MXPA00009340A - Paroxetine compositions - Google Patents

Abstract

Paroxetine is adsorbed on a carrier to form a free-flowing powder useful for capsule filling or for tablet formation;and used in therapy to treat depression.

Description

PAROXETINE COMPOSITIONS DESCRIPTIVE MEMORY The present invention relates to new formulations of a pharmaceutically active compound and, in particular, to a novel formulation of paroxetine. Pharmaceuticals with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those described 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 a hydrochloride salt and has been proposed for the treatment and prophylaxis of, among other conditions, depression, obsessive-compulsive disorder (OCD) and panic. Paroxetine hydrochloride has been described in the literature as a crystalline hemihydrate (see EP-A-0223403 by Beecham Group) and as various forms of crystalline anhydrate (see WO96 / 24595 from SmithKine Beecham). The paroxetine free base has hitherto been described in the literature only as an oil and, therefore, the free base has not been considered in itself for therapeutic use, with preference being given to crystalline forms that can be purified and processed more easily in dosed forms. The present invention is based on the discovery that paroxetine, for example paroxetine free base, is advantageously formulated in pharmaceutical compositions when they are adsorbed on or absorbed by a solid carrier. The present invention provides a composition comprising paroxetine or a pharmaceutically acceptable derivative thereof adsorbed to or absorbed by a pharmaceutically acceptable carrier, and the use of the composition as a therapeutic agent or for the manufacture of a medicament. By means of this invention, paroxetine can be obtained as a free-flowing powder that can be used directly (for example, by direct compression in the form of a tablet) or with a subsequent combination of ingredients in therapy. The paroxetine used to carry out this invention, preferably is paroxetine free base, but may alternatively be a pharmaceutically acceptable derivative such as a salt, more specifically the hydrochloride. The composition of this invention is obtained simply by combining a paroxetine solution with a suitable adsorbent or absorbent material and evaporating the solvent, for example, by spray drying. Preferably, the solvent is toluene, ethanol, acetone, propan-2-ol, or ethyl acetate, or any other suitable solvent or solvent mixtures, in a paroxetine concentration of between 1 and 20%, preferably between 1 and 20%. 4%. Alternatively, an oil obtained by removing the solvent from a solution can be mixed with an adsorbent or absorbent solid material. Typically, the material selected as a carrier for paroxetine is a suitable excipient for tablet formation or as a filling material for gelatin 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.

In addition, soluble excipients such as magnesium stearate, can be part of the solution phase. Advantageously, the carrier is one which also has a taste disguising effect, for example resins for ion exchange. A paroxetine free base solution can be prepared through the addition of a base, such as triethylamine, to a solution of a crystalline paroxetine salt, especially the hydrochloride or acetate.

Alternatively, the solution can be prepared by basifying a solution of an amorphous paroxetine hydrochloride or a hydrated or crystalline anhydrous form of paroxetine hydrochloride.

The preparation of the free base and the maleic acid salt are described in Example 2 of US Pat. No. 4,947,996. The acetate salt can also be used as a starting material. The processes for forming salts are described in EP-A-0223403. In addition, the paroxetine free base can be prepared as a solution or oil by adding a base such as potassium hydroxide to a solution of an N-protected paroxetine compound such as N-phenoxycarbonyl paroxetine. The composition of this invention comprising paroxetine adsorbed on or absorbed by a solid carrier can be formulated with or without conventional excipients for tabletting or used as a powder filling for capsules. The amount of paroxetine used is adjusted so that in a single unit dose there is a therapeutically effective amount of paroxetine. Preferably, the unit dose contains from 10 to 100 mg of paroxetine (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 most preferred amount of paroxetine in a unit dose is 20 mg. Therapeutic uses of the paroxetine product of this invention include the treatment of: alcoholism, anxiety, depression, obsessive-compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-existing syndrome menstrual (PMS), adolescent depression, trichotillomania, distimine and drug abuse, referred to below as "the disorders". In this regard, the present invention also provides: a pharmaceutical composition for the treatment or prophylaxis of disorders consisting of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed to or absorbed by a solid carrier and optionally, at least one additional pharmaceutically acceptable excipient; the use of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a solid carrier to make a medicament for the treatment or prophylaxis of the disorders; and a method for treating disorders, which comprises administering an effective or prophylactic amount of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed to or absorbed by a solid carrier to a person suffering from one or more of the disorders. The invention is illustrated by means of the following examples: EXAMPLE 1 Preparation of a pre-mix of paroxetine-free-containing tablet A mixture of calcium dibasic phosphate dihydrate (408 g), hydroxypropylmethylcellulose (25 g) and sodium starch glycolate (25 g) was mixed in a key granulator for 3 minutes at a stirring speed of 240 r.p.m. and a driving speed of 3000 r.p.m. Purified water (57 ml) was added at a rate of about 4 ml / minute for 13.5 minutes while the key granulator was adjusted at a stirring speed of 240 r.p.m. and the driving speed was adjusted to 1500 r.p.m. The mixture was stirred for 1 more minute and the resulting granules were dried in an air oven at 50 ° C for 3 hours. A portion of the granules prepared above (50 g) was added to a paroxetine free base solution (2.0 g) in propan-2-ol (50 ml) and the resulting suspension was dried under vacuum with stirring at 50 ° C. This product is suitable for direct compression in tablets containing 10, 20, or 30 mg of paroxetine.

EXAMPLE 2 Preparation of a supported solid form of paroxetine-free base A stirred mixture of N-phenoxycarbonyl paroxetine (50.0 g), potassium hydroxide (45.0 g) and toluene (750 ml) was heated to reflux under a nitrogen atmosphere for 3 hours. After allowing the mixture to cool to room temperature, distilled water (500 ml) was added and the mixture was stirred for 30 minutes. The organic layer was separated, dried over magnesium sulfate and concentrated a total volume of 85 ml. Toluene (100 ml) was added to an aliquot of the paroxetine-free amine solution in toluene (0.43 g / ml) (2.4 ml) and Celite (25.0 g) was added to this solution and the mixture was stirred for 5 minutes. The solvent was removed under reduced pressure (water bath at 55 ° C) to give the paroxetine free amine supported on Celite as a free-flowing powder solid (26.0 g). This product can be mixed with additional excipients and compressed into tablets or added directly to capsule shells to make a product containing the therapeutic dose of paroxetine.

EXAMPLE 3 Spray drying of paroxetine hydrochloride solution in a suspended vehicle material Anhydrous paroxetine hydrochloride (60 g) was dissolved in anhydrous ethanol (725 ml) and the clear solution was suspended in maltodextrin DE4-6 (506 g). The uniform suspension was spray-dried in a Niro Mobile Minor (TM) closed loop spray dryer using nitrogen as the process gas, a spinning atomizing wheel rotating at 27,000 rpm. (alternatively, one can use a dual fluid source or stream direction nozzle), an inlet temperature of 96-104 C and an outlet temperature of 44-50 C at a feed rate of 4.1 kg per hour . A free-flowing white product (490 g) was recovered, which was found to have an average particle size of 84 microns.

EXAMPLE 4 Preparation of a pre-mix tablet containing paroxetine hydrochloride A mixture of calcium dibasic phosphate dihydrate (408 g), hydroxypropylmethylcellulose (25 g) and sodium starch glycolate (25 g) was mixed in a key granulator for 3 minutes at a stirring speed of 240 r.p.m. and a driving speed of 3000 r.p.m. Purified water (57 ml) was added at a rate of about 4 ml / minute for 13.5 minutes while the key granulator was adjusted at a stirring speed of 240 r.p.m. and the driving speed was adjusted to 1500 r.p.m. The mixture was stirred for 1 more minute and the resulting granules were dried in an air oven at 50 ° C for 3 hours. A solution of paroxetine hydrochloride hemihydrate (2.0 g) in ethanol (100 ml) was added to the granules prepared above (50 g) and the suspension was dried under vacuum at 50 ° C.

EXAMPLE 5 Preparation of a tablet pre-mix containing paroxetine hydrochloride A solution of paroxetine hydrochloride hemihydrate (2.0 g) in ethanol (150 ml) was added to celite (50 g), the mixture was stirred and the suspension was dried under vacuum at 50 ° C to give a free-flowing powdery solid , suitable for use as a component of a tablet or capsule formulation.

EXAMPLE 6 Preparation of a pre-mix tablet containing paroxetine hydrochloride A stirred mixture of N-phenoxycarbonyl paroxetine (50.0 g), potassium hydroxide (45.0 g) and toluene (750 ml) was heated to reflux under a nitrogen atmosphere for 3 hours. After allowing the mixture to cool to room temperature, distilled water (500 ml) was added and the mixture was stirred for 30 minutes. The organic layer was separated, dried over magnesium sulfate and filtered. An aliquot of this paroxetine-free amine solution in toluene [0.048 g / ml] (21.0 ml) was diluted with an additional 30 ml of toluene and heated to 60 ° C. Concentrated hydrochloric acid (0.34 ml) was added and the mixture was stirred for 10 minutes. Tablet granules (25.0 g), prepared as in Example 4, were added and the mixture was stirred at 60 ° C for 5 minutes. The solvent was removed under reduced pressure at 70 ° C to give a mobile solid powder (26.0 g).

EXAMPLE 7 Preparation of a tablet pre-mix containing paroxetine hydrochloride Concentrated hydrochloric acid (0.34 ml) was added to a stirred solution of paroxetine acetate (1.18 g) in toluene (50 ml) at 60 ° C and the mixture was stirred for 10 minutes. The tablet granules (25.0 g), prepared as in Example 4, were added and the mixture was stirred at 60 ° C for 5 minutes. The solvent was removed under reduced pressure at 70 ° C to give a free flowing powder solid (26.0 g).

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. Paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a solid carrier.

2. A pharmaceutical composition comprising paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a solid carrier.

3. Use of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a solid carrier to make a medicament for the treatment of depression in a person.

4. A composition of matter according to claim 1, further characterized in that the paroxetine is in the form of its free base.

5. A process for the preparation of a composition of matter according to claim 1, 2 or 4, which comprises the combination of a paroxetine solution or a pharmaceutically acceptable derivative thereof with the adsorbent solid carrier material or Absorbent and evaporation of the solvent.

6. The process according to claim 5, further characterized in that the carrier material is suspended in the solvent before evaporation of the solvent.

7. - The method according to claim 5, further characterized in that the carrier material is dissolved in the solvent before evaporation of the solvent.

8. The process according to any of claims 5 or 7, further characterized in that the evaporation of the solvent is carried out by spray drying.