Title:  Aqueous process for manufacturing paroxetine solid dispersions

United States Patent:  6,168,805

Assignee:  Endo Pharmaceuticals, Inc. (Chadds Ford, PA)

Filed:  May 7, 1998

A process for preparing solid, amorphous paroxetine comprising: (A) mixing paroxetine free base or a pharmaceutically acceptable paroxetine salt with water and pharmaceutically acceptable polymer; and (B) drying to form a composition comprising amorphous paroxetine and polymer, eliminating the need for organic solvents common for the solvent process. The resultant amorphous solid paroxetine composition is free from crystalline form, and yet has good handling properties, making it suitable for pharmaceutical use in the traditional tablet dosage form.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

Paroxetine is the generic name for the compound described in Example 2 of U.S. Pat. No. 4,007,196, also known as (-)-trans-4-(4'-fluorophenyl)-3-(3',4'-ethylenedioxyphenoxymethyl)-piperid ine, and pharmaceutically acceptable salts thereof. Paroxetine free base is a viscous oil at standard temperature and pressure. The paroxetine salts are acid addition products of paroxetine. For example, the hydrogen chloride acid addition product is called "paroxetine hydrochloride" or "paroxetine hydrochloride salt."

The compound paroxetine herein described has two asymmetric centers. Unless otherwise indicated, the (-)-trans isomer is the preferred enantiomer. However, all chiral, diastereomeric and racemic forms can be used. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. Use of all chiral, diastereomeric, racemic forms are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The pharmaceutically acceptable polymeric carriers used in the invention can be, for example, 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, co(lactic/glycolid) copolymers, poly(orthoester), poly(anhydrate), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, lectins, carbopols, 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 of thereof.

Preferred polymeric carriers are one or more of polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, block co-polymers of ethylene oxide and propylene oxide, and polyethylene glycol, wherein a more preferred polymeric carrier is polyvinylpyrrolidone (PVP) having an average molecular weight of from about 2,500 to about 3,000,000. A most preferred polymeric carrier is polyvinylpyrrolidone having an average molecular weight of from about 10,000 to about 450,000. It is preferred that the polymer is not of a character which controls or delays the release of said paroxetine from a solid tablet formulation since immediate release formulations have been found to be the most preferable.

The pharmaceutically acceptable carrier is preferably miscible with both the paroxetine free base and the salt, capable of keeping the salt in a homogeneous noncrystalline solid state dispersion after the water has been removed by evaporation and chemically inert with respect to the free base of the active ingredient, the salt of the free base, and the aqueous acid solution. The polymer is preferably at least partially water soluble, and more preferably is fully water soluble.

Suitable pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts, quaternary ammonium salts, and the like. Examples of pharmaceutically acceptable 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, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic, isothyanic, and the like.

The pharmaceutically acceptable salts of paroxetine can be prepared by introduction of or delivery of the acid moiety by various means. The acidic moiety could be introduced in neat form or as an aqueous solution. Generally, the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid.

Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The paroxetine may be added in either free base or salt form. When the paroxetine is added in free base form, the process comprises adding an acid corresponding to a pharmaceutically acceptable salt of paroxetine to the mixture or solution of the free base. The free base is then converted to a salt in situ, for example by addition of an inorganic or an organic acid. The acid is added either as a gas, a liquid or as a solid dissolved into water. The preferred acid is hydrogen chloride and the molar quantity of acid added to the solution of paroxetine free base and carrier may either be in stoichiometric proportion to the paroxetine free base or be in excess of the molar quantity of the paroxetine free base, especially when added as a gas.

The preferred range of hydrogen chloride added is about 1.0 to about 1.8 times the molar quantity of paroxetine free base. Preferred molar ratios of paroxetine to HCl are about 1:1 to 1:1.8, more preferably about 1:1.1. Although hydrogen chloride is readily added as a gas, the preferred method to add the hydrogen chloride is in the form of hydrogen chloride dissolved into water. It is understood that upon addition of the acid, the formed free base salt remains dissolved in solution with the polymeric carrier.

The paroxetine, polymeric carrier, and water may be combined in any order. It is preferred that they be combined in a manner so as to form a solution of paroxetine salt and the polymer.

In forming a solution of polymeric carrier and water, heating of the solution is not necessary at lower concentrations but is strongly preferred at higher concentrations, provided that the temperature does not result in decomposition or degradation of any materials. It is preferred to add the paroxetine free base or paroxetine salt after dissolving the polymer in water, suitably at 25 to 100^oC., preferably at 45 to 80^oC. When the paroxetine is added as a free base, it is preferred to form a salt at a temperature at which the final solution is clear. For the most preferred embodiments, a temperature of at least about 60^oC. results in a clear solution of the paroxetine salt being formed, although for other concentrations and embodiments, clear solutions are formed at other temperatures. It is preferred to only add enough heat to form a clear solution.

The ratio by weight of water soluble pharmaceutically acceptable polymeric carrier to paroxetine salt is in the range of about 20:1 to about 0.5:1; preferably about 4:1 to about 1:1; more preferably about 3:1 to about 1.5:1; most preferably about 2:1.

Preferably a clear solution is formed. Upon formation of the preferred clear solution, the process proceeds by recovering the water to form a solid state dispersion of the free base salt in the polymeric carrier. Any method of removal of the water which renders a homogeneous solid state dispersion is intended, although preferred are methods of evaporation under vacuum or spray drying. Preferred methods of evaporation under vacuum 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 water can be removed, provided the temperature is not so high as to cause degradation or decomposition of the materials; however, it is preferred that evaporation occurs at about 25^oC. to about 100^oC. It is also preferred that evaporation of water renders a solid state dispersion which is homogeneous and substantially free of water. By substantially free it is meant that the solid state dispersion contains less than 20% by weight of residual water, preferably less than 10%, more preferably less than 5%, most preferably less than 1%.

In addition to the amorphous paroxetine salt, other active ingredients can be added, preferably in water-soluble salt form, so as to form combinations of more than one drug in amorphous form. In view of the preference for immediate release formulations, it is very much preferred that the solid formulation be free of calcium polycarbophil, which is used in the prior art as a controlled release agent. In fact it is preferred that the composition be free of any water-swellable, insoluble, fibrous cross-linked carboxy-functional polymer, which were used in the prior art for controlled release.

The ratio of paroxetine to the pharmaceutically acceptable polymeric carrier can be varied over a wide range and depends on the concentration of paroxetine required in the pharmaceutical dosage form ultimately administered.

The ratio of paroxetine free base to the pharmaceutically acceptable carrier can be varied over a wide range and depends on the concentration of paroxetine required in the pharmaceutical dosage form ultimately administered. However, the preferred range of paroxetine in the solid dispersion is about 16% to about 50% of the total solid dispersion weight, more preferable is about 20% to about 50%, even more preferable is about 25% to about 40%, most preferable is about 33% of the total dispersion weight. In terms of weight ratio of polymer to paroxetine, a preferred range is about 0.4:1 to 20:1.

Suitable pharmaceutically acceptable excipients can be added in the process. Suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Examples of pharmaceutically acceptable excipients include diluents, binders, disintegrants, coloring agents, flavoring agents, lubricants and/or preservatives. The pharmaceutical composition may be formulated by conventional methods of admixture such as blending, filling, granulation and compressing. These agents may be utilized in conventional manner, for example in a manner similar to that already used clinically for anti-depressant agents.

The composition is usually presented as a unit dose composition containing from 1 to 200 mg, more usually from 5 to 100 mg, for example 10 to 50 mg such as 12.5, 20, 25, or 30 mg. Such composition is normally taken from 1 to 6 times daily, for example 2, 3, or 4 times daily so 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 for a method of treatment of depression in mammals including humans which method comprises administering an effective amount of pharmaceutically acceptable solid state dispersion of paroxetine hydrochloride.

The invention further provides a formulation of paroxetine hydrochloride for use in the treatment of depression.

The method of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, serotonin re-uptake inhibition, in the body of a mammal. They 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 will, of course, vary depending upon 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 recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to 10 milligrams per kilogram of body weight.

Dosage forms (compositions suitable for administration) contain from about 0.1 milligram to about 100 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-50% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders.

Gelatin capsules contain the active ingredient and excipients, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar excipients can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can 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.

A few examples of pharmaceutical dosage-forms for administration of the compounds of this invention are illustrated as follows:

Unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 10 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 10 milligrams of the active ingredient. The capsules would then be washed and dried.

Tablets can be prepared by conventional procedures, for example in the dosage units of 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 may be applied to increase palatability or delay absorption.

The active ingredient may be administered with pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients include calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose derivatives, croscarmallose sodium, cospovidone, dextrates, dextrin, dextrose, fructose, guar gum, lactose, maltodextrin, mannitol, povidone, starch, sorbitol, sucrose, xylitol and mixtures thereof. Pharmaceutically acceptable cellulose derivatives include hydroxypropyl celluose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose and the like. The active ingredient may be mixed with pharmaceutically acceptable excipient and tabletized.

Claim 1 of 33 Claims

What is claimed is:

1. A process for preparing solid, amorphous paroxetine comprising:

(A) mixing paroxetine free base or a pharmaceutically acceptable paroxetine salt with water and pharmaceutically acceptable polymer; and

(B) drying to form a composition comprising solid amorphous paroxetine and polymer wherein said polymer is at least partially water soluble.

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