Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-29
2004-03-02
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S197000
Reexamination Certificate
active
06699882
ABSTRACT:
The present invention relates to new formulations of a pharmaceutically active compound, and in particular to a novel formulation of paroxetine.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in U.S. Pat. Nos. 3,912,743 and 4,007,196. An especially important compound among those disclosed is paroxetine, the (−)trans isomer of 4-(4′-fluorophenyl)-3-(3′,4′-methylenedioxy-phenoxymethyl)-piperidine.
In the literature this compound is usually isolated as an acid salt, especially the hydrochloride. Paroxetine is approved for human use as the hydrochloride salt, and has been proposed for the treatment and prophylaxis of inter alia depression, obsessive compulsive disorder (OCD) and panic.
Paroxetine hydrochloride has been described in the literature as a crystalline hemihydrate (see EP-A-0223403 of Beecham Group) and as various crystalline anhydrate forms (see WO96/24595 of SmithKline Beecham).
Paroxetine free base has hitherto been disclosed in the literature as an oil, and so the free base has not itself been considered for therapeutic use, preference being given to crystalline forms which can be more easily purified and processes into dosage forms.
The present invention is based on the discovery that paroxetine, for example paroxetine free base, is advantageously formulated into pharmaceutical compositions when adsorbed on or absorbed by a solid carrier.
The present invention provides a composition comprising paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a pharmaceutically acceptable solid carrier, and the use of the composition as a therapeutic agent or for the manufacture of a medicament.
By this invention paroxetine may be obtained as a free-flowing powder that can be used directly (for example by direct compression into tablet form) or with further compounding ingredients in therapy.
The paroxetine used in carrying out this invention is preferably paroxetine free base, but may alternatively be a pharmaceutically acceptable derivative such as a salt, more especially the hydrochloride.
The composition of this invention is simply obtained by combining a solution of paroxetine with a suitable adsorbent or absorbent material and evaporating the solvent, for example by spray drying. The solvent is suitably toluene, ethanol, acetone, propan-2-ol, or ethyl acetate, or any other suitable solvent or mixture of solvents, in a paroxetine concentration of between 1 and 20%, more preferably between 1 and 4%.
Alternatively an oil obtained by removal of solvent from a solution may be blended with a solid adsorbent or absorbent material.
Typically the material selected as carrier for the paroxetine is an excipient suitable for tablet formation or as a fill material for gelatine capsules, such as cyclodextrin (beta and/or gamma), porous silicates, starch, lactose or calcium phosphate, silica, sorbitol, maltodextrin, microcrystalline or powdered cellulose, sodium or calcium carboxymethylcellulose, calcium carbonate, kaolin, magnesium aluminum silicate. Additionally, soluble excipients such as magnesium stearate may form part of the solution phase.
Advantageously the carrier is one that also has a taste-masking effect, for example ion-exchange resins.
A solution of paroxetine free base may be prepared by addition of a base such as triethylamine to a solution of a crystalline paroxetine salt especially the hydrochloride or acetate. Alternatively the solution may be prepared by basifying a solution of an amorphous paroxetine hydrochloride or a crystalline anhydrate or hydrated form of paroxetine hydrochloride.
The preparation of the free base and the maleic acid salt are described in Example 2 of U.S. Pat. No. 4,007,196. The acetate salt may also be used as a starting material. Procedures for forming salts are described in EP-A-0223403.
Additionally the paroxetine free base may be prepared as a solution or oil by adding a base such as potassium hydroxide to a solution of a N-protected paroxetine compound such as N-phenoxycarbonyl paroxetine.
The composition of this invention comprising paroxetine adsorbed on or absorbed by a solid carrier may be formulated with or without conventional excipients for tablet formation or used as a powder fill for capsules.
The amount of paroxetine used is adjusted such that in a single unit dose there is a therapeutically effective amount of paroxetine. Preferably the unit dose contains from 10 to 100 mg paroxetine (as measured in terms of the free base). More preferable the amount of paroxetine in a unit dose is 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. The most preferred amount of paroxetine in a unit dose is 20 mg.
Therapeutic uses of the paroxetine product of this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, 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”.
Accordingly, the present invention also provides:
a pharmaceutical composition for treatment or prophylaxis of the disorders comprising paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a solid carrier and, optionally, at least one further pharmaceutically acceptable excipient;
the use of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a solid carrier to manufacture a medicament for the treatment or prophylaxis of the disorders; and
a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a solid carrier to a person suffering from one or more of the disorders.
The invention is illustrated by the following Examples:
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Greenburg, CA 50:47302 (1956).
Unilever, CA 58:51848 (1962).
RN 61790-53-2, Celite.
Craig Andrew Simon
Ward Neal
Chang Ceila
Dustman Wayne J.
SmithKline Beecham p.l.c.
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