HK1068556A - New formulations and use thereof - Google Patents

Description

Novel formulations and uses thereof

Technical Field

The present invention relates to novel nicotine pharmaceutical compositions and uses thereof. More particularly, the present invention relates to compositions comprising nicotine and chocolate, methods of making the compositions, and the use of the compositions in Nicotine Replacement Therapy (NRT) including tobacco replacement and smoking cessation.

Background of the invention and Prior Art

Nicotine replacement therapy has been successful in the past as a means of quitting smoking. Prior invented nicotine-containing compositions, the purpose of which is to reduce nicotine cravings for those who wish to quit use of smoking articles, such nicotine-containing compositions include, for example, chewable compositions disclosed in US3,845,217, highly viscous nicotine nasal drops disclosed in US4,579,858, saliva-soluble nicotine-containing gels disclosed in US5,525,351, low viscosity nicotine-containing compositions suitable for administration by nasal spray disclosed in US5,656,255, inhalable aerosols disclosed in US4,920,989 and US4,953,572, liquid aerosol formulations for oral spray disclosed in BP1,528,391 and BP2,030,862, and devices for transdermal administration of nicotine.

The side effects of nicotine are known to be related to the concentration of local irritation. This side effect is particularly pronounced when nicotine formulations are administered topically, including transmucosal, buccal and nasal, and transdermal routes of administration.

British patent application GB2230439A describes nicotine lozenges with a shell or coating comprising a local analgesic, preferably eugenol, acting in the oral cavity. Although the reason for the inclusion of local analgesics is not specifically stated, the aforementioned invention is said to substantially improve the sensation of burning in the mouth that conventional nicotine lozenges have. Similarly, nicotine compositions in the form of lozenges containing local analgesics have also been disclosed in AU662877, where the latter agents are said to temporarily interfere with taste receptors, and are said to reduce appetite.

Thus, in several of the above inventions, the concentration of nicotine and its product design is limited by side effects caused by or associated with local irritation.

Other capsules, tablets and lozenges for oral administration of nicotine are described in the prior art. For example, WO88/03803 discloses a chewable capsule filled with a liquid containing 0.1-10.0mg nicotine and additives for taste improvement and dispersion. The capsules are provided at various pH levels so that the patient can select the rate of nicotine absorption, particularly as a smoking cessation aid.

Another nicotine capsule formulation is disclosed by Jarvik et al (Clinical pharmacy and nicotine medicaments 1970; 11: 574) for ingestion as a smoking cessation aid. According to theory, intestinal absorption of nicotine produces significant blood concentrations in the subject, however, it is evident that the subject swallows these capsules entirely. Studies have shown that there is a small but significant reduction in the number of cigarettes smoked by subjects, but no quantitative measure of nicotine blood concentration is obtained.

BE899037 discloses a tablet for stopping smoking as an adjuvant, which contains 0.1 to 5mg of nicotine or a water-soluble acid salt as a base.

Shaw (e.g. in GB2142822 and US4,806,356) describes nicotine lozenges prepared by cold pressing from a mixture of an inert filler, a binder and either pure nicotine or a nicotine-containing substance.

US5,512,306 discloses a nicotine product for oral administration in the form of an inclusion complex of nicotine and a cyclodextrin compound. The use of various excipients and direct compression for the preparation of the product is also discussed in this document.

US5,662,920 discloses a nicotine lozenge that may contain a candy taste flavor (flavourant), such as chocolate, orange, vanilla (vanilla), and other flavors. Although not suggested, they are also used as taste masking agents. In addition, there is no disclosure of what amount of these fragrances is needed to achieve a taste masking effect.

WO97/42941 discloses a slowly erodible nicotine lozenge which can be administered through the oral mucosa over a sustained period.

GB2147501A discloses a medicament in oral dosage form comprising a microencapsulated active ingredient embedded in a matrix which is palatable to a confectionery. Such a matrix may be chocolate. The use of nicotine as an effective ingredient is not suggested.

This document describes different tablet designs for delivering nicotine to the oral cavity and to the digestive system.

Wesnes and Warburton (Psychopharmacology 1984; 82: 147; same 1986; 89: 55) discuss the use of nicotine tablets comprising dextrose and magnesium hydroxide. The subject requires that the tablet be held in the mouth for several minutes before swallowing, in order to maximise contact with the oral mucosa.

Several products based on the above patents are now available on the international market. Additionally, several nicotine lozenges are available in the UK as over-the-counter products, such as UK Resolution lozenges, manufactured by Phoenix Pharmaceuticals, distributed by Ernest Jackson, containing 0.5mg nicotine and the antioxidant vitamins A, C and E; stoppers lozenge, distributed by Charwell Pharmaceuticals ltd, containing 0.5mg nicotine with several flavors, chocolate, sweet orange and pepper-mint.

However, the subject may desire a higher dose of nicotine than is acceptable in those prior art applications. Because of unsatisfactory nicotine absorption, the subject may not experience a reduction in other withdrawal symptoms. Furthermore, it has been difficult to administer nicotine in a manner that mimics the blood concentration of nicotine consistent with smoking so far as to satisfy the craving for nicotine by people attempting to quit smoking, and it has therefore been possible, based on prior knowledge, to provide a protection that is more resistant to relapse than nicotine replacement therapy. Therefore, nicotine absorption in mimicking the use of tobacco products, in particular smoking, is not satisfactory when using products currently used on the market and products used in nicotine replacement therapy disclosed in the prior art. Smoking cessation by chewing gum nicotine replacement therapy achieves a peak nicotine concentration in the blood after 30 minutes, with the nicotine concentration in the venous blood being about 1/3 to 2/3 of the concentration at smoking (British Medical Journal 1976; 1: 1043). Smokers typically reach their highest nicotine concentration in their blood 5-10 minutes after starting their smoking. Accordingly, there is a need to provide an improved composition and method that avoids the disadvantages of these conventional nicotine administration devices and methods, while providing an effective method of administering nicotine for smoking cessation, reducing craving for nicotine, and for treating other conditions resulting from nicotine therapy.

In order to solve the above problems, WO00/30641 provides a nicotine-containing composition which is suitable for oral ingestion. Disclosed herein is a composition comprising nicotine, at least one non-polar ingredient, at least one polar ingredient, and at least one surface active ingredient. Many non-polar components may be used, including lipids such as cocoa butter and cocoa butter substitutes, including Cocoa Butter Equivalents (CBE), Cocoa Butter Substitutes (CBS), cocoa butter substitutes (CBR), and Cocoa Butter Improvers (CBI). In summary, the composition of WO00/30641 has the disadvantage of insufficient taste masking of nicotine and buffering agents, which makes some users feel nausea. WO00/30641 does not disclose chocolate as an ingredient.

It has now been surprisingly found that by using a nicotine-containing formulation with chocolate as excipient, nicotine can be rapidly absorbed orally while sufficiently masking unpleasant taste components such as buffering agents and nicotine. To date, no similar formulation has been disclosed.

Chocolate has never been used as an excipient for human medicine, although pharmaceutical laxative products like chocolate exist. There are also veterinary products of the chocolate type, for example chocolate-based laxatives, Ex-Lax  supplied by Novartis, which contain sennosides, formulated with chocolate-like excipients. Purex, marketed in the fifties, is a laxative in which phenolphthalein is formulated with chocolate. The Stoppers lozenge as described above does not include chocolate, only chocolate taste. Such chocolate taste is not useful for the purposes of the present invention. It does not disclose the use of chocolate as a nicotine excipient.

Summary of The Invention

The present invention provides a composition for therapeutic administration of nicotine. The compositions comprise nicotine and provide rapid transmucosal absorption of nicotine. The composition is preferably used for therapeutic administration of nicotine.

"disintegration" in the present description and claims means melting, dissolving, eroding or a combined effect of these physical changes.

Unless otherwise expressly stated, terms such as "comprising," "including," "having," "carrying," and the like, when used herein, are not to be construed as limited to the stated elements only, but are to be construed as including any elements which may be present in whole, in semi-divided or in aggregate, and are intended to implicitly include any stated integer or step or group of integers or steps, rather than to exclude any other integer or step or group of integers or steps.

It is an object of the present invention to provide new nicotine pharmaceutical compositions for oral absorption, in particular to provide such compositions comprising a high amount of chocolate. In this application "oral" refers to absorption through the oral cavity or through other mucous membranes in the oral cavity.

It is a second object of the invention to provide a process for preparing said composition.

A third object of the invention is the use of said formulation in Nicotine Replacement Therapy (NRT) including tobacco replacement and smoking cessation.

Other objects of the present invention will become apparent to those skilled in the art from a reading of the following specification and claims.

Detailed description of the invention

The main object of the present invention is to provide a cigarette supplement or a tobacco substitute for smoking cessation and nicotine replacement therapy that provides the user with a satisfactory nicotine dosage to reduce the symptoms of cigarette withdrawal without causing unacceptable side effects. More specifically, it is an object of the present invention to provide such a nicotine-containing tablet for transmucosal, preferably oral, administration, which disintegrates and/or melts at body temperature, with or without the aid of saliva or mechanical abrasion, or a combination thereof, the formulation preferably exhibiting viscosity to tissues in the oral cavity.

The nicotine may be present in any suitable form, for example as a free base, salt or complex. It is not necessary to use nicotine in microencapsulated form.

The preferred formulation is an intraorally meltable tablet weighing about 400mg and having the following preferred composition:

1)

1-6mg of nicotine (in the form of a base or bitartrate), measured in the form of a base,

the amount of sodium carbonate was about 15mg,

dark chocolate in sufficient quantity

Or

2)

1-6mg of nicotine (in the form of a base or bitartrate), measured in the form of a base,

the amount of sodium carbonate was about 15mg,

white chocolate in sufficient quantity

3)

1-6mg of nicotine (in the form of a base or bitartrate), measured in the form of a base,

the amount of sodium carbonate was about 15mg,

milk chocolate in sufficient quantity

Chocolate is defined according to Industrial Chocolate Manufacture and Use, S.T. Beckett, ed., 2 conclusion, Black academy & Professional, London, 1994, p.382 from ground cocoa beans, cocoa butter, with or without added cocoa butter, with a minimum of 35% dry cocoa powder dry matter content, at least 14% dry non-fat cocoa powder solids and 18% cocoa butter. Chocolate has two main distinctive features: its aroma and its structure. The first feature of the structure is that chocolate must be solid at 20-25℃ and rapidly melt in the mouth at 37℃ and convert to a liquid, presenting a smooth appearance to the tongue. Chocolate processing is related to meeting these two criteria (p 2, supra). In the present invention, the higher the dry cocoa solids content of the chocolate, the better the taste masking effect of the chocolate. Chocolate can also be defined according to different national directives, such as European council directive 2000/36/EC on 23/6/2000, old council directive 73/241/EEC on 24/7/1973 (abolished on 3/8/2003), and US directive 21 CFR CH1 (version 4-1-00), part 163 cocoa products.

Example 1: preparation of the preferred embodiment

A tablet weighing about 400mg having the following preferred composition (w/w):

the effective components are as follows: 1-6mg of nicotine (in the form of a base or bitartrate), which, measured in the form of a base, may also be present in the form of a complex, e.g. with a cation exchange resin or a cyclodextrin;

buffering agent: sodium carbonate about 15 mg;

excipient: sufficient amount of chocolate;

prepared in the following way:

a portion of the chocolate is melted. The solid components, i.e. nicotine and sodium carbonate if in salt form, are added and mixed. The particle size of the solid component is reduced by milling in a roller refiner. If the solid component has reached the desired particle size, for example by grinding prior to mixing with chocolate, roller conching may be omitted. After treatment in the roll refiner, the mixture is mixed with the rest of the melted chocolate, or remelted (if solidified) and mixed with the rest of the melted chocolate. Chocolate can be used in the form of a raw material. Chocolate may also be prepared with the products of the embodiments. The mixing of the melt is carried out in a suitable mixer. The liquid component, i.e. nicotine in the form of a liquid base, is added. When chocolate is used as a raw material, it includes a certain percentage of lecithin (typically about 0.3%). If necessary after suitable pre-treatment, tablets or other solid dosage forms are then prepared using suitable techniques, such as molding, extrusion or agglomeration, including tableting. Other suitable processing methods may also be used.

Example 2: other embodiments

Useful embodiments are obtained by exchanging the above excipients with some functionally equivalent replacement compound.

For example, the buffer sodium carbonate may be exchanged for sodium, potassium or ammonium carbonate, bicarbonate, phosphate, glycinate, acetate, gluconate or glycerophosphate, or mixtures thereof. Most phosphates are unsuitable, however, because their taste is often unpleasant and difficult to mask.

A preferred embodiment is disclosed in example 1. In summary, useful embodiments can be obtained using formulation components in each unit dose within the following concentration ranges:

the effective components are as follows: nicotine (in the form of a base or a salt, preferably bitartrate) from about 0.5mg to about 10mg, measured as a base,

buffering agent: from about 5mg to about 40mg,

excipient: chocolate in sufficient quantity

Optionally, flavoring agents such as mint, coffee, orange, vanilla and butterscotch may be added.

The composition comprising nicotine may be administered with a second agent for nicotine replacement therapy.

The second formulation may be a device for transdermal administration of nicotine, a nasal spray, buccal or pulmonary absorption, a chewing gum, or a dosage form for oral or peroral use, or any device for administration of cigarettes.

The invention may also be used for cessation, reduction and temporary withdrawal of cigarettes, and for the treatment of alzheimer's disease, parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or weight management therapy.

Claims (14)

1. A nicotine-containing pharmaceutical composition, characterized in that it comprises chocolate as an excipient.

2. A nicotine-containing pharmaceutical composition according to claim 1, characterised in that it further comprises one or more buffering agents.

3. A nicotine-containing pharmaceutical composition according to claim 2, characterised in that the one or more buffering agents are selected from the group consisting of carbonates, bicarbonates, phosphates, glycinates, acetates, gluconates or glycerophosphates of sodium, potassium or ammonium salts, or mixtures thereof.

4. A pharmaceutical composition comprising nicotine according to any of the preceding claims, characterised in that it further comprises one or more flavouring agents, such as mint, coffee, orange, vanilla and butterscotch.

5. A nicotine-containing pharmaceutical composition according to any of the preceding claims, characterised in that its unit dose comprises nicotine: from about 0.5mg to about 10mg, measured as the base; buffering agent: about 5mg to about 40 mg; chocolate excipient: in sufficient quantity.

6. A nicotine-containing pharmaceutical composition according to claim 5, characterised in that its unit dose comprises 1-6mg nicotine measured in base form, about 95% (w/w) chocolate, and about 15mg sodium carbonate.

7. A nicotine-containing pharmaceutical composition according to any of the preceding claims formulated as an oral dosage form provided in the form of administration of nicotine mainly through the oral mucosa.

8. Use of a nicotine-containing pharmaceutical composition according to any of the preceding claims in the manufacture of a medicament for Nicotine Replacement (NRT), cigarette cessation, reduction and temporary withdrawal, and for the treatment of alzheimer's disease. Parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or weight management of the drug in therapy.

9. For Nicotine Replacement Therapy (NRT), cigarette disruption, reduction and temporary withdrawal, and for the treatment of alzheimer's disease, parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or weight management therapy, wherein the composition of any one of claims 1-7 is administered to a human in need of such treatment.

10. For Nicotine Replacement Therapy (NRT), cigarette disruption, reduction and temporary withdrawal, and for the treatment of alzheimer's disease, parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or weight management therapy, wherein a composition according to any one of claims 1-7 is administered to a person in need of such treatment, as well as for Nicotine Replacement Therapy (NRT), cigarette discontinuation, reduction and temporary withdrawal, and for the treatment of alzheimer's disease, parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or a second formulation of weight management therapy.

11. Use according to claim 10 for Nicotine Replacement Therapy (NRT), interruption, reduction and temporary withdrawal of cigarettes, and for the treatment of alzheimer's disease, parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or a method of weight management therapy, wherein said second formulation is a device for transdermal administration of nicotine, for nasal spray, oral or pulmonary absorption, a chewing gum, or a dosage form for oral or peroral use, or any device for administration of cigarettes.

12. For the treatment of cigarette dependence, cigarette disruption, reduction and temporary withdrawal, and for the treatment of alzheimer's disease, parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or weight management therapy, wherein the composition of any one of claims 1-7 is administered to a human in need of such treatment.

13. For the treatment of cigarette dependence, cigarette disruption, reduction and temporary withdrawal, and for the treatment of alzheimer's disease, parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or a method of weight management therapy, wherein a composition according to any one of claims 1-7 and a second formulation for nicotine replacement therapy are administered to a person in need of such therapy.

14. Use according to claim 13 for the treatment of cigarette dependence, cigarette interruptions, reductions and temporary withdrawal, and for the treatment of alzheimer's disease, parkinson's disease, ulcerative colitis and/or tourette's syndrome; and/or a method of weight management therapy, wherein the second formulation is a device for transdermal administration of nicotine.