SK19192000A3 - Method of treatment - Google Patents

Abstract

A method for promoting smoking cessation or reduction or preventing relapse smoking, comprises administering an effective, non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate thereof, to human in need thereof.

Description

Technical field

The present invention relates to the use of paroxetine to promote smoking cessation or to reduce or prevent smoking relapses.

BACKGROUND OF THE INVENTION

Pharmaceutical products having anti-depressant and anti-Parkinson's properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the (-) trans isomer of 4 ^{(4-fluorophenyl)} -3- (3 ', 4'-methylenedioxy-phenoxymethyl) -piperidine. This compound is a selective serotonin reuptake inhibitor (SSRI). Paroxetine hydrochloride is approved for use in humans for the treatment of, inter alia, conditions, depression, obsessive-compulsive disorder (OCD), and panic conditions.

For commercial use, paroxetine hydrochloride is supplied as a crystalline hemihydrate (see EP-A-0223403 from Beecham Group). Various forms of crystalline anhydrate are also known (see WO96 / 2495 from SmithKline Beecham plc).

SSRI compounds such as fluoxetine and sertraline are designed for use in the treatment of chemical dependence (see US 4999382). However, various clinical studies show that whilst fluoxetine has a good effect on smoking cessation factors such as e.g. weight gain and alcohol consumption did not affect smoking cessation rates (see Mizes et al., Psychopharmacol. Bull., 32, No. 3, 491, 1996; Sullivan et al., J. Clin. Pharmacol., 29, No. 9). (1989, 850).

Surprisingly, it has now been found that paroxetine has a potential therapeutic use as a medicament to promote smoking cessation or to reduce or prevent smoking relapse.

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2. Summary of the Invention

The present invention provides the use of paroxetine, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for promoting smoking cessation or reducing or preventing smoking relapse.

The paroxetine used in the present invention is suitably in the form of the free base or a pharmaceutically acceptable salt thereof. A preferred pharmaceutically acceptable salt of paroxetine is crystalline hydrochloride. Suitable methods for the manufacture of paroxetine hydrochloride include those disclosed in US Patents 4009196, 4721723, 4902801, 4861893 and 5039803 and PCT / GB93 / 00721. Particularly suitable is a hemihydrate produced as disclosed in EP-A-0223403.

A medicament for use in promoting smoking cessation or reducing or preventing relapse of smoking may be made by mixing paroxetine or a pharmaceutically acceptable salt or solvate thereof with a suitable carrier, which may contain a diluent, binder, filler, disintegrant, flavoring, coloring, lubricant or lubricant. preservative in a conventional manner.

Preferably, the medicament is in unit dosage form and in a form adapted for use in human or veterinary medicine. E.g. such preparations may be in the form of a package accompanied by written instructions for use to promote smoking cessation or to reduce or prevent smoking relapse.

The appropriate dosage range for paroxetine or a pharmaceutically acceptable salt or solvate thereof will depend on the severity of the smoking habits and the condition of the patient. It will also depend on the rate of absorption, frequency and route of administration.

Paroxetine or a pharmaceutically acceptable salt or solvate thereof may be formulated for administration by any route and examples are oral, sublingual, rectal, topical, parenteral, intravenous or intramuscular. If desired, the compositions may be formulated so that the release of paroxetine or a pharmaceutically acceptable salt or solvate thereof is slow. The medicaments may additionally contain other active substances suitable for promoting smoking cessation or for reducing or preventing smoking relapse, such as e.g. nicotine or a pharmaceutically acceptable derivative thereof.

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The pharmaceutical form can be e.g. tablets, capsules, sachets, ampoules, powders, granules, lozenges, dissolving powders or liquid preparations, e.g. solutions or suspensions or suppositories.

Drugs, e.g. those suitable for oral administration may contain conventional excipients such as binding agents, e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers such as e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycerin; tableting lubricants, e.g. magnesium stearate; disintegrants, e.g. starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable stabilizers, such as e.g. sodium lauryl sulphate.

Solid drugs can be obtained by conventional methods of mixing, filling, tabletting, and the like. Repeated blending procedures can be used to distribute paroxetine or a salt or solvate thereof in drugs that contain a large number of fillers. When the drug is in the form of a tablet, powder or lozenge, any carrier suitable for formulating solid pharmaceutical preparations may be used, examples of which are magnesium stearate, starch, glucose, lactose, sucrose, rice flour and calcium carbonate. The tablets may be coated by methods well known in conventional pharmaceutical practice, in particular by enteric coating. The medicament may also be in the form of oral capsules, e.g. gelatin containing paroxetine or a salt thereof, optionally with a carrier or other excipients.

Medicaments for oral administration in the form of fluids may be e.g. emulsions, syrups or brine, or they may be in the form of a dry substance to be dissolved in water or other suitable carrier before use. Such liquid medicaments may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, magnesium stearate, hydrogenated edible fats; emulsifying agents, e.g. Iecithin, sorbitan monooleate or acacia; aqueous or non-aqueous vehicles which include edible oils, e.g. almond oil, fractionated coconut oil, oily esters, e.g. glycerin esters or propylene glycol or ethyl alcohol, glycerin, water or normal saline; preservatives, e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and optionally conventional flavoring or coloring agents.

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Paroxetine, or a pharmaceutically acceptable salt or solvate thereof, may also be administered by a route other than oral. According to routine pharmaceutical procedures, drugs may be formulated, e.g. for rectal administration in the form of suppositories. They can also be made into an injectable form in the form of an aqueous or non-aqueous solution, a suspension in a pharmaceutically acceptable liquid, i. j. sterile pyrogen-free water or in a parenterally acceptable oil or mixture of liquids. The fluid may comprise bacteriostatically active agents, anti-oxidants or other preservatives, buffers or solutes, maintaining a solution isotonic in the blood, thickeners, suspending agents, or other pharmaceutically acceptable additives. Such forms may be in unit dosage form, such as e.g. ampoules or injections, or may exist as multidose forms, such as vials from which a suitable dose can be selected, or as a solid form or concentrate, which can be used to prepare an injectable preparation.

As mentioned above, the effective dose of paroxetine or a pharmaceutically acceptable salt or solvate thereof depends on the severity of the generalized anxiety disorders to be treated, the condition of the patient and the frequency and mode of administration. A single dose will generally contain from 2 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 20, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition may be administered one or more times a day, e.g. 2, 3 or 4 times a day and the total daily dose for an adult weighing 70 kg may range from 100 to 3000 mg. Preferably, a single dose will contain from 2 to 20 mg of paroxetine (calculated on the free base) and will be administered in multiple doses if desired to achieve said daily dose.

Preferably, the present invention is practiced using controlled release or delayed release formulations comprising paroxetine or a pharmaceutically acceptable salt thereof.

By controlled release is meant any modification of the formulation wherein the release of the active ingredient from the dosage form is adapted to be slower than that of the immediate release formulation, such as a conventional swallowable tablet or capsule.

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Delayed release is a modification of the formulation wherein the release of the active ingredient from the dosage form is adapted to take place later than with a conventional immediate release formulation. The sustained release of the active ingredient from the delayed release formulation may be controlled as previously mentioned.

Examples of controlled release that are suitable for incorporating paroxetine are described in:

Sustained-release Medicinal Products, Chemical Technology Review no. 177. Ed. J. C. Johnson. Noyes Data Corporation (1980).

Sustained drug release, bases and use. 2. Vyd. Eds. J.R. Robinson, V. H. I. Lee. Mercel Dekkes Inc. New York 1987.

Examples of delayed release formulations suitable for incorporating paroxetine are described in:

Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing Company. 1980. Ed. A. Osol.

Such controlled release formulations are preferably adapted in such a way that the release of the active ingredient, e.g. paroxetine in particular takes place during passage through the stomach, and the small intestine and the delayed release formulations are preferably adapted such that the release of the active ingredient, e.g. paroxetine, in the stomach, is prevented and occurs mainly during passage through the small intestine.

Said preparations are preferably adapted so that the release of the active ingredient occurs predominantly 1.5 to 3 hours after ingestion.

Preferred formulations are uniquely enteric coated tablets or caplets, wax or polymer coated tablets or caplets, or time release matrices or combinations thereof.

Most preferred formulations are described in U.S. Pat. 5,102,666.

Therefore, a particular aspect of the invention is a controlled release polymer formulation comprising a reaction complex formed by the interaction of (1) a polycarbophilic calcium component that swells in water but is not water soluble by a carboxy-functional fiber-containing polymer, said polymer comprising (a) an amount of repeating units, of which at least 80% comprises one carboxyl functional group, and (b) about 0.05 to about 1.5% of a cross-linking agent substantially. ··· · · · ·

- Without polyalkenyl polyether, the percentages given are based on the weights of unpolymerized repeating units and the crosslinking agent, with (2) water, in the presence of paroxetine. The amount of calcium polycarbophil is from about 0.1 to about 99% by weight, e.g. 10%. The amount of active ingredient is from about 0.0001 to about 65% by weight, e.g. between about 5 to 20%. The amount of water is from about 5 to about 20% by weight, e.g. between 5 and 10%. The interaction takes place at a pH between about 3 to 10, e.g. The calcium polycarbophil is initially present in the form of a calcium salt containing about 5 to 25% calcium.

Other particularly suitable formulations are described in U.S. Pat. 5,422,123.

Therefore, the invention further includes the use of a paroxetine controlled release system comprising (a) a storage core comprising an effective amount of paroxetine and (b) a support base adapted to said storage core, said storage core comprising paroxetine and at least one component selected from the group consisting of (1) a polymeric substance which swells and a gel-like polymeric substance upon contact with water or water-based liquids, wherein the ratio of said polymeric substance to said gel-like polymeric substance is in the range of 1: 9 to 9: 1; and (2) a simple polymeric substance having swelling and gelling properties and wherein the support component is an elastic support material attached to said storage core so as to partially cover the surface of the storage core and monitor changes caused by hydration of the storage core and slowly dissolve and / or forms a gel in aqueous fluids. The support component may comprise polymers such as e.g. hydroxypropylmethylcellulose; plasticizers such as e.g. glyceride, binding agents such as e.g. polyvinylpyrrolidone, hydrophilic substances such as e.g. lactose and silicon and / or hydrophobic substances such as e.g. magnesium stearate and glycerides. The polymers typically comprise 30 to 90 wt. a supporting component, e.g. 35 to 40%. Plasticizing agents comprise at least 2 wt. a supporting component, e.g. 15 to 20%. Binding agents, hydrophilic components and / or hydrophobic components typically comprise up to about 50% of the support component, e.g. about 40 to 50%.

The present invention further provides a pharmaceutical composition for use in promoting smoking cessation or for reducing or preventing relapse of smoking, which comprises an effective amount of paroxetine or a pharmaceutical composition thereof.

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The paroxetine product of the present invention may also be co-administered with a nicotine-containing smoking cessation device, e.g. with a patch, chewing gum or inhaler.

The following examples describe pharmaceutical compositions for use in the present invention.

DETAILED DESCRIPTION OF THE INVENTION Example 1 (Hydrophilic matrix) intragranular % wt. Paroxetine hydrochloride 11.45 Methocel E5 1.25 lactose 12.3 extragranulary Methocel K100LV 30.0 lactose 44.0 Magnesium stearate 1.0 Pretty 100.0

Example 2 (Hydrophilic matrix)

% Intraqranular% wt.

Paroxetine hydrochloride 11,45

Methocel E51,25

Laktóza12,3

extragranulary

Methocel K1OOLV27,5

Methocel K4M7,5

Laktóza39,0

Magnesium stearate1,0

Total100,0 • ·· ··· ··· · ··· · · ··· · · · · ·

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Example 3 (pH sensitive coating on immediate release core) Tablet core % wt. Paroxetine hydrochloride 11.45 lactose 64.05 Microcrystalline cellulose 20.0 Sodium starch glycolate 4.0 Magnesium stearate 0.5 Pretty 100.0

Tablet coating (use approximately 6 to 10% tablet core weight% by weight hydroxypropyl methylcellulose phthalate 90.0

triacetin

10,0

Example 4 (pH sensitive coating on immediate release core)

Tablet core as in Example 3

Tablet coating (use about 6 to 10% by weight of the tablet core% wt.

Cellulose acetate phthalate 90.0

Diethyl phthalate 10.0

Example 5 (Controlled Release Packaging on Immediate Release Core)

Tablet core as in Example 3

Tablet coating (use about 6 to 10% by weight of the tablet core% wt.

Eudragit RS 100 86.0 dibutyl phthalate 10,0 talc 4.0 FD&C yellow no. 6 0.01

Example 6 (pH sensitive coating on immediate release core)

Tablet core as in Example 3

Tablet coating as in Example 3.

-9Example 7 (Controlled Release Encapsulated Grains)

pellet

Uncoated grain

Paroxetine hydrochloride

gelatin

lactose

Talc% wt. (About)

% Wt.

glyceryl

glyceryl

White wax

36.6

53.4

10,0

Example 8 (bilayer controlled release tablet)

Active layer

component mg / tablet feature Paroxetine hydrochloride 22.89 * active Methocel K4M 15,00 hydrogel polymer Lactose monohydrate 62.0 hydrophilic substance polyvinylpyrrolidone 3.0 binding substance Magnesium stearate 1.0 hydrophobic substance Syloid 244 1.0 hydrophilic substance Supporting basis component mg / tablet feature Compritol 888 15.04 plasticizing substance Lactose monohydrate 29.32 hydrophilic substance polyvinylpyrrolidone 4.0 binding substance Magnesium stearate 1.52 hydrophobic substance Iron oxide 0.08 coloring Total tablet weight 184.89 mg

‘Equivalent to 20 mg paroxetine as the free base.

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The powder blend of each layer was wet granulated in a high throughput granulator and dried in an airflow. The bilayer tablets were compressed on a Manesty three-layer press.

Example 9 (Entero-coated calcium polycarbophilic formulation)

component mg / tablet feature Paroxetine hydrochloride 22.89 active Calcium polycarbophil 20.00 matrix Anhydrous lactose 146.11 hydrophilic substance / diluent polyvinylpyrrolidone 10,0 binding substance Magnesium stearate 1.0 hydrophobic substance / lubricant Water** 0,024 granulating fluid Enteroobal component mq / tablet feature Eudragit 22.19 polymer talc 1.53 lubricant triethylcitrate 1.00 plasticizing substance Water** 24.6 thinner Film cover Opadry pink 10.5 filmový obal Water** 94.5 thinner Shiny cover Opadry clear 0,750 Water** 29.3 thinner

‘Equivalent to 20 mg paroxetine free base 'removed during processing.

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The core constituents were wet granulated in a high-performance granulator and dried in a fluidized bed. Magnesium stearate was then added and the mixture was processed in a low knife mixer. Coating was performed on Accela cota.

Example 10 (Two-layer controlled release tablet)

Active layer

component mg / tablet feature Paroxetine hydrochloride 22.89 * active Methocel K4M 20.00 hydrogel polymer Lactose monohydrate 60.0 hydrophilic substance polyvinylpyrrolidone 5.0 binding substance Magnesium stearate 1.0 hydrophobic substance Syloid 244 1.0 hydrophilic substance Support component component mg / tablet feature Compritol 888 14.72 plasticizing substance Lactose monohydrate 30.60 hydrophilic substance polyvinylpyrrolidone 2.80 binding substance Magnesium stearate 0.80 hydrophobic substance Methocel E5 30.60 hydrogel polymer Syloid 244 0.40 hydrophilic substance Iron oxide 0.08 coloring

Total tablet weight 189.89 mg ‘equivalent to 20 mg paroxetine free base.

The procedure was the same as described in Example 8.

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-12Example 11 (Two-layer controlled release tablet) ··· ·· ·· ··· ·· ···

Active layer

component mg / tablet feature Paroxetine hydrochloride 22.89 * active Methocel K4M 15,00 hydrogel polymer Lactose monohydrate 63,31 hydrophilic substance polyvinylpyrrolidone 2.0 binding substance Magnesium stearate 1.0 hydrophobic substance Syloid 244 1.0 hydrophilic substance

Support component - same as Example 10. Total tablet weight 184.60 mg ‘equivalent to 20 mg paroxetine free base.

The procedure was the same as described in Example 8.

Example 12 (Entero-coated bilayer controlled release tablet)

Active layer

component mg / tablet feature Paroxetine hydrochloride 28.61 * active Methocel K4M 18.75 hydrogel polymer Lactose monohydrate 79,14 hydrophilic substance polyvinylpyrrolidone 2.50 binding substance Magnesium stearate 1.25 hydrophobic substance Syloid 244 0.50 hydrophilic substance Support component component mg / tablet feature Compritol 888 15.04 plasticizing substance Lactose monohydrate 30.50 hydrophilic substance polyvinylpyrrolidone 4.00 binding substance

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Magnesium stearate 0.80 hydrophobic substance Methocel E5 29,320 hydrogel polymer Syloid 244 0.32 hydrophilic substance Iron oxide 0.02 coloring Enteroobal component mg / tablet feature Eudragit 13.27 polymer talc 3.31 lubricant triethylcitrate 1.33 plasticizing substance Water** 36,25 thinner

Total tablet weight 228.66 mg * equivalent to 20 mg paroxetine free base ** removed during processing.

The procedure as described in Example 9.

Example 13

The following ingredients are mixed together in a conventional manner and compressed to mg containing approximately 20 mg paroxetine tablets weighing approximately 300 (calculated as the free base)

Paroxetine hydrochloride hemihydrate Calcium phosphate dihydrate Hydroxypropylmethylcellulose 2910 Sodium starch glycolate

Magnesium stearate Total tablet weight

228.8 g

2441.2 g

150.0 g

150.0 g

30,0 g

3000,0 g

Claims (8)

PATENT CLAIMS Use of paroxetine, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament to promote smoking cessation or to reduce or prevent smoking relapse. The use of claim 1, wherein the paroxetine is in the form of the free base or a pharmaceutically acceptable salt thereof. The use of claim 2, wherein the pharmaceutically acceptable salt of paroxetine is paroxetine hydrochloride. The use according to claim 3, wherein the hydrochloride is a hemihydrate. The use according to any one of claims 1 to 4, wherein the paroxetine is administered in the form of a controlled or delayed release formulation. Use according to claim 5, wherein the paroxetine is administered orally. The use of claim 6, wherein the controlled or delayed release formulation comprises (a) a deposit core comprising an effective amount of paroxetine and a defined geometric form, and (b) a support component attached to said core, wherein the deposit core comprises paroxetine and at least one component consisting of (1) a polymeric substance which dissolves upon contact with liquids and from a gel-like polymeric substance, wherein the ratio of dissolved polymeric substance to gel-forming polymeric material is in the range of 1: 9 to 9: 1; and (2) a single polymeric substance wherein the support component is an elastic support component attached to said deposit core so as to partially cover the surface of the deposit core and observe the changes caused by the hydration of the deposit core and are slowly soluble and / or gelling in water containing fluids. Use according to any one of claims 1 to 7, wherein the paroxetine is administered concomitantly with the nicotine withdrawal formulation.