EA003584B1 - A method for promoting smoking cessation or reduction or preventing relapse smoking and use of paroxetine or a pharmaceutically acceptable salt or solvate to produce a medicament - Google Patents

Abstract

1. A method for promoting smoking cessation or reduction or preventing relapse smoking, which method comprises administering an effective, non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate there of, to human in need thereof. 2. A method according to claim 1, wherein paroxetine is administered in a controlled release or delayed release formulation. 3. Use according to claim 2 wherein the paroxetine is administered orally. 4. A method according to claim 3, wherein the paroxetine is administered in a controlled release or delayed release formulation comprising (a) a deposit-core comprising an effective amount of paroxetine and having defined geometric form, and (b) a support-platform applied to said deposit-core, wherein said deposit-core contains paroxetine, and at least one member selected from the group consisting of (1) a polymeric material which swells on contact with water or aqueous liquids and a gellable polymeric material wherein the ratio of the said swellable polymeric material to said gellable polymeric material is in the range 1:9 to 9:1, and (2) a single polymeric material having both swelling and gelling properties, and wherein the support-platform is an elastic support, applied to said deposit-core so that it partially covers the surface of the deposit-core and follows changes due to hydration of the deposit-core and is slowly soluble and/or slowly gellable in aqueous fluids. 5. A method according to any one of claims 2 to 4 wherein the paroxetine is co-administered with a nicotine-containing smoking cessation aid. 6. Use of paroxetine or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in promoting smoking cessation or reduction or preventing relapse smoking. 7. Use according to claim 6 wherein the paroxetine is in the form of the free base or a pharmaceutically acceptable salt thereof. 8. Use according to claim 7 wherein the pharmaceutically acceptable salt of paroxetine is a crystalline hydrochloride. 9. Use according to claim 8 wherein the hydrochloride is the hemihydrate.

Description

The present invention relates to a method of stimulating smoking cessation or reducing or preventing the resumption of smoking, in particular, the use of paroxetine for such treatment.

US patent applications I8-A-3912743 and I8-A-400719b describe pharmaceutical products with antidepressant properties and against Parkinson's disease. Among the disclosed compounds, paroxetine, (-) - the trans-isomer of 4- (4'-fluorophenyl) -3- (3 ', 4'-methylenedioxyphenoxymethyl) piperidine is especially important (see I8A4007196, example 2). This compound is a selective serotonin reuptake inhibitor (88K1). Paroxetine hydrochloride salt is approved for use in human therapy for the treatment of, inter alia, depression, obsessive compulsive disorder (CCA) and fear.

For commercial use, paroxetine hydrochloride is supplied in the form of a crystalline hemihydrate (see EP-A-0223403, Vesyat Sgoir). Various crystalline anhydrous forms are also known (see XVO 96/24595, 8shC11 Kype Veesyat p1c.).

Compounds 88Sh, such as fluoxetine and sertraline, have been proposed for use in the treatment of chemical dependence (see I8 5130338), including symptoms of nicotine withdrawal symptoms (see I8 4940585 and I8 4999382). However, various clinical studies suggest that with all the beneficial effects of fluoxetine on factors related to smoking cessation, such as weight gain and alcohol consumption, it does not increase the degree of smoking cessation (see M1 / e5 and others Rausjoryagtaso. Vi11 32, No. 3, 491, 1996; 8 and Schuap et al., TC1t. Ryagtaso. 29, No. 9, 850, 1989).

Surprisingly, paroxetine has been found to be a potent therapeutic drug to stimulate smoking cessation or to reduce or prevent the resumption of smoking.

Thus, the present invention relates to a method of stimulating smoking cessation or reducing or preventing the resumption of smoking, which comprises administering to a person in need thereof an effective non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to the use of paroxetine or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for stimulating smoking cessation or reduction, or preventing the resumption of smoking.

It is desirable that the paroxetine used according to the invention be in the form of a free base or in the form of a pharmaceutically acceptable salt thereof. A preferred pharmaceutically acceptable salt of paroxetine is crystalline hydrochloride. Suitable methods for preparing paroxetine hydrochloride include those described in US Pat. Nos. 4,009,196, 4,721,723, 4,902,801, 4,861,893 and 5,039,803 and PCT / CB 93/00721. Particularly preferred is the hemihydrate obtained according to EP-A-0223403.

A medicament for use in stimulating smoking cessation or reducing or preventing the resumption of smoking can be prepared by mixing paroxetine or a pharmaceutically acceptable salt or solvate thereof with a suitable carrier, which usually may contain a diluent, a binder, a filler, a disintegrant, a flavoring agent, dye, lubricant or preservative.

Preferably, this drug is in unit dosage form and in a form suitable for use in the field of medicine and veterinary medicine. For example, such preparations may be packaged with written or printed instructions for use to stimulate smoking cessation or reduce or prevent smoking reoccurrence.

A suitable dosage range for paroxetine or a pharmaceutically acceptable salt or solvate thereof depends on the severity of the smoking-related disorders and the patient's condition. This also, among other things, depends on the ratio of effectiveness and absorption capacity, as well as the frequency and method of administration.

Paroxetine or a pharmaceutically acceptable salt or solvate thereof can be formulated for administration by any method, examples are oral, sublingual, rectal, local, transdermal, parenteral, intravenous or intramuscular administration. If necessary, preparations may be prepared to slowly release paroxetine or a pharmaceutically acceptable salt or solvate thereof. In addition, the medicaments may contain other active ingredients useful in methods of stimulating smoking cessation or reduction, or preventing the resumption of smoking, such as nicotine or its pharmaceutically acceptable derivatives.

These medications may, for example, be in the form of tablets, capsules, sachets of vials, powders, granules, lozenges, powders, for preparing solutions or liquid preparations, for example, solutions or suspensions, or suppositories.

Medications, for example, suitable for oral administration, may contain conventional excipients, such as binders, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycerin; tabletting lubricants, for example magnesium stearate; disintegrants, for example, starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable thickeners such as sodium lauryl sulfate.

Solid drugs can be obtained by conventional methods of mixing, filling, tabletting or the like. To mix paroxetine, its salt or solvate in the mass of a medicine using large amounts of excipients, re-mixing operations can be used. If the drug is tablets, powders, or lozenges, then any carrier suitable for preparing solid pharmaceutical compositions can be used, examples are magnesium stearate, starch, glucose, lactose, sucrose, rice flour and honey. The tablets can be coated according to methods well known in normal pharmaceutical practice, in particular enteric coating. The drug may also be in the form of capsules for ingestion, for example, gelatin capsules containing paroxetine or its salt, if necessary, with a carrier or other excipients.

Oral pharmaceutical preparations in the form of liquids can be, for example, emulsions, syrups, elixirs or can be dry products from which liquid preparations are prepared before use using water or another suitable excipient. Such liquid medicaments may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats; emulsifiers, for example lecithin, sorbitan monooleate or gum arabic; aqueous or non-aqueous vehicles that include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example glycerol or propylene glycol esters, or ethyl alcohol, glycerin, water or normal saline; preservatives, for example methyl or propyl parahydroxybenzoate or sorbic acid; and, if required, conventional flavoring agents and coloring agents.

Paroxetine or a pharmaceutically acceptable salt or solvate thereof may be administered by the non-oral route. In accordance with the usual pharmaceutical procedure, it is possible to prepare drugs, for example, for rectal administration in the form of suppositories. They can also be prepared in the form of an aqueous and non-aqueous solution, suspension or emulsion for injection in a pharmaceutically acceptable liquid, for example, sterile pyrogen-free water, oil or a mixture of liquids suitable for parenteral use. The liquid may contain bacteriostatic agents, antioxidants or other preservatives, buffers or dissolved substances to obtain a solution that is isotonic with blood, thickeners, suspending agents or other pharmaceutically acceptable additives. Such forms are presented as unit dosage forms, such as ampoules or available injection devices, or as multi-dose forms, such as bottles, from which an appropriate dose can be taken, either in solid form or as a concentrate that can be used for preparing the drug for injection.

The above-mentioned effective dose of paroxetine or a pharmaceutically acceptable salt or solvate thereof depends on the severity of the smoking disorder to be treated, the patient's condition and frequency and method of administration. A single dose usually contains from 2 to 1000 mg, preferably from 30 to 500 mg, in particular 20, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition can be taken once a day or more, for example 2, 3 or 4 times a day, and the total daily dose for an adult weighing 70 kg is usually from 100 to 3000 mg. A single dose preferably contains from 2 to 20 mg of paroxetine (in terms of the free base) and, if required, it is taken several times, providing the above daily dose.

It is preferable to apply the present invention using a preparation with controlled or delayed release of the active ingredient containing paroxetine or a pharmaceutically acceptable salt thereof.

By controlled release is meant any preparation technology in which the release of the active substance from the dosage form is modified in such a way that it occurs at a lower rate than from the product with immediate release, such as a regular swallowed tablet or capsule.

Slow release is understood to mean any preparation technology in which the release of the active substance from the dosage form is modified in such a way that occurs later than from the product with immediate release. Subsequent release of the active substance from a sustained release preparation can also be controlled as defined above.

Examples of controlled release formulations that are suitable for incorporating paroxetine are described in Zichebc Pc1ca5c Meb1caOosc. Syet1sa1 Tes1po1odu Reu1e \\ · No. 177, Ed. TS. 1OIP8OP. Joeyk Eaa Sogrogabop 1980, Sop1go11eb Aegis Iebuegu, EipbateShack apb ArrNsa

1yupz, 2nd edition, ed. ΙΚ. Kozyzop, U.N. Bie. Megse1 Eekkez 1ps. No. \ ν Wagk 1987.

Examples of sustained release formulations that are suitable for the inclusion of paroxetine are described in Kestdop's Ryagtaseijs1 8c1epsez, ed. 16th, Musk Riezyspd Sotrapu 1980, ed. A. Ozo 1.

Such controlled release preparations are preferably prepared in such a way that the release of the active substance, such as paroxetine, occurs mainly during passage through the stomach and small intestine, and delayed release preparations are preferably prepared so as to avoid the release of the active substance, such like paroxetine in the stomach and small intestine.

It is preferable to prepare these preparations in such a way that the release of the active substance occurs mainly 1.5-3 hours after ingestion.

Preferred formulations are enteric coated tablets or capsules, paraffin or polymer coated tablets or capsules, or gradual release matrices, or combinations thereof.

Particularly preferred formulations are described in US Pat. No. 5,102,666.

Thus, an object of the invention is the use of a controlled release polymer composition containing a reaction complex obtained by reacting (1) a component of calcium polycarbophil, which is a swellable, but not water soluble, fiber crosslinked carboxy functional polymer, wherein said polymer contains (a) a plurality repeating units, among which at least 80% have at least one carboxyl functional group, and (b) from about 0.05 to 1.5% of a crosslinking agent, essentially free of polyalkenylpolyether, the percentages are based on the weights of the unpolymerized repeating unit and the crosslinking agent, respectively; with (2) water in the presence of paroxetine. The amount of calcium polycarbophil is from about 0.1 to 99% by weight, for example about 10%. The amount of active agent is from about 0.0001 to 65% by weight, for example from 5 to 20%. The amount of water is from about 5 to 20 wt.%, For example from 5 to 10%. The interaction is carried out at a pH of from about 3 to 10, for example about 6-7. Polycarbophil calcium is initially present in the form of a calcium salt containing from about 5 to 25% calcium.

Particularly preferred formulations are further described in US Pat. No. 5,422,123.

Thus, an object of the invention is also the use of a system for the controlled release of paroxetine containing (a) a storage core containing an effective amount of paroxetine and having a certain geometric shape, and (b) a protective film deposited on said core, wherein said core the storage contains paroxetine and at least one component selected from the group consisting of (1) a polymeric material that swells upon contact with water or aqueous liquids, and a gelling polymer material, Moreover, the ratio of said swellable polymer material to said gelling polymer material is from 1: 9 to 9: 1, and (2) a separate polymer material having both swelling and gelation properties, and the protective film is an elastic film deposited on said the storage core, in such a way that partially covers the surface of the core, monitors changes due to hydration of the storage core and slowly dissolves and / or slowly forms a gel in aqueous liquids. The protective film may include polymers such as hydroxypropyl methylcellulose, plasticizers such as glyceride, binders such as polyvinylpyrrolidone, hydrophilic agents such as lactose and silicon dioxide, and / or hydrophobic agents such as magnesium stearate and glycerides. The polymer (s) typically comprises from 30 to 90% by weight of the protective film, for example, about 35-40%. The plasticizer can comprise at least 2 wt.% Film protection, for example, about 15-20%. Binder (s), hydrophilic agent (s) and hydrophobic agent (s) typically comprise only about 50% by weight of the protective film, for example, about 40-50%.

In addition, the present invention relates to a pharmaceutical composition for use in stimulating smoking cessation or reducing or preventing smoking cessation, which comprises an effective amount of paroxetine or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. Such compositions can be obtained as previously described.

The paroxetine product of the invention may optionally be used with a nicotine-containing anti-smoking agent such as a patch, chewing gum or inhaler.

The following examples disclose suitable pharmaceutical compositions for use according to the invention.

Example 1. Hydrophilic matrix.

Inside the granules wt.% / weight. Paroxetine hydrochloride 11.45 Me11k> ce1 E5 1.25 Lactose 12.3 Outside pellets MESHOSE1 K100YU 30,0 Lactose 44.0

Magnesium stearate 1,0 Total 100.0

Example 2. Hydrophilic matrix.

Inside the granules wt.% / weight. Paroxetine hydrochloride 11.45 Me11use1 E5 1.25 Lactose 12.3 Outside pellets Melos! K100BU 27.5 Me111ose1 K4M 7.5 Lactose 39.0 Magnesium stearate 1,0 Total 100.0

Example 3. The pH-sensitive shell on the core with immediate release of the active substance.

Tablet core wt.% / weight. Paroxetine hydrochloride 11.45 Lactose 64.05 Microcrystalline cellulose 20,0 Sodium Starch Glycolate 4.0 Magnesium stearate 0.5 Total 100.0 Shell tablets (apply about 6-10% of the weight of the core tablets) wt.% / weight. Hydroxypropylmethylcell Phthalate - lulose 90.0 Triacetin (TPaseip) 10.0

Example 4. The pH-sensitive shell on the core with immediate release of the active substance.

The core of the tablet as in example 3.

Shell tablets (apply about 6-10% of the weight of the core tablets) wt.% / weight. Cellulose Acetate Phthalate 90.0 Diethyl phthalate 10.0

Example 5. A shell with controlled release on the core with immediate release of the active substance.

The core of the tablet as in example 3.

Shell tablets (apply about 5-12% of the weight of the core tablets) wt.% / weight. Eibgady B. 8 100 86.0 Dibutyl phthalate 10.0 Talc 4.0 BB & C Yee! 1o \\ No. 6 0.01

Example 6. The pH-sensitive shell on the core with a controlled release of the active substance.

The core of the tablet as in example 3.

The tablet shell as in example 3.

Example 7. Capsules controlled-release coated granules.

Granule wt.% / weight. (about) Seed (Yop Ragey 8eb) thirty Paroxetine hydrochloride 40 Gelatin 8

Lactose twenty Talc 2 Shell wt.% / weight. Glyceryl monostearate 36.6 Glyceryl distearate 53,4 White wax 10.0

Example 8. A two-layer tablet with controlled release.

Active layer

Component mg / tablet Function Paroxetine hydrochloride 22.89 * Active substance Metocel K4M 15.00 Polymer hydrogel Lactose Monohydrate 62.0 Hydrophilic agent Polyvinylpyrrolidone 3.0 Binder Magnesium stearate 1,0 Hydrophobic agent 8у1оШ 244 1,0 Hydrophilic agent

Protective film

Component mg / tablet Function Sotrgyo1 888 15.04 Plasticizer Lactose Monohydrate 29.32 Hydrophilic agent Polyvinylpyrrolidone 4.0 Binder Magnesium stearate 1,52 Hydrophobic agent Metocel E5 29.32 Polymer hydrogel Iron oxide 0.08 Dye Total tablet weight 184.89 mg

* Equivalent to 20 mg of paroxetine free base

The powder mixture for each layer was wet granulated in a high shear mixer / granulator and dried in a fluid bed dryer. The two-layer tablets are pressed on a three-layer press of Marschu 1pr1e baeger.

Example 9. The preparation of polycarbophil calcium with an enteric coating.

Nucleus

Component mg / tablet Function Paroxetine hydrochloride 22.89 * Active substance Polycarbophil Calcium 20.00 Matrix Anhydrous lactose 146.11 Hydrophilic agent / diluent Polyvinylpyrrolidone 10.0 Binder Magnesium stearate 1,0 Hydrophobic Agent / Lubricant Water** 0.024 Granulating liquid

Enteric coating

Component mg / tablet Function Eibgady 22.19 Polymer Talc 1,53 Lubricant Triethyl citrate 1.00 Plasticizer Water** 24.6 Diluent

Film sheath

Orabgu r1pk 10.5 Film sheath Water** 94.5 Diluent

Glossy shell

Orabgu s1eag 0.750 Film sheath Water** 29.3 Diluent

* Equivalent to 20 mg of paroxetine in the form of a free base ** Remove during processing

The core components are wet granulated in a high shear mixer / granulator and dried in a fluid bed dryer. Magnesium stearate is then added and the mixture is treated in a low shear mixer. After that, the mixture is pressed on a Type B rotary press to make tablets. The coating is carried out using Asseaa!

Example 10. A two-layer tablet with controlled release. Active layer

Component mg / tablet Function Paroxetine hydrochloride 22.89 * Active substance \ [e1 | us1 k4m 20.00 Polymeric hydrogel Lactose Monohydrate 60.0 Hydrophilic agent Polyvinylpyrrolidone 5,0 Binder Magnesium stearate 1,0 Hydrophobic agent 8у1о14 244 1,0 Hydrophilic agent

Protective film

Component mg / tablet Function South America 888 14.72 Plasticizer Lactose Monohydrate 30,60 Hydrophilic agent Polyvinylpyrrolidone 2.80 Binder Magnesium stearate 0.80 Hydrophobic agent \ 1е1 | yuse1 E5 30,60 Polymeric hydrogel 8у1о14 244 0.40 Hydrophilic agent Iron oxide 0.08 Dye Total tablet weight 189.89 mg

* Equivalent to 20 mg of paroxetine free base

Apply the method described in the example

8.

Example 11. A two-layer tablet with controlled release.

Active layer

Component mg / tablet Function Paroxetine hydrochloride 22.89 * Active substance \ 1е1 | yuse1 K4M 15.00 Polymeric hydrogel Lactose Monohydrate 63.31 Hydrophilic agent Polyvinylpyrrolidone 2.0 Binder Magnesium stearate 1,0 Hydrophobic agent 8у1о14 244 0.40 Hydrophilic agent

Protective film as in example 10.

Total tablet weight 184.60 mg * Equivalent to 20 mg of paroxetine free base

Apply the method described in example 8.

Example 12. A two-layer tablet with enteric coating and controlled release.

Active layer

Component mg / tablet Function Paroxetine hydrochloride 28.61 * Active substance MeLose1 K4M 18.75 Polymeric hydrogel Lactose Monohydrate 79.14 Hydrophilic agent Polyvinylpyrrolidone 2,50 Binder Magnesium stearate 1.25 Hydrophobic agent 8u1oP 244 0.50 Hydrophilic agent

Protective film

Component mg / tablet Function Sotrgyo1 888 15.04 Plasticizer Lactose Monohydrate 30.50 Hydrophilic agent Polyvinylpyrrolidone 4.00 Binder Magnesium stearate 0.80 Hydrophobic agent MeLose1 E5 29.32 Polymeric hydrogel 8u1oP 244 0.32 Hydrophilic agent Iron oxide 0.02 Dye

Enteric coating

Component mg / tablet Function Eiigadi 13.27 Polymer Talc 3.31 Lubricant Triethyl citrate 1.33 Plasticizer Water** 36.25 Diluent Total tablet weight 22816689.89 mg

* Equivalent to 250 mg of paroxetine as a free base.

** Removed during processing

Apply the method described in the example

nine.

Example 13

The following components are mixed together in the usual manner and compressed into tablets weighing about 300 mg containing about 20 mg of paroxetine (calculated on the free base).

Paroxetine hydrochloride hemihydrate 228.8 g Calcium Hydrogen Phosphate Dihydrate 2441.2 g Hydroxypropyl methylcellulose 2910 150.0 g Sodium Starch Glycolate 150.0 g Magnesium stearate 30.0 g Total tablet weight 3000.0 g

Claims (9)

CLAIM 1. A method of stimulating smoking cessation or reducing it or preventing the resumption of smoking, which consists in administering to a person in need thereof an effective non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate thereof. 2. The method according to claim 1, characterized in that paroxetine is administered in the form of a drug with controlled or delayed release of the active substance. 3. The method according to claim 2, characterized in that paroxetine is administered orally. 4. The method according to claim 3, characterized in that paroxetine is introduced in the form of a drug with controlled or delayed release comprising (a) a core containing an effective amount of paroxetine and having a certain geometric shape, and (b) a protective film deposited on the specified core, wherein said core contains paroxetine and at least one component selected from the group consisting of (1) a polymer material that swells upon contact with water or aqueous liquids, and a gelling polymer material, where The specified swelling polymer material to the specified gelling polymer material is from 1: 9 to 9: 1, and (2) a separate polymer material having the properties of both swelling and gelation, and the protective film is an elastic film deposited on the specified core, such in a way that partially covers the surface of the core, tracking changes due to hydration of the core and slowly dissolves and / or slowly forms a gel in aqueous liquids. 5. The method according to any one of claims 2 to 4, characterized in that paroxetine is administered together with a nicotine-containing anti-smoking adjuvant. 6. The use of paroxetine or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament to stimulate smoking cessation or to reduce it or to prevent the resumption of smoking. 7. The use according to claim 6, characterized in that paroxetine is in the form of a free base or its pharmaceutically acceptable salt. 8. The use according to claim 7, characterized in that the pharmaceutically acceptable salt of paroxetine is crystalline hydrochloride. 9. The use of claim 8, wherein the hydrochloride is a hemihydrate.