WO1999025355A1 - Method of treating addiction to nicotine products - Google Patents
Method of treating addiction to nicotine products Download PDFInfo
- Publication number
- WO1999025355A1 WO1999025355A1 PCT/US1998/024158 US9824158W WO9925355A1 WO 1999025355 A1 WO1999025355 A1 WO 1999025355A1 US 9824158 W US9824158 W US 9824158W WO 9925355 A1 WO9925355 A1 WO 9925355A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nicotine
- compound
- products
- formula
- addiction
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
Definitions
- This invention is in the field of treating addiction to nicotine products, and especially tobacco products, in particular a compound for use in the treatment of addiction to 5 nicotine (especially tobacco) products and methods of treating addiction to nicotine
- Bupropion hydrochloride (marketed in the United States as ZYBAN ® ) however was the first non-nicotine containing product to be approved as an aid to smoking cessation. Bupropion hydrochloride is also marketed in the United States as WELLBUTRIN ® and is indicated for the treatment of depression.
- Nicotine-containing products will include tobacco products (e.g. cigarettes, cigars, pipe tobacco, chewing tobacco etc,) and nicotine replacement products, such as nicotine gums, sprays, patches and inhalers and the like.
- the invention is directed to a method of treating addiction to nicotine- containing products, especially tobacco products, by the administration of the compound of formula (I)
- a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a patient with an addiction to nicotine-containing products, especially tobacco products.
- Treatment of addiction to such nicotine-containing products includes both partial and complete alleviation of addiction.
- tobacco products, as well as the cessation of the activity, for example smoking this will also include reducing the level or frequency of such activity e.g. reduction of the number of cigarettes smoked in a given period.
- treatment will also involve both cessation of, and a reduction in the level of, usage of such products.
- the compound of formula (I) or the pharmaceutically acceptable salt thereof is preferably administered in unit dosage form to the human being treated.
- the amount of compound of formula (I) required to achieve the desired therapeutic effect will, of course depend on a number of factors, for example, the mode of administration and the recipient. In general, the daily dose will be in the region 0.04 to 0.2 mg/kg, preferably 0.04 to 0.14 mg/kg and more preferably 0.04 to 0.08 mg/kg. As will be understood, the precise dosage will depend upon a number of clinical factors, for example, the age of the recipient and the condition in question and its severity.
- the preferred unit dosage of a compound of formula (I) or a salt thereof (estimated as the base) for parenteral (including subcutaneous, intramuscular and intravenous), oral, rectal or topical (including buccal and sublingual) administration is in the range 1.25 mg to 7.5 mg.
- Typical regimens will generally involve dosing a unit dose of about 2.5mg to about lO.Omg of the compound of formula (I) twice daily, preferably a unit dose of about 2.5mg to about 7.5mg, more preferably a unit dose of about 5.0mg to about 7.5mg, most preferably a unit dose of about 7.5mg. Where dosing can occur once-daily then these ranges and amounts would typically be doubled. To treat addiction to nicotine- containing products, such a dosing regimen would typically be continued for a period of up to about 15 weeks, preferably up to about 12 weeks, more preferably up to about 7 weeks.
- such a dosing regimen would typically be continued for between about 5 weeks and about 15 weeks, preferably between about 7 weeks and about 12 weeks, more preferably for about 7 weeks.
- the aforementioned treatment regime(s) essentially represent acute treatment; however, for some patients a more chronic treatment regime may be appropriate in which the dosing regimen indicated above is typically continued for up to about 26 weeks or even up to about 52 weeks.
- salts of a compound of formula (I) should be pharmaceutically acceptable, but pharmaceutically unacceptable salts may conveniently be used to prepare the corresponding free base or pharmaceutically acceptable salts thereof.
- Such pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, maleic, formic, malonic, succinic, isethionic, lactobionic, naphtalene-2-sulfonic, sulfamic, ethanesulfonic and benzenesulfonic.
- the compound of formula (I) or the pharmaceutically acceptable salt thereof may be employed in the treatment of addiction to nicotine- containing products, and especially tobacco products, as the compound per se or salt thereof, but is preferably presented with an acceptable carrier in the form of a pharmaceutical formulation.
- the carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
- the carrier may be a solid or a liquid, or both, and is preferably formulated with the active ingredient as a unit-dose formulation, for example, a tablet, which may contain from about 1 to 99% by weight of active ingredient.
- the formulations include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration.
- buccal e.g. sub-lingual
- parenteral e.g. subcutaneous, intramuscular, intradermal or intravenous
- Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a compound of formula (I) or the pharmaceutically acceptable salt thereof in a flavoured base, usually sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia.
- Formulations for use in the present invention and suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active ingredient, preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the active ingredient with water and rendering the resulting solution sterile and isotonic with the blood.
- Formulations suitable for rectal administration are preferably presented as unit-dose suppositories. These may be prepared by admixing a compound of formula (I) or the pharmaceutically acceptable salt thereof with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
- Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, transdermal patch, aerosol, or oil.
- Carriers which may be used include vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. Further details as to formulations for use in the present invention are disclosed in US
- results of NA/DA/5HT uptake inhibition experiments shown below demonstrate that the compound of formula (I) is an inhibitor of the neuronal reuptake of dopamine (DA) and noradrenaline (NA).
- DA dopamine
- NA noradrenaline
- Biogenic amine reuptake inhibition was studied using cell lines (porcine kidney NN12 cells) that were stably transfected with clones encoding the human cell-surface transporters for noradrenaline, dopamine or serotonin (obtained from Dr. Gary Rudnick, Yale University). Uptake was studied under initial velocity conditions (5-10 minutes) with either 3H-methylphenylpyridinium (for NA and DA transport) or 3H-serotonin at concentrations ⁇ 1% of their Km values. Blank values were obtained by incubating the cells with 10 uM concentrations of either desmethylimipramine (for NA) mazindol (for DA) or fluoxetine (for serotonin). The uptake was terminated by diluting the medium with cold phosphate buffered saline and washing the cells. Radioactivity retained in the cell pellets was measured by liquid scintillation spectrometry.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed is a method of treating addiction to nicotine-containing products, especially tobacco products, comprising the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof in a non-toxic, effective therapeutic amount to a human in need thereof.
Description
METHOD OF TREATING ADDICTION TO NICOTINE PRODUCTS
This invention is in the field of treating addiction to nicotine products, and especially tobacco products, in particular a compound for use in the treatment of addiction to 5 nicotine (especially tobacco) products and methods of treating addiction to nicotine
(especially tobacco) products.
Smoking continues to be the leading preventable cause of death in the United States. Approximately 45% of smokers will die from smoking related illnesses and
10 complications, namely heart disease, stroke, pulmonary disease, cancer and gastrointestinal disease. The high failure rate reported for smoking cessation (75-90%) challenges health care professionals to explore innovative approaches to treating this highly addictive behaviour. Several nicotine-containing smoking cessation products have been developed such as nicotine replacement gums, sprays, patches and inhalers.
15 Antidepressants have also been investigated as aids to smoking cessation but studies have not generated clear results. Bupropion hydrochloride (marketed in the United States as ZYBAN®) however was the first non-nicotine containing product to be approved as an aid to smoking cessation. Bupropion hydrochloride is also marketed in the United States as WELLBUTRIN® and is indicated for the treatment of depression.
20
Bupropion or (±)- 1 -(3 -chlorophenyl)-2- [( 1 , 1 -dimethylethyl)amino] - 1 -propanone
25 forms several metabolites in both rodents and humans. See Martin, P. et al,
Antidepressant Profile of Bupropion and Three Metabolites in Mice Pharmacopsychiatiy
Express Mail Label No.
23:187-194 (1990). The metabolites most studied are hydroxybupropion, threohydrobupropion and erythrohydrobupropion.
Each of these metabolites possess varying degrees of antidepressant and/or stimulant activity. See Martin, P. et al. Hydroxybupropion has been shown to be the most active of the three metabolites in man. Id. Bupropion is generally well tolerated, however, there is a known small risk for the occurrence of seizures in patients taking bupropion, which makes it inappropriate for some patients to use.
The compound,(2S,3S,5i?)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-mo holinol is disclosed in U.S. 5,104,870. The use of this compound for the treatment of narcolepsy- cataplexy syndrome and depression is also disclosed in U.S. 5,104, 870.
It has now been discovered that this compound is useful for the treatment of addiction to nicotine-containing products, and especially tobacco products. Nicotine-containing products will include tobacco products (e.g. cigarettes, cigars, pipe tobacco, chewing tobacco etc,) and nicotine replacement products, such as nicotine gums, sprays, patches and inhalers and the like.
In a first aspect the invention is directed to a method of treating addiction to nicotine- containing products, especially tobacco products, by the administration of the compound of formula (I)
According to a second aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a patient with an addiction to nicotine-containing products, especially tobacco products.
Treatment of addiction to such nicotine-containing products includes both partial and complete alleviation of addiction. Thus, in respect of tobacco products, as well as the cessation of the activity, for example smoking, this will also include reducing the level or frequency of such activity e.g. reduction of the number of cigarettes smoked in a given period. In respect of other nicotine-containing products, treatment will also involve both cessation of, and a reduction in the level of, usage of such products.
The compound of formula (I) or the pharmaceutically acceptable salt thereof is preferably administered in unit dosage form to the human being treated.
The amount of compound of formula (I) required to achieve the desired therapeutic effect will, of course depend on a number of factors, for example, the mode of administration and the recipient. In general, the daily dose will be in the region 0.04 to 0.2 mg/kg, preferably 0.04 to 0.14 mg/kg and more preferably 0.04 to 0.08 mg/kg. As will be understood, the precise dosage will depend upon a number of clinical factors, for example, the age of the recipient and the condition in question and its severity. The preferred unit dosage of a compound of formula (I) or a salt thereof (estimated as the base) for parenteral (including subcutaneous, intramuscular and intravenous), oral, rectal or topical (including buccal and sublingual) administration is in the range 1.25 mg to 7.5 mg.
Typical regimens will generally involve dosing a unit dose of about 2.5mg to about lO.Omg of the compound of formula (I) twice daily, preferably a unit dose of about 2.5mg to about 7.5mg, more preferably a unit dose of about 5.0mg to about 7.5mg, most preferably a unit dose of about 7.5mg. Where dosing can occur once-daily then these ranges and amounts would typically be doubled. To treat addiction to nicotine- containing products, such a dosing regimen would typically be continued for a period of up to about 15 weeks, preferably up to about 12 weeks, more preferably up to about 7 weeks. Alternatively, such a dosing regimen would typically be continued for between about 5 weeks and about 15 weeks, preferably between about 7 weeks and about 12 weeks, more preferably for about 7 weeks. The aforementioned treatment regime(s) essentially represent acute treatment; however, for some patients a more chronic treatment regime may be appropriate in which the dosing regimen indicated above is typically continued for up to about 26 weeks or even up to about 52 weeks.
When used in medicine, the salts of a compound of formula (I) should be pharmaceutically acceptable, but pharmaceutically unacceptable salts may conveniently be used to prepare the corresponding free base or pharmaceutically acceptable salts thereof.
Such pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, maleic, formic, malonic, succinic, isethionic, lactobionic, naphtalene-2-sulfonic, sulfamic, ethanesulfonic and benzenesulfonic.
The compound of formula (I) or the pharmaceutically acceptable salt thereof (hereinafter the active ingredient) may be employed in the treatment of addiction to nicotine- containing products, and especially tobacco products, as the compound per se or salt thereof, but is preferably presented with an acceptable carrier in the form of a
pharmaceutical formulation. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the active ingredient as a unit-dose formulation, for example, a tablet, which may contain from about 1 to 99% by weight of active ingredient.
The formulations include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g.. subcutaneous, intramuscular, intradermal or intravenous) administration.
Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a compound of formula (I) or the pharmaceutically acceptable salt thereof in a flavoured base, usually sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia.
Formulations for use in the present invention and suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active ingredient, preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the active ingredient with water and rendering the resulting solution sterile and isotonic with the blood.
Formulations suitable for rectal administration are preferably presented as unit-dose suppositories. These may be prepared by admixing a compound of formula (I) or the pharmaceutically acceptable salt thereof with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, transdermal patch, aerosol, or oil. Carriers which may be used include vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. Further details as to formulations for use in the present invention are disclosed in US
5,104,870.
Results of NA/DA/5HT uptake inhibition experiments shown below demonstrate that the compound of formula (I) is an inhibitor of the neuronal reuptake of dopamine (DA) and noradrenaline (NA). The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of addiction to nicotine-containing products is thought to be related, to this neurotransmitter uptake inhibition profile, although the precise mechanism is as yet unknown.
Uptake Inhibition (expressed as IC50 values in nM)
Compound DA NA 5HT
1555U88 60 90 >10,000
Biogenic amine reuptake inhibition was studied using cell lines (porcine kidney NN12 cells) that were stably transfected with clones encoding the human cell-surface transporters for noradrenaline, dopamine or serotonin (obtained from Dr. Gary Rudnick, Yale University). Uptake was studied under initial velocity conditions (5-10 minutes) with either 3H-methylphenylpyridinium (for NA and DA transport) or 3H-serotonin at concentrations ~ 1% of their Km values. Blank values were obtained by incubating the cells with 10 uM concentrations of either desmethylimipramine (for NA) mazindol (for DA) or fluoxetine (for serotonin). The uptake was terminated by diluting the medium
with cold phosphate buffered saline and washing the cells. Radioactivity retained in the cell pellets was measured by liquid scintillation spectrometry.
Claims
1. A method of treating addiction to nicotine-containing products comprising the administration of the compound of formula (I)
or a pharmaceutically acceptable salt thereof in a non-toxic, effective therapeutic amount to a human in need thereof.
2. A method as claimed in claim 1 wherein the nicotine-containing product is a tobacco product.
3. A method as claimed in claim 1 or claim 2 wherein a unit dose of about 2.5mg to about 7.5mg of the compound of formula (I) is administered twice daily for a period of between about 7 weeks and about 12 weeks.
4. The use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a patient with an addiction to nicotine-containing products.
5. The use as claimed in claim 4 wherein the nicotine-containing product is a tobacco product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU14038/99A AU1403899A (en) | 1997-11-14 | 1998-11-12 | Method of treating addiction to nicotine products |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6598497P | 1997-11-14 | 1997-11-14 | |
| US60/065,984 | 1997-11-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999025355A1 true WO1999025355A1 (en) | 1999-05-27 |
Family
ID=22066498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/024158 WO1999025355A1 (en) | 1997-11-14 | 1998-11-12 | Method of treating addiction to nicotine products |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU1403899A (en) |
| WO (1) | WO1999025355A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001026641A2 (en) * | 1999-10-13 | 2001-04-19 | Glaxo Group Limited | Morpholinol derivatives for the treatment of obesity |
| US7819124B2 (en) | 2006-01-31 | 2010-10-26 | U.S. Smokeless Tobacco Company | Tobacco articles and methods |
| US7913699B2 (en) | 2006-01-31 | 2011-03-29 | U.S. Smokeless Tobacco Company Llc | Tobacco articles and methods |
| US7918231B2 (en) | 2006-01-31 | 2011-04-05 | U.S. Smokeless Tobacco Company Llc | Tobacco articles and methods |
| US8387623B2 (en) | 2006-01-31 | 2013-03-05 | U.S. Smokeless Tobacco Company Llc | Smokeless tobacco articles |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5104870A (en) * | 1989-10-31 | 1992-04-14 | Burroughs Wellcome Co. | Heterocyclic pharmaceutical compounds and use |
-
1998
- 1998-11-12 WO PCT/US1998/024158 patent/WO1999025355A1/en active Application Filing
- 1998-11-12 AU AU14038/99A patent/AU1403899A/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5104870A (en) * | 1989-10-31 | 1992-04-14 | Burroughs Wellcome Co. | Heterocyclic pharmaceutical compounds and use |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001026641A2 (en) * | 1999-10-13 | 2001-04-19 | Glaxo Group Limited | Morpholinol derivatives for the treatment of obesity |
| WO2001026641A3 (en) * | 1999-10-13 | 2002-01-10 | Glaxo Group Ltd | Morpholinol derivatives for the treatment of obesity |
| US7819124B2 (en) | 2006-01-31 | 2010-10-26 | U.S. Smokeless Tobacco Company | Tobacco articles and methods |
| US7913699B2 (en) | 2006-01-31 | 2011-03-29 | U.S. Smokeless Tobacco Company Llc | Tobacco articles and methods |
| US7918231B2 (en) | 2006-01-31 | 2011-04-05 | U.S. Smokeless Tobacco Company Llc | Tobacco articles and methods |
| US8387623B2 (en) | 2006-01-31 | 2013-03-05 | U.S. Smokeless Tobacco Company Llc | Smokeless tobacco articles |
| US8627827B2 (en) | 2006-01-31 | 2014-01-14 | U.S. Smokeless Tobacco Company | Tobacco articles |
| US8627826B2 (en) | 2006-01-31 | 2014-01-14 | U.S. Smokeless Tobacco Company | Tobacco articles and methods |
| US9427019B2 (en) | 2006-01-31 | 2016-08-30 | U.S. Smokeless Tobacco Company Llc | Smokeless tobacco articles |
| US10420366B2 (en) | 2006-01-31 | 2019-09-24 | U.S. Smokeless Tobacco Company Llc | Tobacco articles and methods |
| US10555551B2 (en) | 2006-01-31 | 2020-02-11 | U.S. Smokeless Tobacco Company Llc | Tobacco articles and methods |
| US11252988B2 (en) | 2006-01-31 | 2022-02-22 | U.S. Smokeless Tobacco Company Llc | Tobacco articles and methods |
| US11957154B2 (en) | 2006-01-31 | 2024-04-16 | U.S. Smokeless Tobacco Company Llc | Tobacco articles and methods |
Also Published As
| Publication number | Publication date |
|---|---|
| AU1403899A (en) | 1999-06-07 |
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