NICOTINE-CONTAINING CHEWING GUM COMPOSITIONS

Abstract

The present invention relates to nicotine-containing chewing gum compositions and the method of preparing the same. The present invention provides improved and stable nicotine-containing chewing gum compositions for use in nicotine replacement therapy, which provide rapid nicotine release in the oral cavity and effectively satisfy the craving that most smokers experience.

Claims

1. A stable chewing gum for use in nicotine replacement therapy comprising: a buffered gum core, and at least one coating surrounding the core, wherein a buffering agent is present only in an extragranular region of the core and wherein the coating is not a film-coating.

2. A chewing gum according to claim 1, wherein the core comprises: a granular region comprising a compressible chewing gum base that is suitable for tabletting at ambient temperature and at least one nicotine active; and an extragranular region comprising one or more buffering agents.

3. A stable chewing gum for use in nicotine replacement therapy comprising: a core having a granular region comprising a compressible chewing gum base that is suitable for tabletting at ambient temperature and at least one nicotine active; and an extragranular region comprising one or more buffering agents; an inner coating layer comprising at least one polyol; and an outer flavored coating present on top of the inner coating layer and surrounding the core.

4. A chewing gum according to claim 2, which is characterized by comprising the at least one nicotine active in an amount corresponding to from 0.1 to 10 mg of nicotine free base.

5. A chewing gum according to claim 2, wherein the nicotine active is selected from the group consisting of pharmaceutically acceptable salts of nicotine and pharmaceutically acceptable, cellulose-free, nicotine complexes and resins.

6. A chewing gum according to claim 2, wherein the nicotine active is nicotine polacrilex.

7. A chewing gum according to claim 1, wherein the buffering agent is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, alkali metal citrates or alkali metal phosphates, or any mixture thereof.

8. A chewing gum according to claim 1, wherein the coating comprises a polyol selected from the group consisting of maltitol, sorbitol, mannitol, xylitol, erythritol, lactitol, isomalt or any mixture thereof.

9. A chewing gum according to claim 1, wherein the chewing gum further comprises at least one or more additives selected from the group consisting of stabilizers, preservatives, antioxidants, softeners, thickening agents, emulsifiers, glidants, lubricants, sweeteners, gelling agents, enhancers, coloring agents, vitamins, minerals, fluorine and tooth whitening agents and mixtures thereof.

10. A method for preparation of a stable chewing gum for use in nicotine replacement therapy, wherein the method comprises of the steps of: dispersing a nicotine active in a liquid flavoring agent; adsorbing the dispersed nicotine active on a gum base; blending the nicotine active adsorbed gum base with one or more pharmaceutically acceptable excipients to generate a uniform free-flowing mass; and granulating and compressing the uniform free-flowing mass to form one or more tablets.

11. A chewing gum according to claim 2, wherein at least one of the granular region or the extragranular region further comprises one or more pharmaceutically acceptable ingredients.

12. A chewing gum according to claim 3, wherein at least one of the granular region or the extragranular region further comprises one or more pharmaceutically acceptable ingredients.

13. A chewing gum according to claim 3, which is characterized by comprising the at least one nicotine active in an amount corresponding to from 0.1 to 10 mg of nicotine free base.

14. A chewing gum according to claim 3, wherein the nicotine active is selected from the group consisting of pharmaceutically acceptable salts of nicotine and pharmaceutically acceptable, cellulose-free, nicotine complexes and resins.

15. A chewing gum according to claim 3, wherein the nicotine active is nicotine polacrilex.

16. A chewing gum according to claim 3, wherein the buffering agent is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, alkali metal citrates or alkali metal phosphates, or any mixture thereof.

17. A chewing gum according to claim 3, wherein the inner coating layer comprises a polyol selected from the group consisting of maltitol, sorbitol, mannitol, xylitol, erythritol, lactitol, isomalt or any mixture thereof.

18. A chewing gum according to claim 3, wherein the chewing gum further comprises at least one or more additives selected from the group consisting of stabilizers, preservatives, antioxidants, softeners, thickening agents, emulsifiers, glidants, lubricants, sweeteners, gelling agents, enhancers, coloring agents, vitamins, minerals, fluorine and tooth whitening agents and mixtures thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention relates to stable nicotine-containing chewing gum compositions and the method of preparing the same.

[0027] The present invention provides stable nicotine-containing chewing gum products comprising at least one buffered gum core and at least one coating layer, wherein said buffering agent in the core is restricted to the extragranular region.

[0028] The present inventors have found out that the contact between nicotine active and buffering agent potentially jeopardizes the stability of the composition; and by minimizing the same the present invention provides a new and improved product with better stability and release profile.

[0029] Further, the buffer in the core ensures that during chewing of the core of the gum product, the suitable buffer agent or substance produces an increase in pH of the saliva which results in an increase in the transmucosal uptake of nicotine in the oral cavity. Also, since the trans-mucosal uptake of nicotine in the oral cavity according to the invention is faster, less nicotine will be swallowed to reach the gastrointestinal (G.I.) tract. The nicotine that reaches the G.I. tract will be subjected to first pass metabolism which reduces the total amount of intact nicotine absorbed.

[0030] As used herein, the term stable means that the formulation has an acceptable pharmaceutical shelf life of at least 12 months, preferably at least 24 months, when stored at 25 degree C. and at a relative humidity of 60% in a conventional pharmaceutical packaging. Thus in one embodiment of the invention, the chewing gums are chemically and physically stable and have a shelf life of at least 12 months, preferably at least 24 months, when stored at 25 degree C. and at a relative humidity of 60%.

[0031] As used herein, the term nicotine or nicotine active includes pharmaceutically acceptable salts of nicotine, e.g. nicotine bitartrate, nicotine hydrochloride, nicotine dihydrochloride or nicotine sulfate, in particular nicotine bitartrate; and pharmaceutically acceptable nicotine complexes and resins, e.g. nicotine polacrilex.

[0032] Typically, the nicotine chewing gums of the present invention comprise the nicotine active in an amount equivalent to 0.1 to 10 mg, preferably 0.5 to 5 mg of nicotine free base.

[0033] Not only the amount of the nicotine released from the different parts of the chewing gum product is of value as known in the art, but also, according to the present invention the specific transmucosal uptake from the oral cavity of the nicotine to the systemic circulation of the subject is to a great extent governed by the one or more buffering agents, which account for the provision of a suitable adjustment of the pH of the liquid of the oral cavity.

[0034] Suitable buffers are selected from, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, alkali metal citrates or alkali metal phosphates, or any mixture thereof. Preferably, it is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, potassium citrate or dipotassium phosphate, or any mixture thereof. More preferably, the buffering agent is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium citrate and dipotassium phosphate, or any mixture thereof. Especially, it is sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, or any mixture thereof.

[0035] An embodiment of the buffering agent is characterized by using two different buffering agents in the composition of the chewing gum, e.g. a mixture of an alkali metal bicarbonate with an alkali metal carbonate, such as a mixture of sodium bicarbonate and sodium carbonate.

[0036] The dissolution of the one or more buffering agents in the extragranular region of the core provides for optimized adjustment of the pH of the liquid in the oral cavity. Said buffering of the core generates a coated chewing gum product giving improved absorption kinetics of nicotine compared to in the art known chewing gum products.

[0037] In order to increase the buffering capacity still further without correspondingly increasing the pH, one may in specific embodiments use a second or auxiliary buffering agent to the first buffering agent, such as e.g., sodium or potassium bicarbonate buffers. The second or auxiliary buffering agent may be selected from the group consisting of alkali metal bicarbonates that are preferred for this purpose. Thus, further embodiments of the invention may comprise a mixture of an alkali metal carbonate or phosphate and alkali metal bicarbonate.

[0038] The amount of the buffering agent or agents in the chewing gum composition is preferably sufficient in the specific embodiments to raise the pH of the saliva to above 7, as specified above, to transiently maintain the pH of the saliva in the oral cavity above 7, e.g., pH 7-11.

[0039] The present invention provides stable nicotine-containing chewing gum products comprising at least one buffered gum core and one or more coating layers surrounding the core, wherein none of the coating layers is a film-coat.

[0040] The present inventors have also found that the coating layers surrounding the gum core are critical to the efficient release of nicotine from the composition and its rapid transmucosal uptake in the oral cavity of the subject. Thus, another feature of the present invention is the judicious selection and application of the various types of coating layers surrounding the gum core, whereby chewing gum compositions free of a film-coat is designed. As a result a superior cost-effective chewing gum product is obtained that provide a high rate of release of nicotine from the chewing gum and an environment in the oral mucosa that enhance buccal absorption of nicotine.

[0041] Moreover, the presence of a coating increases the stability of the chewing gum by hampering access of water and oxygen to the uncoated chewing gum core. Typically, polyol coatings come into consideration, of which the sugar free coating formulations are preferred.

[0042] Thus, in one embodiment, the chewing gums of the invention are coated with a coating that comprises at least one polyol, preferably and surprisingly xylitol. Typically, the amount of coating is approximately 5-50%, preferably 10-30%, of the uncoated chewing gum. Typically, a sugar free coating mixture comprises a polyol (e.g. maltitol, sorbitol, mannitol, xylitol, erythritol, lactitol or isomalt) a binder, be it, e.g., (a) a gum (e.g. arabic gum, tragacanth gum, guar gum, acacia gum, xanthan gum, alginic acid, salts of alginic acid e.g. sodium alginate, gellan gum, glucomannan gum, carrageenan gum, karaya gum, locust bean gum or tara gum, in particular arabic gum) or (b) a protein-type binder such as gelatin; and optionally flavors, dyes, and traces of any polishing agents used (especially talc and/or Carnauba wax).

[0043] In a preferred embodiment of the invention, the chewing gums of the present invention are coated with a coating that comprises a polyol as defined above, in particular xylitol, and a gum as defined above, in particular xanthum gum. Typically, the polyol is present in an amount of 70-95%, especially 80-90%, of the total coating mass. Typically, the gum is present in an amount of 0.05-5%, especially 0.1-1%, of the total coating mass.

[0044] The chewing gums of the present invention further comprise of at least one flavored coating. These coatings allow for addition of a large percentage of flavors thereby aiding in prolonging the flavoring sensation.

[0045] The flavoring agents may comprise one or more synthetic or natural flavouring or aromatizing agents.

[0046] Flavoring agents may be selected from essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit comprising mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavour of the fruit, e.g., strawberry, raspberry and black currant; artificial and natural flavours of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder, flour, or vegetable material parts including tobacco plant parts, e.g., genus Nicotiana, in amounts not contributing significantly to the level of nicotine, and ginger.

[0047] In a typical embodiment, the chewing gums of the present invention are coated with a flavored coating that further comprises a binder preferably selected from, but not limited to, the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, pullulan, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, gelatin, zein, gluten, soy protein isolate, whey protein-isolate, casein and mixtures thereof.

[0048] In a preferred embodiment of the invention, the chewing gums of the present invention are coated with a flavored coating that comprises a flavoring agent as defined above, in particular mint flavor; and a binder as defined above, in particular hypromellose. Typically, the binder is present in an amount of 0.5-10%, especially 3-5%, of the total coating mass.

[0049] The chewing gums of the present composition may further comprise an outer hard coating over the flavored coating whereby the objectionable taste of the API or of other excipient in the flavored coating which directly affects the oral mucosa is avoided.

[0050] The chewing gums of the present composition may further comprise an outer glow coating over the flavored coating or outer hard coating.

[0051] Further, the coating layers of the chewing gums of the present invention typically do not include any nicotine active and buffering agents.

[0052] The present invention provides stable nicotine-containing chewing gum products comprising at least one buffered gum core and one or more coating layers surrounding the core, wherein said buffer in the core is restricted to the extragranular region and wherein none of the coating layers is a film-coat.

[0053] In a preferred embodiment of the invention, the chewing gums of the present invention comprise a core comprising gum base, nicotine active, buffering agents and other pharmaceutically acceptable excipients. The said core further comprises a granular and an extragranular region; and the said buffering agents are typically restricted to the extragranular region. The said gum core is further coated with polyol coat, followed by a flavored coat and an outer glow coat.

[0054] When the nicotine active and the buffering agent or agents are incorporated in the chewing gum mass in accordance with the present invention, it is possible to employ a wide variety of chewing gum compositions and amounts of the chewing gum base.

[0055] The amount of gum base in the chewing gum according to the invention is about 15-85% by weight of the total gum core. The amount of gum base employed for the most desirable slow release of nicotine is usually in the higher ranges when nicotine is employed per se or when an absorbed form is used.

[0056] The gum base may be of any conventional nature known in the art. For example it may comprise a gum base of natural or synthetic origin readily available from a commercial source. Natural gum bases include e.g. chicle, jelutong-, lechi de caspi-, soh-, siak-, katiau-, sorwa-, balata-, pendare-, malaya-, and peach gums, natural cautchouc and natural resins such as dammar and mastix. Synthetic gum bases are a mixture of: elastomers (polymers, masticating substances), plasticizer (resin, elastomers, solvent, hydrophobic resin), filler (texturizer, water-insoluble adjuvant), softener (fat), emulsifier, wax, antioxidant, and anti-tacking agents (vinyl polymer, hydrophilic resin). Other examples of gum bases are gums including agar, alginate, arabic gum, carob gum, carrageenan, ghatti gum, guar gum, karaya gum, pectin, tragacanth gum, locust beam gum, gellan gum and xanthan gum.

[0057] Other additives may be added optionally to the chewing gum core and/or to coating layers in the chewing gum.

[0058] Optional additives comprise at least one or more additive selected from the group consisting of stabilizers, preservatives, e.g., antioxidants; softeners, thickening agents, emulsifiers, glidants, lubricants, sweeteners, gelling agents, enhancers, coloring agents, vitamins, minerals, fluorine and tooth whitening agents and mixtures thereof. According to the invention, at least one of such additives is optionally added to the product.

[0059] Examples of gelling agents comprise gum arabic, starch, gelatine, agar, and pectin.

[0060] Enhancers are added essentially to improve, i.e., increase, the transmucosal uptake from the oral cavity.

[0061] Sweeteners are added essentially to improve the taste.

[0062] Sweeteners comprise one or more synthetic or natural sugars, i.e., any form of carbohydrates suitable for use as sweetener, as well as so called artificial sweeteners such as saccarin, sodium saccarin, aspartame, e.g., NutraSweet, acesulfame K or acesulfame, potassium acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, stevside.

[0063] Suitable sweeteners may be selected from the group consisting of sugar alcohols, such as sorbitol, xylitol, single sugars including sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called leavulose), and lactose (also called milk sugar); sorbitol, mannitol, glycerol, xylitol, maltitol syrup (or hydrogenated starch hydrolyzate), isomalt, lactitol; and mixtures of sugars including glucose syrup, e.g., starch hydrolysates, containing a mixture of dextrose, maltose and a range of complex sugars, invert sugar syrup, e.g., sucrose inverted by invertase (also called sucrase or sacchrase) containing a mixture of dextrose and fructose, high sugar content syrups such as treacle and honey containing a mixture of particular leavulose, dextrose, maltose, lactitole, sucrose, resins, dextrin and higher sugars; and malt or malt extracts.

[0064] Colouring additives may be selected from dyes being approved as a food additive.

[0065] Stabilizing additives may be selected from the group consisting of antioxidants including vitamin E, i.e., to copherole, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid and edetate salts; and preservatives including citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid. Preferred embodiments comprise an antioxidant as the stabiliser, and even more preferably the antioxidant vitamin E and/or butylated hydroxytoluene (BHT).

[0066] Different chewing gum products may be composed depending on the consumers preference and the purpose of use, in respect of the nicotine level, nicotine distribution and other additives.

[0067] The present invention further provides nicotine chewing gums that can be manufactured by tabletting techniques, and thus, do not require the specific (e.g. melt extrusion) equipment necessary in the manufacture of conventional chewing gums.

[0068] The term tabletting on the one hand includes, preferably, conventional tabletting techniques but also, on the other hand, any sophisticated ones. They all have in common the application of force, i.e. the compression of the mixture of all components of the chewing gum.

[0069] Coated chewing gum products according to the invention can be maintained in several production steps depending on the total number of cores and the total number of coated layers to be included.

[0070] A typical method for the production of the coated chewing gum according to the invention is disclosed. The method comprises the steps of

a) providing a nicotine containing chewing gum core that is buffered,
b) providing at least one coating layer, and
c) coating the buffered chewing gum core with the at least one coating layer.

[0071] In a typical embodiment of the invention, the core composition may be formed simply by mixing, rolling and scoring or compression of the chewing gum base with the nicotine-active, e.g., the nicotine-ion exchanger complex, or the nicotine as a free base or a salt. Before adding any solid component, except for the gum base, it is desirable to grind and size the solid component first, to ensure good distribution.

[0072] In one of the preferred embodiments of the present invention, the nicotine containing chewing gum was prepared by the following steps: [0073] a) The nicotine active is dispersed in liquid flavoring agent; [0074] b) The dispersion obtained in step a) is then adsorbed on gum base; [0075] c) The nicotine active adsorbed gum base obtained step b) are then blended with other pharmaceutically acceptable excipients to get a uniform free-flowing mass; [0076] d) The blend obtained in step c) is then granulated and compressed to form tablets.

[0077] Chewing gums produced by compression, i.e., tabletted gums are made out of a special gum base. Such a gum base gives a rapid hydration of the cud in the mouth. High velocity mixers can be used for granulation to give correctly sized particles of the mixture. This mixture is then compressed in a tablet machine.

[0078] According to the method disclosed in the invention the coating of the buffered chewing gum core with at least one layer of the at least one coating comprises the steps of:

[0079] a) press coating, and/or

[0080] b) polyol coating, and/or

[0081] c) spray coating, and/or

[0082] c) melt coating.

[0083] The present invention, as described herein, provides an advantageous method of dosing active ingredients into a large amount of chewing gum composition, which facilitates an exact dosing of the active ingredients in a series of tablets. This means that large-scale production of chewing gum tablets comprising pharmaceutically active ingredients is made possible with improved results concerning distribution of the active ingredients in the tablets and thereby an improved uniformity in content of active ingredient in a series of chewing gum tablets.

[0084] The product may then be analyzed and further wrapped. The analysis of nicotine uptake and effect according to the invention may be done according to standard procedure known in the art, e.g., using a bioanalysis for the determination of nicotine or its metabolites in the plasma of a subject.

[0085] Further, in another embodiment, the present invention provides efficient and effective chewing gum compositions for use in nicotine replacement therapy, which provide rapid nicotine release in the oral cavity and fastbut non-toxic, pharmaceutically acceptable buccal absorption of nicotine, and which is characterized by comprising a compressible chewing gum base that allows the chewing gum to be manufactured by tableting at least one nicotine active and at least one buffering agent.

[0086] Fastbut non-toxic, pharmaceutically acceptablebuccal absorption of nicotine typically is further characterized by high in-vivo truly delivered total doses of nicotine in the mouth of a patient over a time period of 30 minutes, e.g. by a delivery of at least 80%preferably at least 90% and more preferably at least 95%of the original amount of nicotine in the gum over 30 min.

[0087] Preferably, rapid nicotine release is characterized by an in vitro release of at least 60% in 5 minutes (250 chews), of at least 75% (more preferably at least 85%) in 10 minutes (500 chews) and more than 90% in 30 minutes (1500 chews) of the nicotine assay value.

[0088] The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.

[0089] The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.

EXAMPLES

Example: Chewing Gum Composition of Nicotine Polacrilex

[0090] I) Preparation of Buffered Gum Core:

TABLE-US-00001 Component % w/w Nicotine polacrilex 20% 0.69 Gum Base 76.0 Sodium carbonate anhydrous 1.02 Sodium hydrogen carbonate 0.51 Silica, colloidal hydrated 1.67 Magnesium stearate 1.67 Mint flavor 0.83 Acesulfame potassium 0.45

Procedure:

[0091] a) Nicotine polacrilex is dispersed in the mint flavor manually, and adsorbed to a part of the gum base, [0092] b) Colloidal silica is added to the mixer in step a) and kneaded for sufficient time at suitable speed to form granules, [0093] c) The remaining ingredients, except magnesium stearate, are mixed with the remaining part of the gum base, [0094] d) The extragranular mass obtained in step c) is then blended with the API adsorbed granules of step (b), [0095] e) The blend obtained in step d) is then lubricated and compressed.

[0096] II) Preparation of Sub Coat:

TABLE-US-00002 Component % w/w Xylitol 10.5 Xanthum gum 0.06 Talc 0.20 dye 0.30 Purified water

Procedure:

[0097] f) Xanthum gum is dissolved in required quantity of purified water under continuous stirring to get a clear viscous solution, [0098] g) Xylitol, talc and the dye are added to the solution of step f) and stirred continuously.

[0099] III) Preparation of Flavored Coat:

TABLE-US-00003 Component % w/w Mint flavor 0.75 Xylitol 2.75 Hypromellose 0.67 Talc 0.03 Dye 0.1 Purified water

Procedure:

[0100] h) Hypromellose is dissolved in required quantity of purified water under continuous stirring to get a clear viscous solution, [0101] i) The remaining ingredients are added to the solution of step h) one at a time and stirred continuously.

[0102] IV) Preparation of Coated Chewing Gum: [0103] j) The API containing gum cores obtained in step e) are transferred to a coating pan and the coating dispersion obtained in step g) was sprayed on to the cores, and the coated cores were dried. [0104] k) The coating dispersion obtained in step i) was sprayed on to the polyol coated gum cores obtained in step j). [0105] l) The coated gum cores of step k) were then coated with a solution Insta glow in purified water.