SK10312001A3 - Method to aid smoking cessation - Google Patents

Abstract

This invention relates to a method to aid smoking cessation by treating a patient who wishes to stop smoking with an effective amount of a compound, in particular a phenylcyclobutylbutylamine, in order to aid the patient in overcoming the craving following smoking cessation. The method relates to preventing weight gain in a patient who ceases to smoke and optionally is using a nicotine patch or other agent or program to aid in ceasing to smoke.

Description

Technical field

The invention relates to a method of assisting in quitting smoking. More particularly, the invention relates to a method of administering an effective amount of a compound, in particular phenylcyclobutyl butylamine, to a patient wishing to quit smoking in order to help the patient overcome the craving accompanying the quitting. Further, the method relates to preventing weight gain of a patient who stops smoking.

BACKGROUND OF THE INVENTION

The interruption of nicotine use is extremely difficult for many smokers, and many who seek support in quitting smoking in formal programs return to smoking within a year. Although nicotine withdrawal causes symptoms that are most intense 48 to 72 hours after smoking cessation, such as increased restlessness, hostility and depression, the former smoker is at risk of weight gain and the desire to return to smoking in the long run.

Because of the adverse health effects of smoking and the difficulties many smokers have with completely abandoning the smoking habit, it would be advantageous to have an effective way to quit smoking.

SUMMARY OF THE INVENTION

The present invention relates to compositions comprising agents that selectively enhance noradrenergic effects, and to a method of administering such compositions to exploit the effect of noradrenergic agents on the flavors of various types.

In addition to the effect on nicotine craving accompanying smoking cessation, it is preferred that the agent has a positive effect on other smoking cessation symptoms, such as increased appetite and other activities of the nervous system associated with nicotine withdrawal. More particularly, the present invention relates to the use of sibutramine to achieve these objectives.

According to one embodiment of the invention, persons attempting to quit smoking are administered sibutramine in an amount sufficient to ameliorate or prevent mood disorders and / or to suppress weight gain often apparent in those attempting to quit smoking, as well as to reduce relapses.

According to another embodiment of the invention, sibutramine is administered in conjunction with a patient's participation in a regimen adjustment program.

According to another embodiment of the invention, sibutramine is administered in conjunction with a nicotine patch and the patient's participation in a regimen adjustment program.

The administration of a noradrenergic compound of the invention may be of great benefit to persons suffering from withdrawal symptoms and an increased appetite associated with cessation of smoking, as these compounds act to alleviate or prevent such adverse symptoms.

Although the biochemistry of nicotine addiction and cigarette withdrawal is not fully understood, the theoretical basis of treatment is known. Withdrawal or addictive withdrawal syndrome is associated with a sudden increase in sympathetic output from the brainstem. In particular, noradrenergic neurons in the locus coeruleus (containing half of the noradrenergic neurons in the mammalian brain) show a marked increase in the rate of combustion when taken (Amaral and Sinnamon, 1978).

DETAILED DESCRIPTION OF THE INVENTION

The method described below provides treatment for the symptoms of smoking cessation, and optional steps allow for variants.

More particularly, the present invention relates to a method of promoting smoking cessation by administering a therapeutically effective amount of a compound of Formula I

CH

HaCCHCH 3 CHNR, ^{α α} "O-Τ1, including their enantiomers and pharmaceutically acceptable salts thereof, in which R | and _R2 are, independently, H or methyl, and is administered in combination with a pharmaceutically acceptable diluent or carrier to people in need of it.

A preferred compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine or pharmaceutically acceptable salts thereof, for example hydrochloride or hydrobromide or other salts known in the art.

A particularly preferred form of this compound is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate (sibutramine hydrochloride), which is described in European Patent No. 230 742.

When a compound of formula I contains a single chiral center, it may exist in two enantiomeric forms. The present invention encompasses the use of individual enantiomers and mixtures of enantiomers. The enantiomers may be resolved by methods known to those skilled in the art, for example by carrying out diastereomeric salts or complexes, which may be separated, for example, by crystallization; by carrying out diastereomeric derivatives which can be separated, for example, by crystallization, gas-liquid chromatography; selectively reacting one enantiomer with an enantiomer-specific reagent, for example, by enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or by gas-liquid or liquid chromatography by chiral medium, for example on a chiral support, for example silica with a chiral ligand attached, or in the presence of a chiral solvent. It will be appreciated that when the desired enantiomer is converted to another chemical moiety by one of the separation procedures described above, an additional step is required to release the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active agents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

Preferred compounds of formula I are Ν, Ν-dimethyl-1- (1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine, and 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine including racemates, individual enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof.

The compound of formula I may be administered in any known dosage form. The amount of compound administered depends on a number of factors, including the age of the patient, the severity of the condition and the prior treatment of the patient, and is always within the discretion of the physician administering it, but it is generally considered that the dose administered is in the range of 0.1 to 50 mg. preferably 1 to 30 mg per day in one or more doses.

Preferred compositions for use according to the invention are oral dosage forms which are known dosage forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions. The excipients used to prepare these compositions are excipients known in the medical art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrants, for example, corn starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients known in the art to allow tabletting of the mixture by known methods. The tablets may, if desired, be coated using known methods and excipients, which may include an enteric coating comprising, for example, hydroxypropylmethylcellulose phthalate.

Tablets may be formulated in a manner known to those skilled in the art to provide sustained release of the compounds of the invention. Such tablets may, if desired, be provided with an enteric coating in a known manner, for example using cellulose acetophthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipient and, if necessary, enteric coated in known manner can be prepared by known methods. The contents of the capsule can be formed by known methods to provide sustained release of the active compound. Tablets and capsules suitably contain 1 to 50 mg each of the active compound.

Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as carboxymethylcellulose, and an oily suspension containing the compound of the invention in a suitable vegetable oil, for example arachis oil. The active compound may be incorporated into granules with or without an additional excipient. The granules can be sieved r

directly to patients, or may be added to a suitable liquid carrier (e.g., water) prior to swallowing. The granules may contain disintegrants, e.g. an effervescent couple formed by acid and carbonate or bicarbonate to facilitate dispersion in the liquid medium.

The therapeutically active compounds of formula I may be incorporated into a composition which the patient holds in the mouth so that the active ingredient is administered through the mucous membrane in the mouth.

Dosage forms suitable for rectal administration are known dosage forms for such administration, for example, cocoa butter or polyethylene glycol laces.

Dosage forms suitable for parenteral administration are known dosage forms for such administration, for example, sterile suspensions or sterile solutions in a suitable solvent.

Dosage forms for topical administration may consist of a matrix in which the pharmacologically active compounds of the present invention are dispersed, such that the compounds are maintained in contact with the skin and are administered transdermally. A suitable transdermal composition can be prepared by mixing the pharmaceutically active compound with a topical vehicle such as mineral oil petrolatum and / or wax, e.g. paraffin wax or beeswax, together with a possible transdermal accelerator such as dimethylsulfoxide or propylene glycol. Alternatively, the active ingredients may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in the topical composition should be such that over the period of time the topical skin composition is to be administered a therapeutically effective amount of the compound.

The therapeutically active compound of Formula I may be incorporated into a composition dispersed as an aerosol in a patient's oral or nasal cavity. Such aerosols may be delivered from a pump pack or a press pack containing a volatile propellant.

The therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion, or from a source of the compound placed in the body. Internal sources include implanted reservoirs containing an infused compound that is continuously released, for example, by osmosis, and implants that may be (a) a liquid, such as an oil suspension of the compound, infused as a poorly water-soluble derivative such as a dodecanoic acid or lipophilic acid salt. or (b) a solid in the form of an implanted carrier, for example a synthetic resin or a waxy material, for a compound or series of several bodies each containing a portion of the compound to be administered. The amount of active compound present in the internal source should be such that a therapeutically effective amount of the compound is administered over a long period.

In some compositions, it may be advantageous to use the compounds of the present invention in the form of particles of very small size, for example by intensive fluid grinding.

In carrying out the method of the invention, a regime adjustment program may also be offered to a patient attempting to quit smoking. A variety of mode adjustment programs are known to those skilled in the art. These programs include self-help and taught programs, as well as programs that combine both methods.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are illustrative only and in no way limit the scope of the invention.

Example 1

The invention applies to patients who want to quit smoking and who are determined on the date of quitting. One week before the scheduled date of cessation, administration of sibutramine 15 mg orally once daily (or 10 mg daily) is initiated. Sibutramine is continued at this daily dose six months after the scheduled cessation date. In conjunction with sibutramine, a mode adjustment program is offered. This program may consist of individual counseling sessions or group counseling sessions. Patients are examined by the attending physician two weeks before the scheduled cessation date, one month after the scheduled cessation date, three months after the scheduled cessation date, six months after the scheduled cessation date, and nine months after the scheduled cessation date.

Example 2

The invention applies to patients who want to quit smoking and who are determined on the date of quitting. Two weeks before the scheduled date of cessation, administration of sibutramine 15 mg orally once daily (or 10 mg daily) is initiated. Sibutramine is continued at this daily dose six months after the scheduled cessation date. In conjunction with sibutramine, a mode adjustment program is offered. This program may consist of individual counseling sessions or group counseling sessions. Starting from the scheduled date of cessation, a nicotine patch is also applied for two months. Patients are examined by the attending physician two weeks before the scheduled cessation date, one month after the scheduled cessation date, three months after the scheduled cessation date, six months after the scheduled cessation date, and nine months after the scheduled cessation date.

Example 3

The invention was used for patients who wanted to quit smoking and who had decided on the date of quitting. Two weeks prior to the scheduled date of cessation, administration of sibutramine 15 mg orally once daily was started. Sibutramine was continued at this daily dose four weeks after the scheduled cessation date. A regime adjustment program was provided in conjunction with sibutramine. The program consisted of providing a self-help leaflet on smoking cessation to each patient at the start of the program, and five to ten minute structured lifestyle adjustment sessions aimed at increasing their abstention efforts at all visits and telephone contacts. This clinical debate, based on ACHPR guidelines, included advice on the successful cessation or continuation of abstinence (eg alcohol withdrawal, other household smokers), explanation of the severity of smoking (eg family impact, social and health consequences, and experience before recognizing the risks of smoking (acute, long-term, partner and child risks), explaining that low tar cigarettes do not eliminate these risks, and explaining the benefits of cessation.

The following results were obtained.

Sibutramine (15mg) vs. Sibutramine (15mg) placebo

placebo (N = 212) sibutramine (N = 211) p value 4-week retention ratio 11.8% 10.9% Average weight change 0.8 kg -1.0 kg <0.0001 Average change in weight on leaving 2,2 kg -0.4 kg <0.005 % of those who did not lose weight on leaving 16% 52% <0.02

Example 4

The invention was used for patients who wanted to quit smoking and who had decided on the date of quitting. Two weeks prior to the scheduled date of cessation, administration of sibutramine 15 mg orally once daily was started. Sibutramine was continued at this daily dose four weeks after the scheduled cessation date. A regime adjustment program was provided in conjunction with sibutramine. The program consisted of providing a self-help leaflet on smoking cessation to each patient at the start of the program, and five to ten minute structured lifestyle adjustment sessions aimed at increasing their abstention efforts at all visits and telephone contacts. This clinical debate, based on ACHPR guidelines, included advice on the successful cessation or continuation of abstinence (eg alcohol withdrawal, other household smokers), explanation of the severity of smoking (eg family impact, social and health consequences, and experience early recognition), recognizing the risks of smoking (acute, long-term, risks for partner and children), explaining that low tar cigarettes do not eliminate these risks, and explaining the benefits of quitting.

Starting with the scheduled date of cessation, nicotine patch has also been applied for one month. Patients were examined by the attending physician two weeks before the scheduled cessation date and one month after the scheduled cessation date.

The following results were obtained.

Sibutramine (15 mg) plus patch vs. placebo plus patch

Placebo plus plaster (N = 190) sibutramine plus patch (N = 189) p value 4-week retention rate 24.7% 33.3% 0,063 Average weight change 0.7 kg -0,5 kg <0,0001 Average change in weight on leaving 0.5 kg -0.2 kg <0.02 % of those who did not lose weight on leaving 28% 33.3% <0.005

The invention has been described in connection with various specific embodiments. However, many variations and modifications can be made to the extent and spirit of the invention.

Claims (14)

PATENT CLAIMS Use of a compound of formula I CH ₃ HaCCHCHjCHNR ^ R Or the pharmaceutically acceptable salts and hydrates thereof, wherein R 1 and R ₂ are independently, H or methyl, for the manufacture of a medicament to promote smoking cessation by overcoming craving that accompanies smoking cessation and / or to control the weight gain of a patient who quits smoking or using a smoking cessation agent or program. Use according to claim 1, characterized in that the compound of formula I comprises N, N-dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride. Use according to claim 1, characterized in that the compound of formula I is N, N-dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine in the form of the monohydrate. Use according to claim 1, characterized in that the compound of formula I is administered in conjunction with a patient's participation in a smoking cessation regimen. Use according to claim 4, characterized in that the compound of formula I is administered in conjunction with a patient's participation in a smoking cessation regimen, and in conjunction with nicotine replacement therapy. A process according to claim 1, 3 or 4 wherein the compound of formula I is (+) N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N-methylamine. Use according to claim 1, 3 or 4, characterized in that the compound of formula I is (-) N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -N-methylamine. Use according to claim 1, 3 or 4, characterized in that the compound of formula I is (+) 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine. Use according to claim 1, 3 or 4, characterized in that the compound of formula I is (-) 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine. Use according to claim 1, 3 or 4, characterized in that the compound of formula I is (+) N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -N-N-dimethylamine. Use according to claim 1, 3 or 4, characterized in that the compound of formula I is (-) N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -N-N-dimethylamine. Use according to claim 1, 3 or 4, characterized in that the compound of formula I is (±) N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -N-methylamine. Use according to claim 1, 3 or 4, characterized in that the compound of formula I is (±) 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine. Use according to claim 1, 3 or 4, characterized in that the compound of formula I is (±) N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -N-N-dimethylamine.