SK14102000A3 - 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 or a pharmaceutically acceptable derivative thereof, a pharmaceutical composition thereof and its use

Technical field

The invention relates to novel formulations of pharmaceutically active compounds and in particular to new formulations of paroxetine.

BACKGROUND OF THE INVENTION

Pharmaceutical products with antidepressant and anti-Parkinsonian properties are described in US-A-3912743 and US-A-4007196. Among the compounds described above, paroxetine, the (-) trans isomer of 4- (4'-fluorophenyl) -5- (S) -4 '- methylenedioxy-phenoxymethylpiperidine, is particularly important.

In the literature this substance is usually isolated as an acid salt, in particular the hydrochloride. Paroxetine is approved for human use as the hydrochloride salt and has been suggested for the treatment and prevention of, inter alia, depression, obsessive compulsive disorder (OCD) and panic.

Paroxetine hydrochloride has been described in the literature as crystalline hemihydrate (see EP-A-0223403 Beecham Group) and as various crystalline anhydride forms (see WO96 / 24595 SmithKline Beecham).

Paroxetine free base has hitherto been reported in the literature as an oil and thus the use of the free base itself has not been contemplated for therapeutic use, preference being given to crystalline forms which can be more readily purified and formulated.

SUMMARY OF THE INVENTION

The present invention provides paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on a solid carrier or absorbed by a solid carrier.

The invention further provides a composition comprising paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on a pharmaceutically acceptable solid carrier or absorbed in a pharmaceutically acceptable solid carrier and the use of the composition as a therapeutic agent or for the manufacture of a pharmaceutical composition.

According to the present invention, paroxetine can be obtained as a free-flowing powder which can be used for treatment directly (for example, directly compressed in the form of tablets) or with other admixed ingredients.

The paroxetine used according to an embodiment of the invention is preferably a paroxetine free base, but may alternatively be a pharmaceutically acceptable derivative, such as a salt, in particular a hydrochloride.

The composition of the invention is readily obtained by combining the paroxetine solution 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 solvent mixture, with a paroxetine concentration between 1 and 20% by weight, more preferably between 1 and 4% by weight.

Alternatively, the oil obtained by solvent removal may be mixed with a solid adsorbent or absorbed by the material.

Typically, the material selected as a carrier for paroxetine is a vehicle suitable for tableting or as a fill 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-calcium silicate. In addition, soluble vehicles such as magnesium stearate may form part of the solvent phase.

Preferably, the carrier is one which also has a taste-masking effect, for example ion exchange resins.

A solution of paroxetine free base can be prepared by adding a base, such as triethylamine, to a solution of the crystalline paroxetine salt, especially the hydrochloride or acetate. Alternatively, the solution may be prepared by alkalizing the solution

-3-amorphous paroxetine hydrochloride or a crystalline unhydrated or hydrated form of paroxetine hydrochloride.

The preparation of the free base and the maleic acid salt are described in Example 2 of US 4007196. An acetate salt may also be used as a starting material. Processes for preparing 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 a N-protected paroxetine compound such as N-phenoxycarbonyl-paroxetine.

The composition of the invention comprising paroxetine adsorbed on a solid carrier or absorbed by a solid carrier may be formulated with or without conventional tablet-forming excipients or may be used as a capsule fill powder.

The amount of paroxetine used is adjusted so that a therapeutically effective amount of paroxetine is in a unit dosage form. Preferably, the unit dose contains from 10 to 100 mg of paroxetine (based on the free base). More preferably, the unit dose is an amount of paroxetine of 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. Most preferably, the amount of paroxetine in a unit dose is 20 mg.

The therapeutic use of the paroxetine products of the invention includes the 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, hypertension and substance abuse, hereinafter referred to as “disorders.

The invention also provides:

a pharmaceutical composition for the treatment and prevention of disorders comprising paroxetine or a pharmaceutically acceptable derivative thereof adsorbed to a solid carrier or absorbed by a solid carrier and optionally at least one other pharmaceutically acceptable vehicle;

the use of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed to a solid carrier or absorbed in a solid carrier for the manufacture of

A pharmaceutical composition for treating or preventing a disorder; and a method of treating a disorder comprising administering an effective or prophylactic amount of paroxetine, or a pharmaceutically acceptable derivative thereof, adsorbed on a solid carrier or absorbed in a solid carrier to a person suffering from one or more disorders.

The invention is illustrated by the following examples:

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of a tablet premix containing paroxetine free base

A mixture of dibasic calcium phosphate dihydrate (408 g), hydroxypropyl methylcellulose (25 g) and sodium starch glycolate (25 g) was stirred in a key granulator for 3 minutes at a stirring speed of 240 rpm and a circulation speed of 3000 rpm. Purified water (57 mL) was added at a rate of approximately 4 mL / minute over

13.5 minutes while the key granulator was set to a stirring speed of 240 rpm and the orbital speed was set to 1500 rpm. The mixture was stirred for an additional 1 minute and the resulting granules were dried in an air dryer at 50 ° C for 3 hours.

A portion of the prepared granules (50 g) was added to a solution of paroxetine free base (2.0 g) in propan-2-ol (50 ml) and the resulting slurry was dried under vacuum at 50 ° C under vacuum.

This product is suitable for direct compression into tablets containing 10, 20, or 30 mg paroxetine.

Example 2

Preparation of a solid form of carrier paroxetine free base

A stirred mixture of N -phenoxycarbonyl-paroxetine (50.0 g), magnesium hydroxide (45.0 g) and toluene (750 mL) was heated under reflux in nitrogen.

-5atmosphere for 3 hours. After the mixture was cooled 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 to a total volume of 85 mL.

To an aliquot of a solution of paroxetine free base in toluene (0.43 g / ml) (2.4 ml) was added toluene (100 ml) and to this solution was added Celite (25.0 g) and the mixture was stirred for 5 minutes . The solvent was removed under reduced pressure (water bath 55 ° C) to give the free amine of paroxetine supported by Celite as a free-flowing solid (26.0 g).

This product may be mixed with other vehicles and compressed into tablets or applied directly to capsule shells to form a product containing a therapeutic dose of paroxetine.

Example 3

Spray-dried solution of paroxetine hydrochloride on a suspended solid support

Paroxetine hydrochloride anhydride (60 g) was dissolved in anhydrous ethanol (725 mL) and the clear solution was suspended with maltodextrin DE4-6 (506 g). The uniform suspension was spray dried in a Niro Mobile Minor (TM) in a closed spray cycle using nitrogen as the process gas, the rotary spray wheel rotated at 27,000 rpm (alternatively a jet or fountain dual-liquid nozzle may be used), inlet temperature 96 to 104 ° C and outlet temperature 44-50 ° C at a feed rate of 4.1 kg per hour. A white free-flowing product (490 g) was obtained, which was found to have an average particle size of 84 microns.

Example 4

Preparation of a tablet premix containing paroxetine hydrochloride

A mixture of dibasic calcium phosphate dihydrate (408 g), hydroxypropyl-6-methylcellulose (25 g) and sodium starch glycolate (25 g) was stirred in a key granulator for 3 minutes at a stirring speed of 240 rpm and a circulation speed of 3000 rpm. Purified water (57 mL) was added at a rate of approximately 4 mL / minute over

13.5 minutes while the key granulator was set to a stirring speed of 240 rpm and the orbital speed was set to 1500 rpm. The mixture was stirred for an additional 1 minute and the resulting granules were dried in an air oven at 50 ° C for 3 hours.

To the prepared granules (50 g) was added a solution of paroxetine hydrochloride hemihydrate (2.0 g) in ethanol (100 mL), and the slurry was dried under vacuum at 50 ° C.

Example 5

Preparation of a tablet premix containing paroxetine hydrochloride

A solution of paroxetine hydrochloride hemihydrate (2.0 g) in ethanol (100 mL) was added to Celite (50 g), the mixture was stirred, and the slurry was dried under vacuum at 50 ° C to give a free-flowing powdery solid. for use as a tablet component or for the preparation of capsules.

Example 6

Preparation of a tablet premix containing paroxetine hydrochloride

A stirred mixture of N -phenoxycarbonyl-paroxetine (50.0 g), magnesium hydroxide (45.0 g) and toluene (750 mL) was heated under reflux under nitrogen for 3 hours. After the mixture was cooled 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 solution of paroxetine free amine in toluene [0.048 g / mL] (21.0 mL) was dissolved in 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

-7 at 60 ° C for 5 minutes. The solvent was removed under reduced pressure at 70 ° C to give a mobile powder solid (26.0 g).

Example 7

Preparation of a tablet premix 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. 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 powder solid (26.0 g).

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Claims (8)

PATENT CLAIMS 1. Paroxetine, or a pharmaceutically acceptable derivative thereof, adsorbed on a solid carrier or absorbed by a solid carrier. 2. A pharmaceutical composition comprising paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on a solid carrier or absorbed by a solid carrier. Use of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on a solid carrier or absorbed by a solid carrier for the manufacture of a medicament for the treatment of depression. 4. A method of treating depression comprising administering to a subject suffering from depression an effective amount of paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on a solid carrier or absorbed by a solid carrier. The composition of the substance, the use or the method according to any one of the preceding claims, characterized in that the paroxetine is in the form of the free base. A process for preparing a composition of a substance according to claim 1, 2 or 5, comprising combining a solution of paroxetine or a pharmaceutically acceptable derivative thereof with an adsorbent or absorbent solid carrier material and evaporating the solvent. The process of claim 6, wherein the carrier material is suspended in a solvent prior to evaporation of the solvent. -98. The method of claim 6 wherein the carrier material is dissolved in the solvent prior to evaporation of the solvent. The method according to any one of claims 6 or 8, characterized in that the evaporation of the solvent is carried out by spray-drying.