formulations of this invention can also be used when appropriate for veterinary treatment. The following examples illustrate the invention: (10.0 mg of paroxetine anhydrous free base equals 1 1.38 ml of paroxetine HCl - paroxetine HCI conversion factor to anhydrous paroxetine is 0.8787). In Examples 1 to 10, paroxetine is dissolved in a vehicle, optionally assisted by a cosolvent and filled into capsules.

EXAMPLE 1 Excipient mg per capsule Paroxetine hydrochloride 22.22 Polyethylene glycol 400 450.0 Capsule Size 11 Soft gel oblong Example 2 Excipient mg per capsule Paroxetine hydrochloride 22.22 Polyethylene glycol 400 400.0 Ethanol 45.0 Size 0 Hard cover, with strips Capsule Example 3 Excipient mg per capsule Hydrochloride paroxetine 22.22 Propylene glycol 350.0 Capsule: Size 8 Soft Gel oblong Enteric layer Methacrylic acid 32.0 Copolymer Type C Propylene glycol 8.0 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 soft oblong gel Example 5 Excipient mg per capsule Paroxetine hydrochloride 22.22 GHcerol 100.0 Propylene glycol 100.0 Propylgalato 0.3 Capsule: Size 5 soft gel oblong Example 6 Excipient mg per capsule Paroxetine hydrochloride 22.22 Glycolurol 100.0 Polyethylene glycol 300 50.0 Citric acid 1.5 BHT 0.02 Capsule: Size 4 soft gel oblong Example 7 Excipient mg per capsule Paroxetine hydrochloride 22.22 Pharmasolve 50.0 High purity cottonseed oil 150.0 Propylgalate 0.2 Capsule: Size 4 soft oblong gel Example 8 Mg Excipient per capsule Paroxetine Hydrochloride 22.22 Polyethylene Glycol 400 50.0 Pharmasolve 10.0 Citric Acid 2.0 Capsule: Size 3 soft oval gel Example 9 Excipient mg per capsule Paroxetine hydrochloride 22.22 Lauroglycol 400 100.0 Pharmasolve 10.0 Citric acid 2.0 Capsule: Size 3 hard cover, with strips Example 10 Excipient Mg per capsule Paroxetine hydrochloride 22.22 Polyethylene glycol 400 50.0 Pharmasolve 10.0 Citric acid 2.0 Capsule: Capyl-Starch In example 11, paroxetine is dissolved in a hydrophobic vehicle.

Example 11 Mg Paroxetine Hydrochloride 22.22 Labraf? L M 2125CS 227.78 Capsule Weight 250.0 In Examples 12 to 30, paroxetine was dissolved in a cosolvent and then mixed with a molten polymer. Transparent paroxetine solutions were obtained before solidification of the polymers.

Example 12 Paroxetine HCL 22.76 mg PEG 300 200.00 mg PEG 4000 300.00 mg DI alpha tocopherol 0.1% w / w Ascorbyl Palmitate Tablet 0.1% w / w Example 13 Paroxetine Hydrochloride 42.52 mg Gelucire 44/14 227.78 mg Pharmasolve Tablet 100.00 mg Example 14 Paroxetine Hydrochloride 22.76 mg Gelucire Tablet 44/14 227.78 mg Example 15 Paroxetine Hydrochloride 68.28 mg Solan E (Ethoxy 75 Lanolin) 350.00 mg Pharmasolve Tablet 150.00 mg Example 16 Paroxetine Hydrochloride 22.76 mg PEG 1450 227.78 mg Tablet Example 17 Paroxetine Hydrochloride 22.76 mg PEG 4000 Tablet 227.78 mg Example 18 Paroxetine HCL 19.91 mg PEG 300 200.00 mg PEG 1450 300.00 mg DI alpha tocopherol 0.1% w / w Ascorbyl Palmitate Tablet 0.1% w / w Example 19 Paroxetine Hydrochloride 22.76 mg Suppocire Tablets DM 227.78 mg Example 20 HCL of paroxetine 73.96 mg Gelatin 100.00 mg Purified water 350.00 mg Pharmasolve 150.00 Polysorbate 80 1 drop Gel Methylparaben 0.2% w / w Example 21 HCL of paroxetine 42.67 mg Gelatin 50.00 mg Purified water 200.00 mg Propylene glycol 400.00 mg Propilgalate 0.1% w / w Ascorbic acid 0.1% w / w Polysorbate 80 1 drop Example 22 HCL of paroxetine 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 Metiiparaben Gel 0.2% p / p Example 23 Paroxetine HCL 102.41 mg Gelatin 50.00 mg Purified water 200.00 mg Pharmasolve 200.00 mg Ethanol 200.00 mg Polysorbate 80 1 drop Methylparaben Gel 0.2% p / p Example 24 HCL of paroxetine 28.45 mg Gelatin 50.00 mg Purified water 200.00 mg Ethanol 200.00 mg Propylene glycol 200.00 mg Polysorbate Gel 1 drop Example 25 Paroxetine HCL 45.52 mg Gelatin 50.00 mg Purified water 200.00 mg Propylene glycol 400.00 mg PEG 300 50.00 mg 80 Polysorbate Gel 1 drop Example 26 Paroxetine HCL 11.38 mg Gelatin 50.00 mg Purified water 500.00 mg Propylene glycol 100.00 mg 80 Polysorbate Gel 1 drop Example 27 Paroxetine HCL 28.45 mg Gelatin 50.00 mg Purified water 300.00 mg Propylene glycol 300.00 mg 80 Polysorbate Gel 1 drop Example 28 Paroxetine HCL 68.28 mg Gelatin 50.00 mg Purified water 300.00 mg Pharmasolve 150.00 mg Propylene glycol 150.00 mg 80 Polysorbate Gel 1 drop Example 29 Paroxetine HCL 76.95 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% w / w Example 30 HCL of paroxetine 17.07 mg Gelatin 50.00 mg Purified water 300.00 mg Propylene glycol 150.00 mg Ethanol 150.00 mg Polysorbate Gel 80 1 drop In examples 31 to 44, paroxetine is initially dissolved in Pharmasolve and the resulting solution is mixed with oil and lipid vehicles, so that paroxetine is dissolved in the vehicle to give liquid formulations that can be encapsulated (36-42) and also provided with an enteric coating (43-45) * stored at RT for 25 days (observation at first sight)? at the time of preparation (fresh samples) Appearance Composition Stability Compatibility with capsule Example System / Solution Pxt solution * Licaps * Labrafac CM10 4.50 ml Pharmasolve 0.50 ml Yellow solution Yellow solution Yes Tween 80 1 clear pale pale transparent drop Drug 250 mg Labrafil M 1994Cs 450 ml Yellow solution Semisolid / viscous Pharmasolve 0.50 ml Yes pale transparent yellow Tween 80 1 drop Drug 250 mg Labrasol 4.50 ml Pharmasolve 0.50 ml Yellow solution Yellow solution Yes Tween 80 1 clear pale pale transparent drop Drug 250 mg Cithrol 4DL 4.50 ml Pharmasolve 0.50 ml Yellow solution Very pink solution Yes Tween 80 1 transparent clear drop Drug 250 mg * stored at RT for 10 days (observation at first glance)? at the time of preparation (fresh samples) * stored at RT for 10 days (observation at first glance)? at the time of preparation (fresh samples) Example 43 Labrasol 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops Ascorbic acid 1.0 mg Propilgalato 1.0 mg Sureteric 32.0 mg 500 mg drug Capsule: Licaps size 1 (fill 20 capsules) Example 44 Labrasol 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops Ascorbic acid 1.0 mg Propilgalato 1.0 mg Eudragit L30D55 42.0 mg 500 mg drug Capsule: size 11 oblong soft gel (fill 15 soft gel capsules) Example 45 Labrafac CM10 9.0 ml Pharmasolve 1.0 ml Tween 80 2 drops Ascorbic acid 1.0 mg Propilgalato 1.0 mg Aquateric 52.0 mg 500 mg drug Capsule: size 0 hard cover, with stripes (fill 15 capsules)

Claims (18)

NOVELTY OF THE INVENTION CLAIMS

1. - A swallowable capsule containing paroxetine dissolved in a vehicle.

2. A swallowable capsule consisting of a capsule shell containing paroxetine as the free base or a pharmaceutically acceptable salt or solvate thereof in solution in a liquid or solid carrier.

3. A capsule according to claim 2, further characterized in that the vehicle is a liquid solvent present in the capsule as a flowable liquid, as a viscous or semi-solid liquid or as a gel.

4. A capsule according to claim 2, further characterized in that the vehicle is a solid or semi-solid solvent.

5. A capsule according to claim 4, further characterized in that the solid or semi-solid solvent is selected from natural and synthetic fats and waxes and film-forming and thermoplastic polymers.

6. A solid swallowable dosage form containing paroxetine dissolved in a solid, semi-solid or gel vehicle.

7. - A solid dosage form comprising tablets, pills, spheroids, granules, pellets or gels in which paroxetine is present as a solid solution in a polymer vehicle.

8. Capsules and solid dosage forms according to any of claims 1 to 7, further characterized in that they are coated to aid in the administration of the active ingredient.

9. Capsules and solid dosage forms according to claim 8, further characterized in that they are coated with coatings to retard or control the release of paroxetine and / or coatings to disguise the taste.

10. Capsules and solid dosage forms according to any of claims 1 to 9, further characterized in that paroxetine is used as the hemihydrated or dehydrated hydrochloride.

11. Capsules and solid dosage forms according to any of claims 1 to 10, further characterized in that paroxetine is used as paroxetine hydrochloride in a form different from the hemihydrate, which is formulated under conditions such that there is no detectable conversion to hemihydrate during the manufacturing process.

12. Capsules and solid dosage forms according to claim 1, further characterized in that the paroxetine hydrochloride is used in an amorphous form or as a crystalline anhydrous.

13. Capsules and solid dosage forms according to claim 12, further characterized in that the paroxetine hydrochloride is dissolved in a vehicle that is essentially hydrophobic or anhydrous.

14. Capsules and solid dosage forms according to claim 12 or 13, further characterized in that the paroxetine hydrochloride is dissolved in a carrier in the presence of excipients, which are essentially hydrophobic or anhydrous.

15. A pharmaceutical formulation comprising a solution of paroxetine in a mixture of a solubilizing agent and a lipid and / or oil.

16. A process for preparing a formulation according to claim 15, further characterized in that it comprises the dissolution of paroxetine in a solubilizing agent and the mixing of the resulting solution with a lipid and / or oil.

17. The use of paroxetine dissolved in a vehicle for manufacturing swallowable capsules or solid dosage forms according to any of claims 1 to 14 for the treatment or prophylaxis of one or more of alcoholism, anxiety, depression, obsessive compulsive disorder, panic, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia and substance abuse.

18. The use of paroxetine dissolved in a solubilizing agent to manufacture a formulation according to claim 15 for the treatment or prophylaxis of one or more of alcoholism, anxiety, depression, obsessive compulsive disorder, panic, chronic pain, obesity, dementia senile, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia and substance abuse.