WO1996000069A1

WO1996000069A1 - Treatment of nicotine craving and/or smoking withdrawal symptoms with a solid or semi-solid composition containing nicotine and caffeine or xanthine, especially for nasal administration

Info

Publication number: WO1996000069A1
Application number: PCT/US1995/007380
Authority: WO
Inventors: Satyanarayana Majeti
Original assignee: The Procter & Gamble Company
Priority date: 1994-06-23
Filing date: 1995-06-09
Publication date: 1996-01-04
Also published as: AU2702795A; PE39996A1; IL114130A0; ZA955033B; MA23586A1

Abstract

The subject invention encompasses a solid or semi-solid composition for the treatment or nicotine craving or smoking withdrawal symptoms comprising nicotine and caffeine or caffeine equivalent.

Description

Treatment of nicotine craving and/or smoking withdrawal symptoms with a sol id or sem1-sol 1d composition containing nicotine and caffeine or xanthl ne, especial ly for nasal admini stration .

BACKGROUND OF THE INVENTION 5 The health hazards from smoking tobacco are well known. Of the many by¬ products of combustion found in cigarette smoke, the substances most studied have been tars, carbon monoxide, and nicotine. Tars are the agents linked to the causation of various cancers and pulmonary diseases such as emphysema and chronic bronchitis. Carbon monoxide is a deadly gas which reduces the ability of blood 0 hemoglobin to carry sufficient oxygen. Carbon monoxide has also been causally linked to coronary artery disease and atherosclerosis. Nicotine appears to be the most pharmacologically active substance in tobacco smoke, yet it seems not to be as significant from a health standpoint as the tars and carbon monoxide. However, nicotine is the reinforcing substance in tobacco which maintains the addiction. Various efforts have been made by smokers to discontinue smoking.

Chewing beeswax, eating candy and peppermints as well as cold turkey interruption have been tried without much success. The addition of chemicals designed to sicken the user or otherwise render smoking repulsive to the user have also not produced good results. More recent therapies for smoking cessation have focused on the administration of nicotine to the smoker. These therapies allow the indiv. dual to satisfy a nicotine habit while minimizing or eliminating side effects cε ed by absorbing nicotine through the lungs along with the other harmful by-products of combustion of tobacco.

Nicotine supplementation has proven to be an effective therapy as an adjunct to smoking cessation in helping to reduce the craving for smoking and provide relief from smoking withdrawal symptoms. However, there are many smokers for whom nicotine supplementation alone is inadequate. In accordance with the present invention, it has been discovered that a composition can be formulated which provides the combination of nicotine and caffeine or caffeine equivalent in a single therapy. It has also been discovered that such a combination may offer the advantage of providing treatment and/or relief of nicotine craving and/or smoking withdrawal symptoms to a broader spectrum of smokers who wish to break the smoking habit. It has further been discovered that these compositions may also curb the appetite which may aid in reducing the weight gain that is commonly experienced by individuals who stop smoking.

It is an object of the present invention to provide a composition comprising the combination of nicotine and caffeine or caffeine equivalent in a single therapy. It is also an object of the present invention to deliver the nicotine and caffeine combination therapy in a convenient delivery system. It is a further object of the invention to provide a method for the treatment and/or relief of nicotine craving and/or smoking withdrawal symptoms in individuals who wish to break or decrease the habit of smoking tobacco or the use of any tobacco product. These and other objects will become readily apparent from the detailed description which follows.

SUMMARY OF THE INVENTION

The present invention relates to solid or semi-solid composition for the treatment of nicotine craving and/or smoking withdrawal symptoms comprising nicotine and caffeine or caffeine equivalent, wherein the composition delivers from about 0.0 l g to about 3mg of nicotine, and from about lmg to about 30mg of caffeine or caffeine equivalent.

The present invention also relates to a method for providing treatment and/or relief of nicotine craving and/or smoking withdrawal symptoms to a human or lower animal in need of such treatment comprising the administration of a safe and effective amount of a solid or semi-solid composition comprising nicotine and caffeine or caffeine equivalent.

DETAILED DESCRIPTION OF THE INVENTION The subject invention comprises nicotine, caffeine or caffeine equivalent, and preferably one or more pharmaceutically-acceptable carriers suitable for direct or indirect nasal administration. These compositions are useful for the treatment and/or relief of nicotine craving and/or smoking withdrawal symptoms.

The terms "nicotine craving" and "smoking withdrawal symptoms" as used herein both refer to any physical or psychological reaction relating to breaking the habit of smoking tobacco or using any tobacco product or decreasing the frequency or intensity of smoking tobacco or using any tobacco product.

In general, the descriptive term "pharmaceutically-acceptable" is used herein to describe materials that are non-toxic and suitable for administration to humans and/or lower animals. The term "pharmaceutically-acceptable aqueous carrier" as used herein means any material safe and effective for use in the compositions of the present invention. Such materials include water, emollients, pH adjusters, emulsifiers, buffering agents, gel-forming compounds, aromatic compounds, solvents, preservatives, agents for regulating isotonicity, wetting agents, thickening agents, humectants, surfactants, agents for aiding the film-forming properties and substantivity of the formulations, antimicrobials for maintaining the antimicrobial integrity of the compositions, antioxidants, agents suitable for aesthetic purposes such as fragrances, pigments, and colorings, non-soluble ingredients, and mixtures thereof.

The terms "safe and effective amount", as used herein, mean a sufficient amount of material to provide the desired benefit without undue adverse side effects commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific safe and effective amount will vary with such factors as the particular condition that is being treated, the severity of the condition, the duration of the treatment, the physical condition of the patient, the nature of concurrent therapy (if any), and the specific formulation and optional components hereinafter. The terms "suitable for direct or indirect nasal administration" as used herein refer to any formulation that is suitable for the convenient administration of the composition whereby the composition is placed in contact with mucous membranes of the nose, inhaled, or delivered in such a way that vapors of the composition are inhaled. The following terms will be designated as follows: milligram as "mg", milliliter as "ml", nanogram as "ng", and microgram as "ug".

A detailed description of essential and optional components of the present invention is given below. Nicotine The present invention comprises nicotine. Nicotine is a tertiary amine composed of a pyridine and a pyrrolidine ring. It is a colorless to pale yellow, which is freely water soluble, strongly alkaline, hygroscopic liquid obtained from the tobacco plant. Nicotine has a characteristic odor and turns brown on exposure to air or light [Physicians Desk Reference. 48th Edition, p. 1306, 1984] Nicotine is delivered in an amount of from about O.Olmg to about 3mg, preferably from about O.lmg to about 2mg, and most preferably from about 0.5mg to about 1.5mg. Nicotine is also described in Remington's Pharmaceutical Sciences. 18th Edition, 1990, p. 891, which is incorporated herein by reference. Caffeine The present inventions also comprise caffeine or a caffeine equivalent.

Caffeine is found as white, fleecy masses or long, flexible, silky crystals. It is odorless, bitter tasting, and slightly soluble in water and alcohol. Caffeine may be derived synthetically or by extraction of coffee beans, tea leaves or kola nuts [Hawleys Condensed Chemical Dictionary. Twelfth Edition, 1993]. Examples of suitable sources of caffeine for use in the present invention are pure caffeine, caffeine combined with acetate, citrate, benzoate, phosphate, sulfate or salicylate. Also suitable are any of the xanthine analogues that match caffeine's effectiveness as a central nervous system stimulant, including salts thereof that are compatible. Xanthine derivatives are described in Remington's Pharmaceutical Sciences. 18th Edition, 1990, pp. 1132-34, which is incorporated herein by reference. The caffeine or caffeine equivalent is delivered in an amount of from about lmg to about 30mg, preferably from about 3mg to about 20mg, and most preferably from about 5mg to about lOmg. Pharmaceutically-Acceptable Carrier

The invention compositions preferably also contain one or more pharmaceutically-acceptable carriers suitable for direct or indirect nasal administration. Such compositions include (but are not limited to) gels or jellies, emulsions, creams, ointments or other solid or semi-solid formulations suitable for directly or indirectly administering the present compositions intranasally. Preferred compositions are ointments, emulsions, gels and suspensions.

While the choice of nasal carrier is not critical to the present invention, the carrier or carriers chosen must be suitable for administering the nicotine and caffeine or caffeine equivalent so that the desired blood levels of these compounds are achieved in the body of the recipient. The desired blood level of nicotine is from about lng/ml to about lOOng/ml, preferably from about 5ng/ml to about 75ng/ml, and most preferably from about lOng/ml to about 50ng/ml, preferably within 1 to 4 hours of administration. . The desired blood level of caffeine or caffeine equivalent is from about O.Olug/ml to about 20ug/ml, preferably from about 0. lug/ml to about 15 ug/ml, and most preferably from about 0.5ug/ml to about lOug/ml, preferably within 1 to 4 hours of administration.

The present compositions will normally be prepared in dosage unit form to contain safe and effective amounts of the nicotine and caffeine (or equivalent) to achieve the desired blood levels. Fractions of the dosage units or multiple dosage units may also be utilized. In general, the solid or semi-solid compositions herein deliver to a human or lower animal from about O.Olmg to about 3mg, preferably from about O. lmg to about 2mg, and most preferably from about 0.5mg to about 1.5mg of nicotine; and from about lmg to about 30mg, preferably from about 3mg to about 20mg, and most preferably from about 5mg to about lOmg, of caffeine or caffeine equivalent. Preferably the present invention may be a solid or semi-solid composition for the treatment of nicotine craving and/or smoking -withdrawal symptoms comprising nicotine, caffeine or caffeine equivalent, and one or more pharmaceutically-acceptable carriers suitable for indirect or direct nasal administration, wherein the composition delivers from about O.Olmg to about 3mg of nicotine, and from about lmg to about 30mg of caffeine or caffeine equivalent. The amount of nicotine and caffeine or caffeine equivalent and frequency .of administration may vary depending on the carrier chosen and the personal needs of the user. However, it is suggested (as an example) that the present invention be administered from about once to about 20 times per day, preferably from about 2 to about 10 times per day, and most preferably from about 4 to about 8 times per day. The compositions of the present invention may be prepared as emulsions. Single emulsion preparations, such as lotions and creams, of the oil-in-water type and water-in-oil type are well-known in the art and are useful in the present invention. Also useful in the present invention are multiphase emulsion compositions, such as the water-in-oil-water type, (as disclosed in U.S. Patent No. 4,254,105, Fakuda et al., issued March 3, 1981), and the triple emulsion systems comprising an oil-in- water-in-silicone fluid emulsion (as disclosed in U.S. Patent Application Serial No. 022,876, Figueroa, et al., filed March 6, 1987), both references incorporated herein. In general, such single or multiphase emulsions contain water, emollients and emulsifiers. Emulsions are described in detail in Remington's Pharmaceutical Sciences. 17th Edition, pp. 298-308, which is incorporated herein by reference.

Emulsion preparations useful in the present invention may also be prepared as ointments comprising a simple base of animal or vegetable oils or semi-solid hydrocarbons (oleaginous). Ointments may also comprise absorption ointment bases which absorb water to form emulsions. Examples of such ointment bases include anhydrous lanolin and hydrophilic petrolatum. Emulsion ointments may be oil-in- water or water-in-oil emulsions. Ointment carriers may also be water soluble. Examples of such ointment carriers include glycol ethers, propylene glycols, polyoxyl stearates, and polysorbates. A more detailed disclosure of suitable components for ointment bases can be found in Remington's Pharmaceutical Sciences. 17th Edition, pp.1573-1580

Water may also be present in the compositions. Water employed should preferably be deionized and free from organic impurities. Water may comprise from about 0% to about 50%, and preferably from about 20% to about 40%, by weight of the compositions. These amounts of water include free water which is added plus that which is introduced with other materials such as with sorbitol.

The composition may also comprise from about 1% to about 10%, preferably from about 2% to about 5%, of one or more pharmaceutically-acceptable emulsifiers. These emulsifiers may be nonionic, anionic or cationic. Suitable emulsifiers are disclosed in, for example, U.S. Patent 3,755,560, issued August 28, 1973, Dicert et al.; U.S. Patent 4,421,769, issued December 20, 1983, Dixon et al.; and McCutcheon's Detergents and Emulsifiers. North American Edition, pages 317-324 (1986); the disclosures of which are incorporated herein by reference. Preferred emulsifiers are anionic or nonionic, although the other types may also be used.

The composition may also comprise from about 2% to about 10% of a pharmaceutically-acceptable emollient and/or from about 0.1% to about 2% of a pharmaceutically-acceptable thickening agent which aids in adjusting the viscosity of the compositions. Suitable emollients include volatile silicone oils, non-volatile emollients such as fatty acid and fatty alcohol esters, highly branched hydrocarbons known as the Permethyl 99 through 108 A series (available from Permethyl Corporation), and mixtures thereof. Suitable emollients are disclosed in U.S. Patent No. 5322689, to Hughes et al., issued 6/21/94, incorporated herein by reference.

Examples of suitable thickening agents include: cellulose derivatives (e.g., methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, and hydroxy propylmethyl cellulose), synthetic high molecular weight polymers (e.g., carboxyvinyl polymer and polyvinyl alcohol), plant hydrocolloids (e.g., karaya gum, xanthan gum, and tragacanth gum), clay thickeners (e.g., colloidal magnesium aluminum silicate and bentonite), and carboxyvinyl polymers are described in detail in U.S. Patent 2,798,053, Brown, issued July 2, 1975, incorporated herein by reference). A more complete disclosure of thickening agent useful herein can be found in Segarin, Cosmetics. Science and Technology. 2nd Edition, Vol. 1, pp. 72-73 (1972), incorporated herein by reference.

The present compositions may also be prepared as gels. Such gels may be suspensions, or solutions. The gels may be hydrogels (with a water based solvent) or organogels (with a nonaqueous solvent). Xerogels, such as dry gelatin, tragacanth ribbons and acacia tears, and dry cellulose and polystyrene, are also useful in the present inventions. Pharmaceutically-acceptable gels may be prepared from gel forming compounds including but not limited to: natural gums such as guar gum; tragacanth; alginates and salts thereof; gelatin; carrageenan; cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, methylhydroxyethyl cellulose, ethyl cellulose, hydroxyethyl cellulose; carbomer; polyvinyl alcohol; polyoxyethylene- polyoxypropylene; pectin; xanthan gum; and mixtures thereof.

The present inventions may contain a pharmaceutically-acceptable surfactant. Typical surfactants useful in the present compositions include polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides such as Tween 80, Polyoxyl 40 Stearate, Polyoxyethylene 50 Stearate and Octoxynol, as well as Oxyethylated tertiary octyl phenol formaldehyde polymer (available from Sterling Organics as tyloxapol). The usual concentration is from about 0.5% to 10%, by weight of the composition. The compositions of the present invention may also include one or more pharmaceutically-acceptable solvents. The terms "pharmaceutically-acceptable solvent" refer to a solvent which possesses acceptable safety. The most typical example of such a solvent is water. Examples of other suitable organic solvents include: glycerin, propylene glycol, polyethylene glycol (200-600), polypropylene glycol (425-2025), glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, isopropanol, butanediol, and mixtures thereof.

One or more pharmaceutically-acceptable humectants may also be included in the present compositions. A variety of humectants can be employed and may be present at a level of from about 1% to about 10%, more preferably from about 2% to about 8% and most preferably from about 3% to about 5%. These materials include urea; guanidine; glycolic acid and glycolate salts (e.g. ammonium and quaternary alkyl ammonium); triethanolamine; glycerol, lactic acid and lactate salts (e.g. ammonium and quaternary alkyl ammoniu.n); polyhydroxy alcohols such as sorbitol, glycerin, hexanetriol, propylene glycol, hexylene glycol and the like; polyethylene glycol; sugars and starches; sugar and starch derivatives (e.g. alkoxylated glucose);

D-panthenol; hyaluronic acid; lactamide monoethanolamine; acetamide monoethanol- amine; and mixtures thereof. Preferred humectants are the C -C diols and triols.

3 6 Especially preferred is the triol, glycerin. Most preferably, the compositions are isotonic, i.e., they have the same osmotic pressure as blood and lacrimal fluid. If desired, sustained release compositions, e.g., sustained release gels, can be conveniently employed. The desired isotonicity of the compositions of this invention may be accomplished by using, for example, sodium chloride or other pharmaceutically-acceptable agents such as dextrose, boric acid, sodium tartrate, sodium phosphate, potassium phosphate, propylene glycol or other inorganic or organic solutes. Sodium chloride is preferred particularly for buffers containing sodium ions.

The compositions of the present invention also include microencapsulation of either the nicotine or caffeine (or caffeine equivalent) or both. Techniques and materials for microencapsulation are well known in the art. Microencapsulation is discussed more fully in Kirk and Othmer's Encyclopedia of Chemical Technology, Vol. 13, 2nd Edition, pp.436-456, which is incorporated herein by reference.

The compositions of the present invention may also contain one or more aromatic components. These aromatics include, for example, menthol, eucalyptol, benzaldehyde (cherry, almond); citral (lemon, lime); neral; decanal (orange, lemon); aldehyde C-8, aldehyde C-9 and aldehyde C-12 (citrus fruits); tolyl aldehyde (cherry, almond); 2,6-dimethyl-octanal (green fruit); 2-dodecenal (citrus, mandarin); thymol; cedar leaf oil, myristica oil, lavender oil, nutmeg oil, turpentine; 3-1-menthoxy propane- 1,2-diol; N-substituted-p-menthane-3-carbox-amides and acyclic carboxamides; and mixtures thereof. Preferred are menthol, eucalyptol, thymol, cedar leaf oil, myristica oil, lavender oil, nutmeg oil, turpentine, and mixtures thereof. Aromatic compounds may be present at a level of from about 0.0001% to about 1%, preferably from about 0.001% to about 1%, and most preferably from about 0.001% to about 0.5%, by weight of the compositions.

Other pharmaceutically-acceptable ingredients may also be present including but not limited to: pH adjusters such as sodium hydroxide; buffering agents such as sodium bicarbonate; preservatives such as benzyl alcohol, parabens, benzalkonium chloride, chlorhexidine gluconate and disodium EDTA; surfactants, plasticizers; wetting agents; various polymers for aiding the film-forming properties and substantivity of the formulations; antimicrobials for maintaining the antimicrobial integrity of the compositions; antioxidants; agents suitable for aesthetic purposes such as fragrances, pigments, and colorings; and mixtures thereof.

The compositions may also contain low levels of pharmaceutically-acceptable insoluble ingredients added, for example, for visual effect purposes, e.g., thermochromic liquid crystalline materials such as the microencapsulated cholesteryl esters and chiral nematic (nonsterol) based chemicals such as the (2-methylbutyl) phenyl 4-alkyl(oxy)benzoates available form Hallcrest, Glenview, Illinois 60025, U.S.A. Method of Treatment

The present invention also encompasses a method of treatment. The method of providing treatment and/or relief of nicotine craving and/or smoking withdrawal symptoms to a human or lower animal in need of such treatment, as, disclosed herein, comprises the administration of a safe and effective amount of a solid or semi-solid composition comprising nicotine and caffeine or caffeine equivalent. Such compositions preferably further comprise one or more pharmaceutically acceptable carriers suitable for direct or indirect nasal administration. The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLE I Ointment Base Composition An ointment base composition according to the present invention is prepared as follows:

Ingredient Weight %

Petrolatum (White) 40.0

L-Menthol 2.8

Lavender Oil 4.3

Borynl Acetate 5.2

Triethanolamine 0.5

Acrylates/Steareth-20 Methacrylate 0.3

1

Copolymer

Disodium EDTA 0.1

Caffeine 10.0

Nicotine 1.0

Water 35.8

Available as Acrosyl ICS-1 from Rohm and Haas

Petrolatum is added to a suitable size container and heated to about 50°C. While mixing at a moderate speed, the, L-menthol, lavender oil and bornyl acetate are added and mixed until uniform. In a separate vessel, some of the water and triethanolamine are combined. In a separate vessel, the disodium EDTA is added to a portion of the water, mixed until completely dispersed, then heated to about 70°C. The oil phase (petrolatum mixture) is added to the water phase with mixing (high shear, for example, a Tek Mar mixer). Cool the resulting mixture to about 40°C and add the triethanolamine solution. The resulting combination is then cooled to room temperature.

Claims

What is Claimed is:

1. A solid or semi-solid composition for the treatment of nicotine craving or smoking withdrawal symptoms comprising nicotine and caffeine or caffeine equivalent, wherein the composition delivers: a) from O.Olmg to 3mg of nicotine; and b) from lmg to 30mg of caffeine or caffeine equivalent.

2. The composition according to Claim 1 wherein (b) is caffeine.

3. A solid or semi-solid composition for the treatment of nicotine craving or smoking withdrawal symptoms comprising nicotine, caffeine or caffeine equivalent, and one or more pharmaceutically-acceptable carriers suitable for direct or indirect nasal administration, wherein the composition delivers: a) from O.Olmg to 3mg of nicotine; and b) from lmg to 30mg of caffeine or caffeine equivalent.

4. The composition according to Claim 3 wherein the composition is in the form of an ointment based emulsion.

5. The composition according to Claim 4 wherein (b) is caffeine.

6. The composition according to Claim 4 wherein (b) is the caffeine equivalent xanthine.

7. The solid or semi-solid composition according to Claim 3 comprising: a) from 0.1 mg to 2mg of nicotine; b) from 3mg to 20mg of caffeine or caffeine equivalent.

8. The composition according to Claim 7 wherein the composition further 'comprising one or more aromatic compounds selected from the group consisting of menthol, eucalyptol, thymol, cedar leaf oil, myristica oil, lavender oil, nutmeg oil, turpentine, and mixtures thereof.

9. The composition according to Claim 8 further comprising from 0.01% to 5% of a pharmaceutically-acceptable humectant.

10. The composition according to Claim 9 further comprising from 0.5% to 10% of a pharmaceutically-acceptable surfactant.

11. The composition according to Claim 10 wherein the composition is in the form of a nasal gel.

12. The composition according to Claim 10 wherein the composition is in the form of a solid wherein vapors from the solid are inhaled.

13. The composition according to Claim 10 wherein the composition is in the form of an ointment wherein the nasal cavity is coated with the ointment