Serotonin reuptake inhibitor formulations

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills

Reexamination Certificate

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C424S400000, C424S465000, C424S489000, C514S321000, C514S646000

Reexamination Certificate

active

06720003

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to processes for preparing solid dispersions comprising paroxetine or sertraline dispersed in a water-soluble polymer, and preparation of solid oral dosage forms containing the dispersions. The present invention is also related to processes for preparing an amorphous paroxetine salt or sertraline salt, and incorporation of these amorphous drugs into suitable pharmaceutical dosage forms.
BACKGROUND OF THE INVENTION
Paroxetine and sertraline are two of the compounds having anti-depressant properties that are known as selective serotonin reuptake inhibitors (“SSRI”).
Of these, paroxetine, the chemical name of which is (−)-trans-4R-(4′-fluorophenyl)-3S-[(3′4′-methylenedioxyphenoxy)methyl]-piperidine, has been identified in the art as having utility in the treatment of a variety of disease states, including but not limited to depression, anxiety, obsessive compulsive disorders, panic, pain, obesity, senile dementia, migraine, bulimia, anorexia, alcoholism, trichotillomania, dysthymnia, substance abuse, social phobia, depression arising from pre-menstrual tension or adolescence, and premature ejaculation. Paroxetine is indicated for the treatment of depression, obsessive compulsive disorder and panic disorder with or without agoraphobia in a recommended dose of 10 to 60 mg once a day. The antidepressant action of paroxetine and its efficacy in the treatment of obsessive compulsive disorder and panic disorder is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin. Generally speaking, paroxetine hydrochloride is a moderately water-soluble, orally administered antidepressant having a melting point range of 120° to 138° C. and a solubility of 5.4 mg/ml in water. Paroxetine is commercially available in the form of paroxetine hydrochloride hemihydrate, marketed under the name Paxil®(SmithKline Beecham).
Because of its basicity, it has been considered preferable that paroxetine be prepared in the form of an acid addition salt. However, most of the known salts of paroxetine are considered to have unsuitable physico-chemical properties for ensuring safe and efficient handling during production of the final product, since they are unstable and possess undesirable hygroscopicity. Furthermore, their formation by crystallization from both aqueous or non-aqueous solvents provides a low yield.
A number of patents have addressed the preparation of paroxetine. For example, U.S. Pat. No. 4,007,196 (Christensen, et al.) describes the preparation of paroxetine as a free base with the subsequent conversion to the maleic acid salt. The use of the acetate salt of paroxetine is also known, e.g., from
Psychopharmacology
57, 1515-153 (1978). The limited use of the hydrochloride salt of paroxetine in an aqueous solution has also been described, e.g., in
Acta. Phamacol. et Toxicol.
44,289-295 (1979). U.S. Pat. No. 4,721,723 (Barnes et al.) describes crystalline paroxetine hydrochloride hemihydrate, compositions containing the same and processes for its preparation. However, the processes described in the Barnes patent require post-synthetic treatment of the product in order to obtain the crystalline form, which adds to the difficulty and overall cost of production.
U.S. Pat. No. 5,681,962 (Callander) describes a process for preparing paroxetine, and in particular the hydrochloride hemi-hydrate form of paroxetine, using diborane as a reducing agent.
U.S. Pat. Nos. 5,856,493, 5,900,423 and 5,872,132 (each to Ward et al.) describe paroxetine hydrochloride anhydrate which is substantially free of propan-2-ol and methods of preparing the same, which are stated to overcome problems described in the art by removing the solvent from the paroxetine salt. The preparation of the paroxetine hydrochloride anhydrate substantially free of propan-2-ol is said to comprise crystallizing paroxetine hydrochloride in either (I) an organic solvent which forms a solvate with the paroxetine hydrochloride and which is not removable by conventional drying techniques (e.g., alcohols such as ethanol); or (II) an organic solvent which does or does not form a solvate with the paroxetine hydrochloride but which are removable by conventional vacuum oven drying; and thereafter in the case of (I) displacing the solvated solvent using a displacing agent (e.g., water) or in the case of (II) removing the solvent.
U.S. Pat. No. 5,874,447 (Benneker, et al.) describes the preparation of paroxetine sulfonates which are said to exhibit high solubility. According to the method of that patent, paroxetine (or a salt and/or base thereof) is mixed together with a sulfonic acid to form a solution, followed by the separation of the resultant paroxetine sulfonate from this solution. The resultant sulfonate is further said to be useful as a reagent in further syntheses, e.g., as a start reagent for forming further acid addition salts.
Amorphous forms of paroxetine have also been reported. For example, U.S. Pat. No. 4,721,723 (Barnes et al.), in distinguishing the hemihydrate salt form of paroxetine disclosed therein from other forms of paroxetine, reports that such hemihydrate form is desirable because amorphous paroxetine hydrochloride is undesirably hygroscopic and has poor handling qualities.
U.S. Pat. No. 5,672,612 (Ronsen et al.) describes amorphous paroxetine hydrochloride ethanol composition which is purported to be substantially non-hydroscopic and free-flowing. Said composition is prepared by dissolving paroxetine free base in a hydrochloric acid-ethanol solution followed by drying.
U.S. Pat. No. 5,955,475 (Krape et al.) describes processes for preparing a solid dispersion of an anhydrate form of a paroxetine salt. The processes use the free base of paroxetine, an oil, which is said to allow the solid dispersion to be prepared at a low temperature via a fusion process or with decreased organic solvent volumes via a solvent process, and the formation of a paroxetine salt during the solid dispersion manufacture process. Thus, in a first embodiment, Krape, et al. describe a process wherein a solution is formed of a water soluble polymeric carrier (e.g., polyethylene glycol or polyvinylpyrrolidone) and a non-aqueous solvent (e.g., an alcohol such as ethanol); dissolving paroxetine free base into the solution, wherein the ratio of polymeric carrier to paroxetine is 4:1 to 1:1, by weight; contacting the paroxetine free base in solution with at least one equivalent of an acid (hydrogen chloride in the form of dry hydrogen chloride gas or dry hydrogen chloride dissolved into a non-aqueous solvent) to form a paroxetine salt in solution (paroxetine hydrogen chloride); and then removing the non-aqueous solvent by evaporation under vacuum. A second embodiment is described wherein the paroxetine free base is dissolved into the solution of polymeric carrier and non-aqueous solvent to form a mixture having the aforementioned ratio of polymeric carrier to paroxetine free base, and thereafter the mixture is heated to form a molten homogeneous melt of polymeric carrier and paroxetine free base. Thereafter, the molten homogeneous melt of polymeric carrier and paroxetine free base is contacted with at least one equivalent of dry hydrogen chloride to form paroxetine hydrogen chloride in the molten homogeneous melt, and the molten homogeneous melt is then cooled to form a water soluble solid state dispersion of an anhydrate form of paroxetine hydrochloride.
PCT International Application No. WO99/56751 (Hein et al.) describes a process for preparing an amorphous form of paroxetine. The process involves mixing of paroxetine base or salt with water and a polymer, and drying said mixture. This aqueous solvent process purportedly provides an amorphous solid form of paroxetine. Due to the low solubility of paroxetine, however, heating of paroxetine solution to 60° C. is required in this process to prevent recrystallization of a paroxetine salt, especially at higher concentrations, which

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