MXPA00000053A - Novel process for manufacturing paroxetine solid dispersions - Google Patents

Abstract

Solid dispersions of poorly soluble drugs are disclosed which are prepared using a solvent or fusion process. Such dispersions are manufactured with the free base of the drug, specifically paroxetine free base, an oil, allowing for a low temperature for the fusion process, decreased organic solvent volumes for the solvent process and the formation of a paroxetine salt during the solid dispersion manufacture process.

Description

NOVEL PROCESS OF MANUFACTURE OF SOLID PAROXETINE DISPERSIONS FIELD OF THE INVENTION The present invention relates to the field of solid dispersions of poorly water soluble drugs, to processes for their preparation and their uses in pharmaceutical compositions. Specifically, the present invention relates to solid dispersions resulting from melt or solvent methods for the incorporation of poorly water soluble drugs into pharmaceutically acceptable carriers. More specifically, the invention relates to solid paroxetine dispersions, processes for the preparation of these solid dispersions, pharmaceutical compositions containing the same and their uses thereof in therapy.

BACKGROUND The compound (-) - trans-4 - ((4'-fluorophenyl) 3- (3,4'-methylenedioxyphenoxymethyl) -piperidine, commonly known as paroxetine, is a viscous and poorly water soluble oil drug with a commercial need for useful pharmaceutical compositions A solid dispersion of paroxetine or its acid addition salt, never described heretofore in the literature, would provide a solid product on a commercial scale with good handling qualities and physiological acceptability without the need or expense of manufacturing crystalline materials Pharmaceutical compositions can be formulated with good dissolution and bioavailability from solid dispersions of pharmaceutically active ingredients The advantages claimed by pharmaceutical solid dispersions include potential use in controlled release formulations, stabilization of the drug from polymorphic conversions. improvement of the poor management properties of the subst of the drug and protect certain drugs against breakdown during administration. The solid dispersions of the pharmaceutically active ingredients can be formed from a number of pharmaceutically acceptable carriers. U.S. Patent No. 4,933,360 describes a novel process and product comprising chlorothalidone as the active pharmaceutical ingredient and polyvinylpyrrolidone (PVP) as the pharmaceutically acceptable carrier. The techniques have been described in general by W. L. Chiou et al., J. Pharm. Sci. 60 (28) (1971) and by S. Riegelman et al., United States Patent No. 4,151, 273. As defined in the Chiou article the term "solid state dispersion" means a dispersion of one or more active ingredients in an inert carrier or matrix in a solid state prepared by a melting (melting), solvent or solvent-melting method combined The dispersion of an active ingredient in a solid carrier or diluent by traditional mechanical mixing is not included within the definition of this term. In the "solvent method" 7 the active ingredient is conventionally dispersed in a water soluble carrier, dissolving a physical mixture containing the active ingredient and the pharmaceutically acceptable carrier in a common organic solvent and then removing the solvent by evaporation. It is recovered and used in the preparation of the appropriate pharmaceutical compositions formulated using conventional methods.The manufacture of the solid dispersions by the melting process or "melting" involves the combination of the pharmaceutically acceptable carrier and the poorly water soluble drug, where they are It allows the two components to melt at temperatures above or above the melting point of both the drug and the carrier.In the fusion process, the drug and the carrier are physically mixed first and then both are melted. cooled quickly to provide a ma sa frozen which is then ground to produce a powder. The spray-freezing techniques used to produce the granules have been described by Kanig (J. Pharm. Sci., 188 (1964)) for the dispersions containing mannitol and by Kreushchner et al. (Acta Pharm. Tech. 26, 159 (1980)) for phenylbutazone urea. In general, problems that may be associated with melting (melting), solvent, melt-solvent, and coprecipitation techniques may include the use of excess solvent, carrier / drug identification combinations that can be conveniently melted ( fused) or co-dissolved, the use of heat to effect the solution or fusion that may result in the decomposition of the drug and / or carrier, and the conditions and identification properties that effect coprecipitation. The salts of the drugs may present particular problems with the organic identification solvents or solvents capable of dissolving both the drug and a pharmaceutically acceptable carrier. U.S. Patent No. 4,007,196 discloses paroxetine as an uptake inhibitor of 5-hydroxytryptamine (5HT) and thus of therapeutic use as an anti-depressant. Paroxetine is well known and widely marketed as a medicinal agent. As disclosed in U.S. Patent No. 4,007,196, paroxetine is obtained as the free base and then converted to its maleate salt. However, paroxetine is a drug poorly soluble in water and difficult to formulate in useful pharmaceutical compositions. U.S. Patent No. 4,721,723 indicates that because of its basicity, it is preferred that paroxetine be used as a therapeutic agent in the form of an acid addition salt. The free base is a viscous oil that is difficult to handle and formulate in a final dosage form for therapeutic use. As such, U.S. Patent No. 4,721,723 further discloses crystalline paroxetine hydrochloride hemihydrate as a novel material with better handling properties than anhydrous paroxetine hydrochloride which is a hygroscopic solid with poor handling properties. In general, the hydrochloride salt of a basic compound is preferred for therapeutic use because of its physiological acceptability. Additionally, a pharmaceutically active ingredient should not contain appreciable amounts of bound or detached organic solvent. Once the salt has been formed, it must be isolated from the solvents by filtration or other means so that the paroxetine salt is conveniently formulated into a pharmaceutical composition. Many solvents, including water, form paroxetine hydrochloride solvates or clathrates, wherein the solvent can not be removed by conventional drying techniques such as vacuum oven drying. U.S. Patent No. 4,721,723 discloses the hemihydrated solvate form of paroxetine hydrochloride, while International Publication Number WO 96/24595 discloses paroxetine hydrochloride solvates other than propan-2-ol solvate as precursors in the preparation of paroxetine hydrochloride substantially free of bound organic solvent. Additionally, International Publication Number WO 96/24595 also discloses four novel paroxetine hydrochloride anhydrates substantially free of bound solvent. However, none of the above publications specifically discloses the stability or hygroscopic capacity of the non-crystalline paroxetine hydrochloride anhydrates in a solid dispersion. The present invention relates to novel processes for incorporating paroxetine, a drug poorly soluble in water, into a solid dispersion and its use in pharmaceutical compositions containing the same.

It has now been surprisingly found that the solid dispersions of paroxetine hydrochloride anhydrate can be manufactured by a melting process using the free base of paroxetine, and dry hydrogen chloride gas at temperatures substantially lower than the melting point of the hydrochloride of paroxetine using a pharmaceutically acceptable carrier with a melting point significantly lower than that of anhydrous paroxetine hydrochloride. The resulting solid dispersion is substantially free of organic solvent, is anhydrous and has improved handling properties. Furthermore, it has been found that the solid dispersions of the paroxetine anhydrous salts, preferably the hydrochloric acid salt, can be manufactured by a novel solvent process using a pharmaceutically acceptable carrier, a paroxetine free base, a non-aqueous solvent and a solution or gas of acid addition salt. The manufacture of the non-crystalline paroxetine hydrochloride anhydrates in a solid dispersion improves the paroxetine free base formulation, provides a solid that is easily formulated in a commercial dosage form, eliminates the additional steps of manufacturing crystalline material for the purposes of management and presumably reduces manufacturing costs associated with those steps.

BRIEF DESCRIPTION OF THE INVENTION Solid dispersions of poorly soluble drugs are described, which are prepared using a solvent or melt process. These dispersions are manufactured with a free base of the drug, specifically the free base of paroxetine, an oil, allowing a low temperature for the melt process, reduced volumes of organic solvent for the solvent process, and the formation of the paroxetine salt during the manufacturing process of the solid dispersion.

DETAILED DESCRIPTION OF THE INVENTION In a first embodiment, the invention provides a process for preparing a dispersion of paroxetine in the water-soluble solid state and a pharmaceutically acceptable polymer carrier, which process comprises: a) forming a solution of a pharmaceutically acceptable water-soluble polymer carrier; and a non-aqueous solvent; b) dissolving the paroxetine free base in the solution, wherein the weight ratio of pharmaceutically acceptable water soluble polymer carrier to the paroxetine is within the range of about 4: 1 to about 1: 1; c) contacting the paroxetine-free base in solution with at least one equivalent of an acid, wherein the acid is a non-toxic, inorganic or organic acid, to form a pharmaceutically acceptable paroxetine salt in solution; and d) removing the non-aqueous solvent by evaporation under vacuum. In a preferred embodiment, the invention provides a process for preparing a water soluble solid state dispersion, wherein the polymeric carrier is polyethylene glycol or polyvinyl pyrrolidone. In a more preferred embodiment, the invention provides a process for preparing a dispersion of paroxysine in the solid state, soluble in water, and a pharmaceutically acceptable polymeric carrier, which process comprises: a) forming a solution of polyethylene glycol and ethanol; b) dissolving the paroxetine free base in the solution, wherein the weight ratio of polyethylene glycol to paroxetine are in the range of about 4: 1 to about 1: 1; c) contacting the paroxetine-free base in solution with at least one equivalent of dry hydrogen chloride, wherein the dry hydrogen chloride is dissolved in methanol or ethanol, to form the pharmaceutically acceptable paroxetine hydrogen chloride solution;; and d) removing the non-aqueous solvent by evaporation under vacuum. In an even more preferred embodiment, the invention provides a method for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymeric carrier, which process comprises: a) forming a solution of polyvinyl pyrrolidone and ethanol; b) dissolving the paroxetine free base in the solution, wherein the weight ratio of the polyvinyl pyrrolidone to the paroxetine are in the range of about 4: 1 to about 1: 1; c) contacting the paroxetine-free base in solution with at least one equivalent of dry hydrogen chloride, wherein the dry hydrogen chloride is dissolved in methanol or ethanol, to form the pharmaceutically acceptable paroxetine hydrogen chloride solution;; d) remove the non-aqueous solvent by evaporation under vacuum. In a second embodiment, the invention provides a process for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymeric carrier, which process comprises: a) contacting a pharmaceutically acceptable water-soluble polymeric carrier; with the paroxetine free base to form an intimate mixture, wherein the weight ratio of the pharmaceutically acceptable, water-soluble polymer carrier to the paroxetine free base is in the range of about 4: 1 to about 1: 1; b) heating the mixture to form a melted homogenous melted substance of the polymeric carrier and the paroxetine free base; c) contacting the melted homogenous melted substance, the polymeric carrier and the free base with paroxetine with at least one equivalent of the dry hydrogen chloride to form the pharmaceutically acceptable paroxetine hydrogen chloride in the molten, homogeneous melted substance; and d) cooling the molten homogeneous melt to form a water soluble solid dispersion. In a second preferred embodiment, the invention provides a process for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymer carrier, which process comprises: a) contacting a polyethylene glycol with the free base of paroxetine to form an intimate mixture, wherein the weight ratio of polyethylene glycol to the paroxetine free base is in the range of about 4: 1 to about 1: 1; b) heating the mixture to form a homogeneous molten melt of polyethylene glycol and paroxetine free base; c) contacting the homogeneous, melted molten substance of polyethylene glycol and the free base with paroxetine with at least one equivalent of the dry hydrogen chloride to form the pharmaceutically acceptable paroxetine hydrogen chloride in the molten homogeneous melted substance; and d) cooling the molten homogeneous melt to form a water soluble solid dispersion.

In a third embodiment, the invention provides a solid state dispersion comprising a pharmaceutically acceptable polymeric carrier and paroxetine. In a fourth embodiment the invention provides a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a solid state dispersion comprising paroxetine and a pharmaceutically acceptable polymeric carrier. In a fifth embodiment, the invention provides a method for treating depression in a warm-blooded animal comprising administering to said animal a dispersion in the solid state, comprising paroxetine and a pharmaceutically acceptable polymer carrier, the amount of paroxetine hydrochloride being effective for treat depression. By "paroxetine" is meant the generic name for the compound described in Example 2 of U.S. Patent No. 4,007,196, also known as (-) - trans-4- (4'-fluorophenyl) - 3- (3 ', 4'-methylenedioxyphenoxymethyl) -piperidine, and the pharmaceutically acceptable salts thereof. Therefore, as used herein, the term paroxetine refers to the "paroxetine free base" or the "paroxetine salt". The term "paroxetine free base", or simply "free base", specifically refers to paroxetine as a material which is a viscous oil at standard temperature and pressure. The term "paroxetine salt" is used to describe an acid addition product of paroxetine. For example, in the case of hydrogen chloride, the acid addition product is called "paroxetine hydrochloride" or simply "hydrochloride salt". The paroxetine compound described herein has two asymmetric centers. Unless indicated otherwise, the (-) - trans isomer is the preferred enantiomer. However, all chiral, diastereomeric and racemic forms are included in the present invention. It is well known in the art how to prepare the optically active forms, such as by resolution of the racemic forms or by synthesis, from the optically active starting materials. The use of all chiral, diastereomeric and racemic forms is attempted, unless specific stoichiometry or isomer form is specifically indicated. As used herein, the term "non-aqueous solvent" refers to any of the following: methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, toluene, benzene, Supercritical liquid CO2, chloroform, methylene chloride, acetonitrile, ketones (for example, but not limited to, dimethyl ketone, methyl ethyl ketone, and diethyl ketone), dimethylformamide, dimethylsulfoxide, esters (eg, but not limited to, ethyl acetate), ethers (for example, but not limited to, diethyl ether and dipropyl ether), 1,4-dioxane, tetrahydrofuran, pentanes, hexanes, heptanes, trichloroethane, or suitable mixtures thereof. Preferably, the solvent must be (a) capable of dissolving both the active ingredient and the carrier, (b) chemically inert with respect to the active ingredient and the carrier; and (c) sufficiently volatile to allow removal by evaporation using conventional techniques. Alkanes having one to four carbon atoms would generally be expected to be useful for preparing dispersions in the solid state by the solvent method. In the present invention, additional features that are important have been found. The organic solvent must be (d) capable of dissolving both the free base and the pharmaceutically acceptable salt of the active ingredient; (e) chemically inert with respect to both of the free base of the active ingredient and the salt formed after the reaction with the acidified organic solvent; and (f) capable of dissolving sufficient acid to allow complete or almost complete conversion of the free base to the salt. As used herein, the term "pharmaceutically acceptable polymeric carrier", or "polymeric carrier", refers to any of the following: hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol, polypropylene, dextrans, dextrins, hydroxypropyl-beta-cyclodextrin, chitosan, copolymers of co (lactic / glycolide), poly (orthoester), poly (anhydrate), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, lecithins, carbopoles, silicon elastomers, polyacrylic polymers , maltodextrins, lactose, fructose, inositol, trehalose, maltose, raffinose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and alpha-, beta-, and gamma-cyclodextrins, or suitable mixtures thereof. In the present invention, it has been found that additional features are important. The pharmaceutically acceptable carrier must be (a) capable of being miscible with both the free base and the salt form of the drug substance, (b) capable of maintaining the salt in a dispersion in solid, non-crystalline, homogeneous, after the solvent has been removed by evaporation and (c) chemically inert with respect to the free base of the active ingredient, the free base salt, and the acidified organic solvent. As used herein, the term "pharmaceutically acceptable salt" refers to the paroxetine derivatives wherein the paroxetine is modified to form the acid addition salts of the compound. Examples of the pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic piperidine residue, and the like. The pharmaceutically acceptable salts of paroxetine include the conventional non-toxic salts or the quaternary ammonium salts. For example, said conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like.; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pam, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable paroxetine salts which can be prepared according to the method of the present invention would include the introduction of or release of the acid portion by various means. In the fusion method, the acid portion would be introduced in the nested form. In the solution method, the acid portion can be introduced in the nested form or by the non-aqueous solvent, which is subsequently removed. In general, the salts are prepared by reacting the free base with the stoichiometric amounts or with an excess of the organic or inorganic acid which forms the desired salt. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985 page 1418, the disclosure of which is hereby incorporated by reference. As used herein, the term "dry hydrogen chloride gas" refers to the hydrogen chloride gas commercially available in cylinders containing compressed gas, which is dry before use. Generally, dry hydrogen chloride gas is commercially prepared by bubbling the hydrogen chloride gas through concentrated sulfuric acid or a comparable drying agent. The disclosure of all references used herein are hereby incorporated by reference. It is an object of the present invention to provide improved processes for the preparation of a water soluble solid dispersion of a poorly water soluble drug or the drug combination prepared by a melt process and / or by solvent to produce solid dispersions. The methods of the present invention, by way of example, and without limitation, can be further understood by the following descriptive procedures.

The general method for the preparation of a solid dispersion by the solvent process proceeds by (1) forming a solution comprising a pharmaceutically acceptable carrier and a non-aqueous solvent. A preferred polymeric carrier is selected from one or more of polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, block copolymers of ethylene oxide and propylene oxide, and polyethylene glycol, wherein a most preferred polymeric carrier is any of polyethylene glycol (PEG) having an average molecular weight of about 1,000 to about 20,000 or polyvinyl pyrrolidone (PVP) having an average molecular weight of about 2,500 to about 3,000,000. A more preferred polymeric carrier is polyvinylpyrrolidone having an average molecular weight of from about 10,000 to about 450,000. A preferred non-aqueous solvent is an alcohol selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, so-butanol, and sec-butanol, wherein a more preferred solvent is either methanol or ethanol, where a most preferred solvent is ethanol. It is also preferred that the non-aqueous solvent be dry or anhydrous. By forming a solution of a polymeric carrier and a non-aqueous solvent, it is understood that the solution can be heated, but is not required, provided that the temperature does not result in the decomposition or degradation of any of the materials. Upon formation of said solution, the process progresses by (2) dissolving the free base of a poorly water soluble drug in the solution formed in this manner. Heating is permissible as in step (1) but is not required. It is understood that the addition of the poorly soluble drug is not limited to a drug but could encompass a combination of one or more drugs with the proviso that at least one drug is a drug poorly soluble in water in the form of a free base. It is preferred that the drug poorly soluble in water in the free base form is paroxetine. The weight ratio of the pharmaceutically acceptable water soluble polymer carrier to paroxetine is in the range of about 5: 1 to about 1: 1, preferably from about 4: 1 to about 1: 1, more preferably about 3: 1. at about 1: 1; most preferably about 2: 1. It is also understood that the order of addition for the polymeric carrier, the non-aqueous solvent and the free base of the drug poorly soluble in water is interchangeable. For example, the free base drug can be dissolved in the non-aqueous solvent after which the polymeric carrier is added. Upon dissolution of the free base drug, the process proceeds by (3) converting the free base to a pharmaceutically acceptable salt. The free base salt, preferably the paroxetine salt, can be formed by the addition of an inorganic acid or an organic acid, which is preferably non-toxic and pharmaceutically acceptable. The acid is added either as a gas, a liquid or a solid dissolved in a non-aqueous solvent. The preferred acid is dry hydrogen chloride and the molar amount of the acid added to the paroxetine free base solution and the carrier can be either in the stoichiometric ratio to the paroxetine free base or in excess of the molar amount of the paroxetine free base, especially when added as a gas. For example, the preferred range of added hydrogen chloride is, but is not limited to, from about 1.0 to about 1.8 times the molar amount of paroxetine free base. Although dry hydrogen chloride is easily added as a gas, the preferred method for adding hydrogen chloride is in the form of hydrogen chloride dissolved in a non-aqueous solvent, preferably hydrogen chloride saturated with methanol or ethanol. It is understood that when adding the acid, the free base salt formed remains dissolved in the solution with the polymeric carrier. Finally, to the free base salt form, the process progresses by (4) recovering the non-aqueous solvent to form a solid state dispersion of the free base salt in the polymeric carrier. Any method of removing the non-aqueous solvent is tried, which makes a dispersion in homogeneous solid state, although preferred are the methods of evaporation under vacuum. Preferred vacuum evaporation methods include rotoevaporation, static vacuum drying and the combination thereof. It is understood that one skilled in the art of pharmaceutical formulations can determine a reasonable temperature at which the non-aqueous solvent can be removed, provided that the temperature is not so high to cause the degradation or decomposition of the materials; however, it is preferred that the evaporation occurs from about 20 ° C to about 50 ° C. It is also preferred that the evaporation of the aqueous solvent forms a dispersion in the solid state, which is homogeneous and substantially free of non-aqueous solvent. By "substantially free" it is meant that the solid state dispersion contains less than 20% by weight of the residual non-aqueous solvent, preferably less than 10%, more preferably less than 5%, most preferably less than 1%. The ratio of the paroxetine free base to the pharmaceutically acceptable carrier can be varied over a wide range and depends on the concentration of the paroxetine required in the form of the pharmaceutical dosage finally administered. However, the preferred range of paroxetine in the solid dispersion is from about 16% to about 50% of the total weight of the solid dispersion, more preferable is from about 20% to about 50%, even more preferable is about 25% at about 40%, most preferably about 33% of the total weight of the dispersion. Alternatively, the general method for the preparation of a solid dispersion can proceed by a melt process wherein a pharmaceutically acceptable water soluble polymer carrier is mixed with a poorly water soluble drug, preferably the paroxetine free base, or a drug combination, to form an intimate mixture. The mixture is heated to or close to the temperature of the highest melting point of either the pharmaceutically acceptable carrier or the poorly water soluble drug or drug combination, thereby forming a melted substance. A preferred polymeric carrier is polyethylene glycol. A preferred weight ratio of pharmaceutically acceptable water-soluble polymeric carrier to poorly water-soluble drug is within the range of from about 5: 1 to about 1: 1, preferably from about 4: 1 to about 1: 1, more preferably from about 3: 1 to about 1: 1; most preferably about 2: 1. It is understood that the addition of a poorly water soluble drug is not limited to a drug, but could encompass a combination of one or more drugs with the proviso that at least one drug is a drug poorly soluble in water in the form of a free base. It is preferred that the drug poorly soluble in water in the form of a free base is paroxetine. Alternatively, the pharmaceutically acceptable water-soluble polymeric carrier can be heated to the melt condition over which the poorly water-soluble drug, such as the free base, can be added to the molten carrier, thereby forming a substance melted homogeneous, melted. In forming the molten, homogeneous molten substance, the process proceeds by (2) diffusing the dry hydrogen chloride gas through the molten drug / carrier mixture to effect the formation of the drug salt. Finally, upon formation of the free base salt, the process proceeds by (4) cooling the homogeneous melted substance, melted by conventional methods to form a dispersion in the water soluble solid state.

The ratio of the paroxetine free base to the pharmaceutically acceptable carrier can be varied over a broad spectrum and depends on the concentration of the paroxetine required in the pharmaceutical dosage form finally administered. However, the preferred range of paroxetine in the solid dispersion is from about 16% to about 50% of the total weight of the solid dispersion, more preferable is from about 20% to about 50%, even more preferable is about 25% at about 40%, most preferably about 33% of the total weight of the dispersion. Alternatively, the general method for the preparation of a solid dispersion can proceed by a combination of the melt method and the solvent method. Specifically, the poorly water soluble drug is paroxetine; for the melt process the preferred pharmaceutically acceptable carrier is polyethylene glycol; for the solvent process the preferred pharmaceutically acceptable carrier is polyvinylpyrrolidone or polyethylene glycol, the preferred solvent is ethanol, the preferred pharmaceutically acceptable salt is hydrogen chloride, the preferred method for adding hydrogen chloride is in the form of ethanolic hydrogen chloride and the preferred method for recovering the solvent is by evaporation from about 20 ° C to about 50 ° C by a combination of evaporation and drying with static vacuum. The present invention also provides a pharmaceutical composition comprising the pharmaceutically acceptable excipients and a dispersion of paroxetine hydrochloride in the solid state and a pharmaceutically acceptable polymeric carrier. Examples of the pharmaceutically acceptable excipients include diluents, binders, disintegrants, coloring agents, flavoring agents, lubricants and / or preservatives. The pharmaceutical composition can be formulated by conventional combination methods such as mixing, filling, granulation and compression. These agents can be used in a conventional manner, for example, in a manner similar to that already clinically used for antidepressant agents. The composition is generally presented as a unit dose composition containing from 1 to 200 mg, more usually from 5 to 100 mg, for example from 10 to 50 mg such as 12.5, 20, 25 or 30 mg. This composition is usually taken 1 to 6 times a day, for example, 2, 3 or 4 times a day such that the total amount of active agent administered is within the range of 5 to 400 mg. Preferred unit dosage forms include tablets or capsules. The invention also provides a method of treating depression in mammals including the human, which method comprises administering an effective amount of the paroxetine hydrochloride dispersion in the solid, pharmaceutically acceptable state. The invention further provides a dispersion of paroxetine hydrochloride in the solid state, for use in the treatment of depression. The following examples illustrate the invention. Examples 1 to 16 show the preparation of the solid state dispersions while examples 17 and 18 show the pharmaceutical compositions.

EXAMPLE 1 PEG-8000 / paroxetine free base, 2: 1 base by weight: melt method To a 50 ml round bottom flask in the shape of a pear (equipped with a small magnetic stir bar, a rubber septa and a pipette glass) was added PEG-8000 (2,009 g) and the paroxetine free base (0.75 g). The flask is immersed in a water bath, which was heated to a temperature to effect the fusion of the PEG. Once it flows freely, the glass pipette was carefully lowered below the level of the melted substance, and a stream of hydrogen chloride gas (dried through concentrated sulfuric acid) was bubbled through the pipette for 30 minutes . Agitation was maintained during this process. After the introduction of gas, the pipette and stirrer were removed and allowed to cool to the mixture at room temperature overnight. The solidified product was carefully scraped from the flask. This material can optionally be crushed / ground to a desired particle size. The 1H NMR analysis (CDCI3) was completely consistent with a mixture of PEG and paroxetine hydrochloride, and shows the expected resonance for PEG (3.63, m) and the characteristic signal for paroxetine hydrochloride (2.03, br, d) . Elemental Analysis: Calculated for 2009: 0.83 (base weight) PEG-8000 and paroxetine HCl:% C, 56.82; % H, 8.07; % N, 1.04; % CI, 2.83. Found:% C, 56.71; % H, 8.28; % N, 1.00; % CI, 3.44.

EXAMPLE 2 PEG-8000 / paroxetine free base, 2: 1 base by weight: method per solution To a 200 ml round bottom flask (equipped with a small magnetic stir bar, rubber septa) was added PEG-8000 (10.0 g ) and methanol (140 ml).

The free base of paroxetine (4,994 g) was added and stirred about 5 minutes until completely dissolved. In a separate procedure, methanolic HCl was prepared by bubbling the HCl gas (50 ml). This standard solution (0.196 g / l) can be used for other experiments.

The methanolic HCl (5 ml), prepared above, was added to the 200 ml flask and stirring was continued for 10 minutes. The stirring bar was removed, the flask was placed on a rotary evaporator and concentrated with a bath at a temperature of 35 ° C. Once a thick paste was obtained, the flask was placed under a high pressure static vacuum, which was continued for 18 hours. In due course, the material was scraped freely from the sides of the flask to aid in the removal of residual volatiles. The product was scraped from the flask and can be crushed / milled to an acceptable particle size. The 1H NMR analysis (CDCI3) was completely consistent with a mixture of PEG and paroxetine hydrochloride, and shows the expected resonance for PEG (3.63, m) and the characteristic signal for paroxetine hydrochloride (2.03, br, d) . No residual methanol was detected. Elemental analysis: Calculated for 10,000: 5.54 (base weight) PEG-8000 and paroxetine HCl:% C, 57.31; % H, 7.86; % N, 1.27; % CI, 3.43. Found:% C, 57.31; % H, 8.07; % N, 1.21; % CI, 4.38.

EXAMPLE 3 PEG-8000 / paroxetine free base. 4: 1 weight basis: method per solution Using PEG-8000 (4.013 g) and paroxetine free base (1015 g), and methanolic HCl (1 ml of a 0.19 g / ml solution) and the method of Example 2 , a solid dispersion of PEG / paroxetine hydrochloride of 4: 1 base by weight was prepared. The 1H NMR analysis (CDCI3) was completely consistent with a mixture of PEG and paroxetine hydrochloride, and shows the expected resonance for PEG (3.63, m) and the characteristic signal for paroxetine hydrochloride (2.03, br, d) . No residual methanol was detected.

Elemental analysis: Calculated for 4.013: 1.126 (base weight) PEG-8000 and paroxetine HCl:% C, 56.23; % H, 8.32; % N, 0.78; % CI, 2.11. Found:% C, 56.11; % H, 8.60; % N, 0.72; % CI, 2.63.

EXAMPLE 4 PEG-8000 / paroxetine free base, 1: 1 base in weight; method by solution using ethanolic HCl A solution of ethanolic HCl was prepared by bubbling the HCi gas (3.23 g) into a solution (50 ml) of absolute ethanol. Using PEG-8000 (20077 g) and paroxetine free base (2.066 g), in an ethanol (15 ml) and methanol (8 ml) mixture was added ethanolic HCl (3 ml) and the method of example 2 , a solid dispersion of PEG / paroxetine hydrochloride of 1: 1 base by weight was prepared. The 1H NMR analysis (CDCI3) was completely consistent with a mixture of PEG and paroxetine hydrochloride, and shows the expected resonance for PEG (3.63, m) and the characteristic signal for paroxetine hydrochloride (2.03, br, d) . No residual ethanol was detected. Elemental analysis: Calculated for 2007: 2,292 (base weight) PEG-8000 and paroxetine HCl:% C, 58.77; % H, 7.29; % N, 1.90; % CI, 5.15. Found:% C, 59.18; % H, 7.72; % N, 1.98; % CI, 4.95.

EXAMPLE 5 PVP 29 / 32K / paroxetine free base, 2: 1 base in weight; method by solution Using PVP 29 / 32K (2.077 g), the free base of paroxetine (1,008 g), methanol (28 ml), methanolic HCl (1.0 ml of a solution of 0.196 g / ml) and the method of example 2, a solid dispersion of PVP / paroxetine hydrochloride, 2: 1 base by weight was prepared. The 1H NMR analysis (CDCI3) was completely consistent with a mixture of PVP and paroxetine hydrochloride, and shows the expected resonance for the PVP (series of br.M 3.4 - 1.6) and the characteristic signal for paroxetine hydrochloride (2.03, br, d). 4% methanol (base by weight) was detected. Elemental analysis: Calculated for 2007: 1118 (basis in weight) PVP and paroxetine HCl:% C, 61.13; % H, 7.74; % N, 8.82; % CI, 5.89. Found:% C, 62.49; % H, 7. 63; % N, 9.12; % CI, 6.33.

EXAMPLE 6 PEG-8000 / paroxetine free base, 2: 1 base in weight; method per solution As in Example 2, using ethanol instead of methanol as a solvent, ethanolic HCl (solution prepared in Example 4), PVP 29 / 32K / paroxetine free base, 2006: 1.048 (Base by weight). The 1H NMR analysis (CDCI3) was completely consistent with a mixture of PVP and paroxetine hydrochloride, and shows the expected resonance for PVP (series of br. M 3.4 - 1.6) and the characteristic signal for paroxetine hydrochloride (2.03 , br, d). 4% methanol (base by weight) was detected.

Elemental analysis: Calculated for 2006: 1.048: 0.124 (basis in weight) PVP / HCl of paroxetine / HCl:% C, 59.96; % H, 7.23; % N, 8.59; % CI, 7.07. Found:% C, 61.39; % H, 7.32; % N, 8.67; % CI, 7.96.

Using the methods described above and the modifications thereof, the following additional examples can be prepared by one skilled in the art.

Example Excipient Prc [HCL Method2 7 PVP 1/1 1.0 Solution 8 PVP 2/1 1.0 Solution 9 PVP 3/1 1.0 Solution 10 PEG 1/1 1.0 Solution 11 PEG 2/1 1.0 Solution 12 PEG 3/1 1.0 Solution 13 PEG 4/1 1.0 Solution 14 PEG 1/1 excess Fusion 15 PEG 3/1 excess Fusion 16 PEG 4/1 excess Fusion 1- Base in weight of E ixcipiei 2- See example 2 for the Mé DOSAGE AND FORMULATION The method of this invention can be administered by any means that produces contact of the active agent with the site of action of the agent, inhibition of serotonin re-uptake, in the body of a mammal. These can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. The dosage of the novel compounds of this invention administered, of course, will vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the container; the nature and extent of the symptom; the type of concurrent treatment; the frequency of treatment; and the desired effect. A daily dose of the active ingredient can be expected to be from about 0.001 to 10 milligrams per kilogram of body weight. Dosage forms (compositions suitable for administration) contain from about 0.1 milligrams to about 100 milligrams of the active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5 to 50% by weight based on the total weight of the composition. The active ingredient can be administered orally in the form of solid doses, such as capsules, tablets, and powders. Gelatin capsules contain the active ingredient and powder carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Both the tablets and the capsules can be manufactured as sustained release products to provide continuous release of the drug over a period of hours. Compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Acceptable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The pharmaceutical dosage forms useful for the administration of compounds of this invention can be illustrated as follows: CAPSULES A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules, each with 10 milligrams of active ingredient powder, 150 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams of magnesium stearate.

SOFT GELATINE CAPSULES A mixture of the active ingredient in a digestible oil such as soybean oil, sunflower seed oil or olive oil was prepared and injected by means of a positive displacement pump into the gelatin to form the capsules of Soft gelatin containing 10 milligrams of the active ingredient. The capsules are washed and dried.

TABLETS A large number of tablets are prepared by conventional procedures such that the dosage unit was 10 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings can be applied to increase the good taste or delay absorption.

The following examples further illustrate a specific embodiment of the present invention, and is considered an illustrative, but not limiting, description of the invention.

EXAMPLE 17 A 10 mg tablet of paroxetine base (such as the HCl salt) using a solid dispersion as described in Example 8 Ingredient mg / tablet gm / 1000 lot of tablet paroxetine HCl * 22.21 22.21 Polyvinylpyrrolidone * 40.00 40.00 Dicalcium phosphate dihydrate Dibasic 210.79 210.79 Sodium starch glycolate 24.00 24.00 Magnesium stearate 3.00 3.00 Total 300 mg 300 gm * Theoretical quantities for a solid dispersion of paroxetine HCl and polyvinylpyrrolidone as described in Example 8.

Procedure: Grind the paroxetine / polyvinylpyrrolidone HCl solid dispersion by passing through a 20 mesh screen. Mix the ground solid dispersion with the dicalcium dicalcium phosphate dihydrate, the sodium starch glycolate and the magnesium stearate. Compress the tablets to a weight of 300 mg with a tablet hardness of approximately 17 units of Strong-Cobb.

EXAMPLE 18 A 20 mq tablet of paroxetine base (as the HCl salt) using a solid dispersion as described in Example 11 Ingredient mg / tablet gm / 1000 batch of paroxetine HCl tablet * 22.21 22.21 Polyethylene glycol * 40.00 40.00 Dicalcium phosphate dihydrate Dibasic 210.79 210.79 Sodium starch glycolate 24.00 24.00 Magnesium stearate 3.00 3.00 Total 300 mg 300 gm * Theoretical amounts for a solid dispersion of paroxetine HCl and polyethylene glycol as described in Example 11.

Procedure: Grind the paroxetine / polyethylene glycol HCl solid dispersion by passing through a 20 mesh screen. Mix the ground solid dispersion with the dicalcium dicalcium phosphate dihydrate, the sodium starch glycolate and the magnesium stearate. Compress the tablets to a weight of 300 mg with a tablet hardness of approximately 17 units of Strong-Cobb.

Claims (29)

1. A process for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymeric carrier, which process comprises: a) forming a solution of a pharmaceutically acceptable polymeric carrier, soluble in water, and a non-aqueous solvent; b) dissolving the paroxetine free base in the solution, wherein the weight ratio of the pharmaceutically acceptable water-soluble polymer carrier to paroxetine is in the range of about 4: 1 to about 1: 1; c) contacting the free base of paroxetine in solution with at least one equivalent of an acid, wherein the acid is a non-toxic inorganic or organic acid, to form the paroxetine salt in solution, pharmaceutically acceptable; and d) removing the non-aqueous solvent by evaporation under vacuum.

2. The process according to claim 1, wherein the polymeric carrier is selected from one or more of the following: polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, block copolymers of ethylene oxide and propylene oxide, and polyethylene glycol.

3. The process according to claim 1, wherein the free base of paroxetine is dissolved in an aqueous solvent before the polymeric carrier is dissolved in the aqueous solvent.

4. The process according to claim 1, wherein the non-aqueous solvent is an alcohol selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, and sec-butanol.

5. The process according to claim 1, wherein the non-aqueous solvent is ethanol.

6. The process according to claim 1, wherein the acid is hydrogen chloride in the form of dry hydrogen chloride gas or dry hydrogen chloride dissolved in a non-aqueous solvent.

The process according to claim 1 for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymeric carrier, which process comprises: a) forming a solution of polyvinyl pyrrolidone and a non-aqueous solvent; b) dissolving the paroxetine free base in the solution, wherein the weight ratio of the polyvinyl pyrrolidone to the paroxetine are in the range of about 4: 1 to about 1: 1; c) contacting the free base of paroxetine in solution with at least one equivalent of an acid, wherein the acid is a non-toxic inorganic or organic acid, to form a paroxetine salt in solution, pharmaceutically acceptable; and d) removing the non-aqueous solvent by evaporation under vacuum.

The process according to claim 7, wherein the polymeric carrier is polyvinylpyrrolidone having an average molecular weight of from about 2,500 to about 3,000,000.

9. The process according to claim 7, wherein the non-aqueous solvent is an alcohol selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, and sec-butanol.

10. The process according to claim 7, wherein the non-aqueous solvent is ethanol.

The process according to claim 7, wherein the acid is hydrogen chloride in the form of dry hydrogen chloride gas or dry hydrogen chloride dissolved in a non-aqueous solvent.

The process according to claim 1 for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymeric carrier, which process comprises: a) forming a solution of polyvinyl pyrrolidone and ethanol; b) dissolving the paroxetine free base in the solution, wherein the weight ratio of the polyvinyl pyrrolidone to the paroxetine are in the range of about 4: 1 to about 1: 1; c) contacting the paroxetine-free base in solution with at least one equivalent of dry hydrogen chloride, wherein the dry hydrogen chloride is dissolved in methanol or ethanol, to form the pharmaceutically acceptable paroxetine hydrogen chloride solution;; and d) removing the non-aqueous solvent by evaporation under vacuum.

13. A solid state dispersion of a pharmaceutically acceptable polymeric carrier and paroxetine hydrochloride produced by the process of claim 12.

14. The process according to claim 1 for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymer carrier, which process comprises: a) forming a solution of polyethylene glycol and a non-aqueous solvent; b) dissolving the paroxetine free base in the solution, wherein the weight ratio of polyethylene glycol to paroxetine are in the range of about 4: 1 to about 1: 1; c) contacting the free base of paroxetine in solution with at least one equivalent of an acid, wherein the acid is a non-toxic inorganic or organic acid, to form a paroxetine salt in solution, pharmaceutically acceptable; and d) removing the non-aqueous solvent by evaporation under vacuum.

15. The process according to claim 14, wherein the polymeric carrier is polyethylene glycol having an average molecular weight of about 1,000 to about 20,000.

16. The process according to claim 14, wherein the non-aqueous solvent is an alcohol selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, and sec-butanol.

17. The process according to claim 14, wherein the non-aqueous solvent is ethanol.

18. The process according to claim 14, wherein the acid is hydrogen chloride in the form of dry hydrogen chloride gas or dry hydrogen chloride dissolved in a non-aqueous solvent.

The process according to claim 1 for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymeric carrier, which process comprises: a) forming a solution of polyethylene glycol and ethanol; b) dissolving the paroxetine free base in the solution, wherein the weight ratio of polyethylene glycol to paroxetine are in the range of about 4: 1 to about 1: 1; c) contacting the paroxetine-free base in solution with at least one equivalent of dry hydrogen chloride, wherein the dry hydrogen chloride is dissolved in methanol or ethanol, to form the pharmaceutically acceptable paroxetine hydrogen chloride solution;; and d) removing the non-aqueous solvent by evaporation under vacuum.

20. A solid state dispersion of a pharmaceutically acceptable polymeric carrier and paroxetine hydrochloride produced by the process of claim 19.

21. A process for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymer carrier, whose The process comprises: a) contacting a pharmaceutically acceptable water-soluble polymeric carrier with the paroxetine-free base to form an intimate mixture, wherein the weight ratio of the pharmaceutically acceptable water-soluble polymeric carrier to the free base of paroxetine is in the range of about 4: 1 to about 1: 1; b) heating the mixture to form a melted homogenous melted substance of the polymeric carrier and the paroxetine free base; c) contacting the melted homogenous melted substance, the polymeric carrier and the free base with paroxetine with at least one equivalent of the dry hydrogen chloride to form the pharmaceutically acceptable paroxetine hydrogen chloride in the molten, homogeneous melted substance; and d) cooling the molten homogeneous melt to form a water soluble solid dispersion.

22. The process according to claim 21 for preparing a dispersion of paroxetine in the solid state, soluble in water, and a pharmaceutically acceptable polymeric carrier, which process comprises: a) contacting a polyethylene glycol with the free base of paroxetine for forming an intimate mixture, wherein the weight ratio of polyethylene glycol to the paroxetine free base is in the range of about 4: 1 to about 1: 1; b) heating the mixture to form a homogeneous molten melt of polyethylene glycol and paroxetine free base; c) contacting the homogeneous, melted molten substance of polyethylene glycol and the free base with paroxetine with at least one equivalent of the dry hydrogen chloride to form the pharmaceutically acceptable paroxetine hydrogen chloride in the molten homogeneous melted substance; and d) cooling the molten homogeneous melt to form a water soluble solid dispersion.

23. A solid state dispersion comprising a pharmaceutically acceptable polymeric carrier and paroxetine.

24. A pharmaceutical composition comprising a solid state dispersion of claim 7 and one or more pharmaceutically acceptable excipients.

25. A pharmaceutical composition comprising a solid state dispersion of claim 14 and one or more pharmaceutically acceptable excipients.

26. A pharmaceutical composition comprising a solid state dispersion of claim 22 and one or more pharmaceutically acceptable excipients.

27. A method for treating depression in a warm-blooded animal comprising administering to said mammal a solid state dispersion according to claim 7, wherein the amount of paroxetine hydrochloride in said dispersion is effective to treat the depression.

28. A method for treating depression in a warm-blooded animal comprising administering to said mammal a solid state dispersion according to claim 14, wherein the amount of paroxetine hydrochloride in said dispersion is effective to treat the depression.

29. A method for treating depression in a warm-blooded animal comprising administering to said mammal a solid state dispersion according to claim 22, wherein the amount of paroxetine hydrochloride in said dispersion is effective to treat the depression.