Classifications

• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
  • A23G4/00—Chewing gum
  • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23B—PRESERVING, e.g. BY CANNING, MEAT, FISH, EGGS, FRUIT, VEGETABLES, EDIBLE SEEDS; CHEMICAL RIPENING OF FRUIT OR VEGETABLES; THE PRESERVED, RIPENED, OR CANNED PRODUCTS
  • A23B4/00—General methods for preserving meat, sausages, fish or fish products
  • A23B4/10—Coating with a protective layer; Compositions or apparatus therefor
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
  • A23G4/00—Chewing gum
  • A23G4/02—Apparatus specially adapted for manufacture or treatment of chewing gum
  • A23G4/04—Apparatus specially adapted for manufacture or treatment of chewing gum for moulding or shaping
  • A23G4/043—Apparatus specially adapted for manufacture or treatment of chewing gum for moulding or shaping for composite chewing gum
  • A23G4/046—Apparatus specially adapted for manufacture or treatment of chewing gum for moulding or shaping for composite chewing gum with a centre made of chewing gum
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
  • A23G4/00—Chewing gum
  • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
  • A23G4/12—Chewing gum characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
  • A23G4/126—Chewing gum characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins containing vitamins, antibiotics
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
  • A23G4/00—Chewing gum
  • A23G4/18—Chewing gum characterised by shape, structure or physical form, e.g. aerated products
  • A23G4/20—Composite products, e.g. centre-filled, multi-layer, laminated
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/465—Nicotine; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
  • A61K9/0058—Chewing gums
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/34—Tobacco-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to a coated chewing gum product for delivering nicotine to a subject. Also contemplated is a method and a system for delivering nicotine as well as use and production of said coated chewing gum product
• Nicotine is an organic compound and is the principal alkaloid of tobacco. Nicotine is the chief addictive ingredient in the tobacco used in cigarettes, cigars, snuff and the like. Nicotine is also an addictive drug, though, and smokers characteristically display a strong tendency to relapse after having successfully stopped smoking for a time. Nicotine is the worlds second most used drug, after caffeine from coffee and tea.
• the administration of nicotine can give satisfaction and the usual method is by smoking, either by smoking e.g., a cigarette, a cigar or a pipe.
• smoking has health hazards and it is therefore desirable to formulate an alternative way of administering nicotine in a pleasurable manner that can be used to facilitate withdrawal from smoking and/or used as a replacement for smoking.
• Nicotine is an addictive poisonous alkaloid C 5 H 4 NC 4 H 7 NCH 3 , derived from the tobacco plant. Nicotine is also used as an insecticide. Approximately forty milligrams of nicotine is able to kill an adult (Merck Index).
• Nicotine containing formulations are currently the dominating treatments for tobacco dependence.
• Nicotine-containing nose drops have been reported (Russell et al., British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al., Brit. J. of Addiction, Vol. 82, p. 983 (1987)). Nose drops, however, are difficult to administer and are not convenient for use at work or in other public situations. Ways of administrating nicotine by way of delivering directly into the nasal cavity by spraying is known from U.S. Pat. No. 4,579,858, German Patent No. 32 41 437 and International Publication No. WO/9312764. There may, though, be local nasal irritation with use of nasal nicotine formulations. The difficulty in administration also results in unpredictability of the dose of nicotine administered.
• inhaling devices resembling a cigarette are known for uptake of nicotine vapours as suggested in U.S. Pat. No. 5,167,242. Said means and methods address the problems associated with addiction to nicotine.
• Nicorette® One successful product that is used as a smoking substitute and/or as a smoking cessation aid and which is based on nicotine, is the chewing gum Nicorette®.
• This product was one of the first nicotine replacement forms that was approved by the Food and Drug Administration (FDA) and is still one of the most used nicotine replacement products.
• Nicorette® chewing gum has been on the market in about 60 countries for several years. In this chewing gum the nicotine is present in the form of a complex with an insoluble cation-exchanger (polacrilex) that is dispersed in a gum base. The nicotine is slowly released from the gum due to chewing and will reach similar plasma levels as when smoking a cigarette after about 30 minutes depending on the chewing technique, i.e., slow or active.
• Patents related to this product are, e.g., the U.S. Pat. Nos. 3,877,468, 3,901,248 and 3,845,217.
• WO 98/23165 discloses a chewing gum wherein nicotine may be in the coating. This concept may provide rapid release of the nicotine from the coated chewing gum, but not a sufficiently rapid buccal uptake of the nicotine. The fraction of the released nicotine that is not immediately absorbed will be flushed down in the gastrointestinal (G.I.) tracts by the saliva, thereby possibly causing hiccups and other G.I. side effects. Once absorbed by the G.I. route this swallowed nicotine will be subjected to first pass metabolism.
• G.I. gastrointestinal
• WO 00/13662 discloses a chewing gum for systemic, oral administration of an active whereby said active is administered by the chewing gum composition in a bi-phasic manner.
• the bi-phasic delivery is obtained by the gum matrix as such, not from any coating.
• WO 00/19977 discloses a substantially moisture free and possibly coated chewing gum for delivery of an active. The possible coating is not said to be buffered.
• the present invention provides a new and improved product, systems and methods for obtaining a rapid transmucosal uptake of nicotine in the oral cavity of the subject.
• An object of the present invention is to provide an efficient and effective product, as well as methods and systems for a rapid uptake of nicotine in a subject to avoid the disadvantages of such previously known products and methods.
• the present invention provides a method for delivering nicotine in any form to a subject comprising administering to a subject said coated chewing gum product containing nicotine in any form into the oral cavity of the subject and allowing the nicotine in any form in the coated chewing gum product to be released in the saliva in the oral cavity and absorbed into the systemic circulation of the subject as well as a method for producing said coated chewing gum.
• the present invention also provides a method for obtaining reduction of the urge to smoke or use tobacco containing material and/or for providing a sense of smoking satisfaction without smoking, comprising the steps of replacing at least partly the tobacco containing material with above said coated chewing gum product, administering to a subject a coated chewing gum product containing nicotine in any form into the oral cavity of the subject and allowing the nicotine in any form of the coated chewing gum product to be released in the saliva in the oral cavity and absorbed by the subject.
• the present invention provides a system for delivering nicotine in any form to a subject, comprising said coated chewing gum product and at least one other means for obtaining reduction of the urge to smoke or use of tobacco as well as a system for obtaining reduction of the urge to smoke or otherwise use of tobacco and/or for providing a sense of smoking satisfaction without smoking, comprising a coated chewing gum product according to above and at least one other method for obtaining reduction of the urge to smoke or otherwise use of tobacco.
• Said system may be a system wherein the at least other method is selected from the group consisting of administration through mouth sprays, nasal sprays, transdermal patches, inhaling devices, lozenges, tablets and parenteral methods, subcutaneous methods, intravenous methods, rectal methods, vaginal methods and transmucousal methods; or otherwise use of tobacco.
• the present invention relates to a coated chewing gum product comprising at least one chewing gum core, nicotine in any form and/or a nicotine mimicking agent, at least one coating layer and optionally at least one or more other additive, wherein said at least one coating layer is buffered.
• Said product may further comprise at least one core being buffered and further may also the nicotine in any form be a part of the at least one coating layer or at least one of the at least one coating layers.
• the at least one coating is buffered, according to the invention, in such a way that upon administration of the gum the pH of the saliva is increased by 0.3-4 pH units, or preferably increased by 0.5-2 pH units.
• Said product is buffered by the use of a buffer selected from the group consisting of a carbonate, including bicarbonate or sesquicarbonate, glycinate, phosphate, glycerophosphate or citrate of an alkali metal, such as potassium and sodium, e.g., trisodium and tripotassium citrate, or ammonium, and mixtures thereof.
• a buffer selected from the group consisting of a carbonate, including bicarbonate or sesquicarbonate, glycinate, phosphate, glycerophosphate or citrate of an alkali metal, such as potassium and sodium, e.g., trisodium and tripotassium citrate, or ammonium, and mixtures thereof.
• Use of said product will according to the invention rapidly deliver nicotine in any form to a subject and will also be used for obtaining a quick and/or sustained and/or complete reduction of the urge to smoke or use tobacco and/or for providing a sense of smoking satisfaction without smoking resembling the sense of smoking satisfaction and reduction of the urge to smoke obtained after regular smoking or use of tobacco.
• chewing gum product intends to mean all chewable gum products.
• fast reduction of the urge to smoke or use tobacco is herein intended to mean an initial priming of the subject so as to achieve a reduction of the urge to smoke or use tobacco.
• sustained is herein intended to mean prolonged over time.
• controlled release is intended to mean a release of a substance from a gum by the aid of active chewing of the gum in the oral cavity of the subject, whereby the active chewing is controlling the amount of substance released.
• slow release is intended to mean that the nicotine is released from the gum upon, e.g., chewing, over a period of time e.g., several minutes to an hour.
• unit formula is intended to mean one chewing gum product.
• transient is intended to mean a non-permanent change, upon which the relevant state, e.g., biological or physiological state, after a certain period of time will return to its value or behaviour prior to said change.
• the present invention relates to a coated chewing gum product for improving the absorption of nicotine in a subject, and wherein the absorption is quicker than by using current means and methods known in the art of nicotine chewing gums.
• Such a rapid transmucosal uptake of the nicotine in the oral cavity is expected to give more of a cigarette like sense of satisfaction and a more rapid reduction of the urge to smoke and use tobacco.
• a coated chewing gum product is used for improving the absorption of said nicotine.
• the coated chewing gum product comprises at least one chewing gum core, nicotine in any form and/or a nicotine mimicking agent, at least one coating layer and at least one other additive, wherein at least one of said coating layer is buffered.
• the at least one core may be buffered in different embodiments.
• the core may be buffered with the same or different ways of buffering as the at least one coating layer.
• Said buffering of the at least one coating layer and optionally the at least one core generates a coated chewing gum product giving improved absorption kinetics of nicotine compared to in the art known chewing gum products.
• the chewing gum product may be a medicated chewing gum.
• Medicated chewing gums are herein intended to mean solid or semi-solid, single-dose preparations with a base consisting mainly of gum that are intended to be chewed but not swallowed, where the chewing gums act as a drug delivery system. They contain one or more active substances, which are released by chewing. After dissolution or dispersion of the active substance in the saliva, such chewing gums are used for i) local treatment of mouth diseases and ii) systemic delivery after absorption through transmucosal uptake throughout the oral cavity.
• the coated chewing gum product is buffered. This may be achieved by including physiologically acceptable buffering substances or agents, or by other means. With other means it is intended to include buffering by any component in the product, which may not normally act as a buffering agent, such as a self-buffering additive or gum base.
• At least one coating layer is buffered.
• also the at least one core is buffered.
• the at least one coating layer is buffered in such a way that upon administration of the gum the pH of the saliva is increased 0.3-4 pH units, preferably 0.5-2 pH units.
• the buffering is designed so as to achieve a transient buffering of the saliva of a subject during melting, disintegration or dissolution of the coating layer or layers. As the change is transient, the pH will return to its normal value after a certain period of time.
• the at least one core may be buffered. This may allow said change in the pH to be ensured during chewing of the core of the gum product, where the chewing allows the suitable buffer agent or substance or other means to produce a transient change in the pH of the saliva, e.g., an increase in the pH.
• the transmucosal uptake of nicotine in the oral cavity is changed, e.g., increased compared to the nicotine uptake when the saliva is not buffered according to the invention.
• the transmucosal uptake of nicotine in the oral cavity according to the invention is faster than for nicotine not being buffered according to the invention, 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. This means that the bio-availability of nicotine that is not co-administered with a buffer according to the invention will generally be lower than when administered together with a buffer.
• Further embodiments of the invention includes combinations wherein the at least one coating layer is buffered by the use of a buffer selected from the group consisting of a carbonate including bicarbonate or sesquicarbonate, glycinate, phosphate, glycerophosphate or citrate of an alkali metal, such as potassium or sodium, or ammonium, and mixtures thereof.
• a buffer selected from the group consisting of a carbonate including bicarbonate or sesquicarbonate, glycinate, phosphate, glycerophosphate or citrate of an alkali metal, such as potassium or sodium, or ammonium, and mixtures thereof.
• Further embodiments may use trisodium or tripotassium citrate, and mixtures thereof.
• Still further embodiments may use different phosphate systems, such as trisodium phosphate, disodium hydrogen phosphate; and tripotassium phosphate, dipotassium hydrogen phosphate, and calcium hydroxide, sodium glycinate; and mixtures thereof.
• phosphate systems such as trisodium phosphate, disodium hydrogen phosphate; and tripotassium phosphate, dipotassium hydrogen phosphate, and calcium hydroxide, sodium glycinate; and mixtures thereof.
• Alkali metal carbonates, glycinates and phosphates are preferred buffering agents.
• the one or more buffering agents may to some extent be microencapsulated or otherwise coated as granules with polymers and/or lipids being less soluble in saliva than is the one or more buffering agents. Such microencapsulation controls the dissolution rate whereby is extended the time frame of the buffering effect.
• 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.
• further embodiments of the invention may comprise a mixture of an alkali metal carbonate or phosphate and alkali metal bicarbonate.
• 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.
• the nicotine may be administered in different forms, e.g., in different complexes or salts.
• the amount of buffer required to achieve such an increase in pH of the different administered nicotine form is readily calculated by the skilled man in the art. The extent and duration of the increase in pH is dependent on type and amount of the buffering agent(s) used as well as where, i.e., in the at least one coating layer and optionally in the at least one core, the buffer is distributed in the product and is further described within the paragraphs below.
• the process of coating a chewing gum is well known in the art.
• the present invention provides a coating, to facilitate the uptake of administered nicotine in any form to the subject.
• Known intentions of coating a chewing gum product may be to add crispiness, enhance taste, or to protect the gum, e.g., during storage, or as to tone down bad or irritating taste of the gum product.
• the chewing gum is a coated chewing gum comprising at least one coating layer.
• the different embodiments according to the invention may use sugar coating, film coating, press/compression coating or melt coating.
• the coating procedure may be manual or the coating may be sprayed onto the gum core/pellet in rotating pans of different shapes or fluidised beds in combination with evaporation of the solvent, e.g., water or organic solvent.
• the solvent e.g., water or organic solvent.
• Sugar coating is a multistep process and may be divided into the following steps: 1. sealing of the cores; 2. subcoating; 3. smoothing, or glossing; 4. colouring; 5. polishing; and 6. optionally printing
• Sugar coated cores have a smoother profile with less visible edges remaining from the original core.
• Sub-coating e.g., either by dusting with powder on the sucrose solution or application of dry powder in the sucrose solution, may be used.
• the core may be sugar coated by a panning technique, e.g., using a sugar coating pan, or other more sophisticated techniques capable of some degree of automation.
• the sugar in a sugar coating may not be just sucrose. Also other types of sugar may do as well, e.g., sugar alcohols (polyalcohol, polyol).
• the sugar used in the sugar coating may according to specific embodiments also be an artificial sweetener, being low or substantially free of calories and less caries promoting than regular sugar, or a combination with sugar and/or sugar alcohol.
• Film coating involves the deposition, usually by a spray method, of a thin film of polymer surrounding the core.
• the solution may be sprayed on to a rotated, mixed bed.
• the drying conditions permit the removal of the solvent so as to leave a thin deposition of coating material around each core.
• composition of the coating solutions and suspensions may differ during different parts of the process.
• Press coating involves the compaction of granular material around an already manufactured core. Using press/compression coating, a further core is pressed on the outside of the initial core/cores.
• Example 1-4 describes four different coatings and coating compositions that may be used according to the invention, i.e., sugar coating in example 1, film coating in example 2, press coating in example 3 and melt coating in example 4, all onto a chewing gum core.
• the coating is buffered in each case and contains nicotine as well.
• the coatings in example 1-4 may be combined with different cores. Examples of cores are given in Example 5 and further described below.
• NHT nicotine hydrogen tartrate
• buffer are suitably separated from each other in the coating by keeping them in separate layers, especially when sugar coating is used.
• a moisture barrier between the NHT-containing layer and the coating comprising the buffer may be applied to prevent interaction between the acid salt NHT and the buffer during the coating process. Suitable moisture barriers are e.g.
• ethylcellulose or a combination of ethylcellulose and hydroxypropyl methylcellulose (HPMC) and/or plasticizer from an organic solvent or solvent mixture aqueous ethylcellulose dispersion such as Aquacoat EDC (FMC Corp.) or Surelease (Colorcon) preferably in combination with plasticizer, Sepifilm LP 007 or LP 010 (Seppic)—based mainly on HPMC and stearic acid—, Opadry AMB or High Performance Opadry II (Colorcon)—based mainly on polyvinylalcohol—, and polymethacrylates as Eudragit L30 D-55 or EPO (Röhm).
• the moisture barrier preferably accounts for a weight of around 0.3% to around 5% of the total weight of the coating.
• An additive may be added to the coating or the core/s. Additives are further described in the paragraph entitled “Other additives to the chewing gum”.
• the amount of gum base in the coated chewing gum according to the invention is about 15-80% by weight of the total gum core, and preferably at least about 40%.
• 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.
• the gum base may be of any conventional nature known in the art.
• 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:
• plasticizer resin, elastomers, solvent, hydrophobic resin
• filler texturizer, water-insoluble adjuvant
• anti-tacking agents vinyl polymer, hydrophilic resin.
• gum bases include agar, alginate, arabic gum, carob gum, carrageenan, ghatti gum, guar gum, karaya gum, pectin, tragacanth gum, locust beam gum, gellan gum and xanthan gum.
• gelling agents comprise gum arabic, starch, gelatine, agar, and pectin.
• the nicotine in any form 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. 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.
• the chewing gum product comprises nicotine in any form and/or a nicotine mimicking agent.
• the nicotine is part of the at least one coating layer or at least one of the at least one coating layers.
• the nicotine is a part of the chewing gum core or at least one of the chewing gum cores.
• the nicotine is part of the at least one coating layer or at least one of the at least one coating layers and the chewing gum core or at least one of the chewing gum cores to give a fast transmucosal uptake of the nicotine in the oral cavity of a subject so as to obtain a rapid kick or reduction of the urge to smoke and/or use tobacco. Thereby may also be achieved a systemic maintenance level of nicotine.
• the nicotine should be in a saliva soluble form to facilitate the release of the agent into the saliva in the oral cavity and, further, the subsequent uptake of the nicotine from the saliva in the oral cavity into the systemic circulation of the subject.
• the nicotine in any form is selected from the group consisting of a nicotine salt, the free base form of nicotine, a nicotine derivative, such as a nicotine cation exchanger, a nicotine inclusion complex or nicotine in any non-covalent binding; nicotine bound to zeolites; nicotine bound to cellulose or starch microspheres; and mixtures thereof.
• the inclusion complex may be a cyclodextrin, such as ⁇ -cyclodextrin.
• the cation exchanger may be a polyacrylate.
• the nicotine salt may be a tartrate, hydrogen tartrate, citrate or malate.
• the uptake of the nicotine through any tissue or mucosa in the oral cavity i.e., the absorption kinetics
• the uptake obtained by known chewing gum products for nicotine uptake is improved in relation to the uptake obtained by known chewing gum products for nicotine uptake.
• the nicotine may act as a stimulant to e.g., obtain a rapid reduction of the urge to smoke or to use tobacco.
• nicotine it is intended to include nicotine, 3-(1-methyl-2-pyrrolidinyl)-pyridine, with its base form, including synthetic nicotine as well as nicotine extracts from tobacco plants, or parts thereof, such as the genus Nicotiana alone or in combination; or pharmaceutically acceptable salts.
• the most preferable embodiment incorporates nicotine as the free base form or as a water-soluble pharmaceutically acceptable salt, either per se or adsorbed on a adsorbent, or as a complex with a cation exchanger or mixtures of the foregoing, as an inclusion complex, such as a cyclodextrin complex, e.g., ⁇ -cyclodextrin, but any other suitable pharmaceutically acceptable form may also be employed.
• a cyclodextrin complex e.g., ⁇ -cyclodextrin, but any other suitable pharmaceutically acceptable form may also be employed.
• the product according to the invention may also comprise a nicotine mimicking agent.
• a nicotine mimicking agent may be any suitable agent with an acrid burning taste.
• nicotine mimicking agents with an acrid burning taste are capsaicin, piperine and zingerone.
• additives may be added to the coating or the core/s. Additives are further described in the paragraph entitled “Other additives to the chewing gum”.
• the nicotine in any form is according to the invention formulated to provide the subject with a dose to achieve an effect.
• the effect may be to provide a sense of smoking satisfaction without smoking.
• Another effect of the administered nicotine in any form may be a reduction of the urge to smoke or use tobacco.
• the effect may also be a combination of reduction of said urge and providing a sense of smoking satisfaction without smoking.
• the amount of the nicotine should be sufficient to provide such an effect in a subject. This amount may, of course, vary from person to person.
• embodiments of the chewable gum product comprise embodiments wherein nicotine in any form is present in an amount of 0.05-10 mg calculated as the free base form of nicotine per piece coated chewing gum product.
• This may in different embodiments include 0.05, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg calculated as the free base form of nicotine per piece coated chewing gum product.
• Still preferred embodiments may contain embodiments where the nicotine in any form is present in an amount of 0.5-6 mg calculated as the free base form of nicotine per piece coated chewing gum product.
• Even more preferred embodiments contain the nicotine in any form in an amount of 0.5-4 mg calculated as the free base form of nicotine per piece coated chewing gum product.
• the nicotine in any form is part of the at least one coating layer or at least one of the at least one coating layer.
• the nicotine in any form may be in an amount of 0-10 mg calculated as free base form in at least one of the at least one coating layer. Still further embodiments comprise nicotine in an amount of 0.2-6 mg in at least one of the at least one coating layers, or even more preferably, in an amount of 0.5-5 mg in at least one of the at least one coating layer.
• the nicotine in any form may be distributed in the core and/or different coating layers in different embodiments. Different distributions of the nicotine throughout the coated chewing gum will imply administration of the nicotine to the subject in different ways. This may, then, provide several possibilities to adjust the composition of the coated chewing gum according to different needs of different subjects depending on the urge to smoke or use tobacco of the subject.
• t max i.e., the time-point where the nicotine has its maximum level measured in the plasma of venous blood, after a single dose at about 30 minutes after administration.
• the t max is initially preceded by a lag period of a couple of minutes where no nicotine can be detected in the blood. Then, the plasma level is gradually increasing till the t max is reached.
• the time point for reaching a sense of satisfaction or reduction of urge to smoke or use tobacco after the initial lag period is individual, but may in existing chewing gums generally be reached after approximately 30 minutes when regarded as coinciding with t max . According to the present invention, such a sense of satisfaction may be reached after a shorter period of time due to a rapid initial burst dose of nicotine in the coating followed by a rapid transmucosal uptake in the oral cavity due to the buffered coating.
• the release of the nicotine in the coated chewing gum according to the invention proceeds in at least one step.
• the nicotine is, as in preferred embodiments, in a defined amount, such as the amounts described above according to different embodiments, in at least one of the at least one coating layers defined above the release of the nicotine takes place when the coating of the coated chewing gum is allowed to melt, disintegrate or dissolve to uncover the chewable gum core in said product.
• the nicotine and forms thereof is released from the coating into the saliva in the oral cavity during the time period when the coating is allowed to melt, disintegrate or dissolve.
• the at least one coating layer is allowed to melt, disintegrate or dissolute a chewable gum is uncovered.
• the nicotine in any form may then further be released to the subject.
• the nicotine in any form from the chewable gum is released by controlled release, e.g., by chewing the gum core whereby the chewing is controlling the amount of released nicotine from the gum core.
• the release of the nicotine is thereby sustained over a period of time. This period of time may be, in different embodiments about 10, 20, 30, 40, 50, or 60 minutes.
• the dissolution of the one or more buffering agents in the coating, and optionally in the core(s), provides for optimized adjustment of the pH of the liquid in the oral cavity.
• the release may be varied by the incorporation of the nicotine in any form in a given quantity into the coating layers and/or the gum core.
• Suitable cat ion exchangers are given in table 2 and are further disclosed in U.S. Pat. No. 3,845,217, hereby included as a reference.
• Preferred are nicotine cation exchangers of polyacrylates, such as the Amberlite collection from Rohm & Haas in table 2. Examples of different salts are given in Table 1.
• TABLE 2 Representative cation exchangers Name Manufacturer Amberlite IRC 50 Rohm & Haas Amberlite IRP 64 Rohm & Haas Amberlite IRP 64M Rohm & Haas BIO-REX 70 BIO-RAD Lab.
• Duolite ES-63 Chemical Process Duolite ES-65 Chemical Process Ohelex 100 BIO-RAD Lab.
• Dow Chelating Resin A-1 Dow Chemical Company Purolite C115HMR Purolite International Ltd.
• CM Sephadex C-25 Pharmacia Fine Chemicals SE Sephadex C-25 Pharmacia Fine Chemicals
• 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 whereby the one or more buffering agents account for provision of a suitable adjustment of the pH of the liquid of the oral cavity.
• the uptake according to the invention is further discussed in the method paragraphs below.
• additives may be added optionally to the chewing gum core and/or to coating layers in the chewing gum.
• Optional additives comprise at least one or more additive selected from the group consisting of stabilisers, such as preservatives, e.g., antioxidants; softeners, thickening agents, emulsifiers, glidants, lubricants, sweeteners, flavours, aromatics, enhancers, colouring agents, vitamins, minerals, fluorine and tooth whitening agents and mixtures thereof.
• additives such as preservatives, e.g., antioxidants; softeners, thickening agents, emulsifiers, glidants, lubricants, sweeteners, flavours, aromatics, enhancers, colouring agents, vitamins, minerals, fluorine and tooth whitening agents and mixtures thereof.
• at least one of such additives is optionally added to the product.
• Enhancers are added essentially to improve, i.e., increase, the transmucosal uptake from the oral cavity.
• Sweeteners are added essentially to improve the taste.
• 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.
• 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.
• 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
• flavour and aroma additives may comprise one or more synthetic or natural flavouring or aromatizing agents.
• Flavour and aroma 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;
• Colouring additives may be selected from dyes being approved as a food additive.
• Stabilizing additives may be selected from the group consisting of antioxidants including vitamin E, i.e., tocopherole, 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).
• a method for delivering nicotine in any form to a subject comprises the steps of
• the transmucosal uptake of the nicotine in the oral cavity is more rapid than with presently known chewing gum not being buffered in the coating.
• One embodiment results in a t max of nicotine in venous blood of the subject after about 5-20 minutes.
• said nicotine in any form is absorbed resulting in a t max of nicotine in venous blood of the subject after about 3-15 minutes.
• the method for delivering nicotine in any form may further comprise the steps of
• Such a time period may be at least 10, 20, 30, 40, 50 or 60 minutes.
• a method for obtaining reduction of the urge to smoke or use tobacco containing material and/or for providing a sense of smoking satisfaction without smoking comprises the steps of
• said nicotine in any form results in a t max of nicotine in venous blood of the subject after about 5-20 minutes.
• the absorbing of said nicotine released from the at least one coating layer is resulting in a t max of nicotine in venous blood of the subject after about 3-15 minutes.
• the method according to the invention further comprises the steps of administering the nicotine in any form in a sustained way over a period of time to the subject.
• the period of time may be at least 10, 20, 30, 40, 50 or 60 minutes.
• Yet further embodiments of the method for delivering nicotine to a subject may comprise the steps of combining at least one other method for obtaining reduction of the urge to smoke or use of tobacco.
• Tobacco containing material may be material used for e.g., smoking, snuffing or chewing and may comprise a cigarette, a cigarr, snuff, pipe tobacco and also chewing tobacco.
• the coated chewing gum product may be used for obtaining a quick and/or sustained and/or complete reduction of the urge to smoke or use of tobacco and/or for providing a sense of smoking satisfaction without smoking as further discussed below.
• the fast relief provides the subject with a sense of rapid smoking satisfaction without smoking. Such a satisfaction will decrease the craving more rapidly than other known nicotine chewing gum products.
• the quick craving relief is obtained when a dosage of nicotine is released from at least one of the at least one coating layers of the coated chewing gum in embodiments wherein nicotine is in the coating layers in the presence of one or more buffering agents in the coating and optionally in the core(s).
• This provides the subject with an initial rapid transmucosal uptake of nicotine in the oral cavity that will induce an initial peak, a maximum, in the blood plasma nicotine levels after a certain time, t max .
• the result will be that the subject gets a feeling or sense of satisfaction and the initial craving will disappear.
• One embodiment reduces the urge to smoke or use of tobacco by reaching a t max of nicotine in venous blood of the subject after about 5-20 minutes by the use of a coated chewing gum according to the invention.
• Still one embodiment reduces the urge to smoke or use of tobacco quickly resulting in a t max of nicotine in venous blood of the subject after about 3-15 minutes when said nicotine in any form is released from the at least one coating layer after use of a coated chewing gum according to the invention.
• a sustained craving relief may be obtained after the initial craving relief.
• a sustained craving relief is obtained by chewing the gum part, or core, of the coated chewing gum to allow a sustained uptake of the nicotine.
• the sustained craving relief and/or feeling or sense of satisfaction of the subject will continue as long as the subject maintains the blood plasma levels of nicotine at a level high enough to reach this sense of feeling.
• the subject may achieve this by chewing the gum part of the chewing gum over a period of time, such as 10, 20, 30, 40, 50, or even 60 minutes or longer, e.g., a slow release of the nicotine caused by a controlled release, e.g., by individual chewing.
• the method described above for obtaining craving relief may further comprise the steps of decreasing the amount of nicotine in the total coated chewing gum product described above gradually over time, so as to achieve a complete relief of tobacco craving. This method results in a weaning process gradually over time.
• Different types of smokers reach the sense of reduced craving at different plasma levels of nicotine. This may, of course, affect the individual types of administration programs of a coated chewing gum according to the invention.
• Different types of smokers include e.g., peak seekers or smokers that crave for a plasma level of nicotine constantly being above the level for withdrawal symptoms.
• One strategy may be to lower the frequency of the administered coated chewing gums.
• Other embodiments include varying the dose of the nicotine in said gums as well as the combination of these two.
• the strategy may include a coated chewing gum with substantially no nicotine in any form. Such a gum may be administered at the end of the treatment period, when the craving is low or substantially absent.
• a system for delivering nicotine in any form to a subject comprises a coated chewing gum according to the invention and at least one other means for obtaining reduction of the urge to smoke.
• Another system according to the invention may also be a system for obtaining reduction of the urge to smoke or use of tobacco and/or for providing a sense of smoking satisfaction without smoking.
• a system comprises a coated chewing gum product according to the invention and at least one other method for obtaining reduction of the urge to smoke or use tobacco.
• Other methods may also be a concomitant or concurrent method selected from the group consisting of administration through mouth sprays, nasal sprays, transdermal patches, inhaling devices, lozenges, tablets and parenteral methods, subcutaneous methods, intravenous methods, rectal methods, vaginal methods and transmucosal methods; or use of tobacco.
• the at least other method comprises administration of nicotine.
• the use of the coated chewing gum product according to the invention is for obtaining a fast and/or sustained and/or complete reduction of the urge to smoke and use tobacco or for providing a sense of smoking without smoking as described above.
• the dose of the nicotine is chosen to give the subject an individual sensory perception and satisfaction with an effect of the nicotine in any form.
• the use of the coated chewing gum product may also be a sole use according to the invention or a combination with other means or methods known in the field of drug abuse. Specifically, the present invention may be used in combination with other means as described above in the methods in the paragraphs above.
• the use may give a quick reduction of the urge to smoke or use tobacco obtained reaching a t max of nicotine in venous blood after e.g., about 5-20 minutes.
• the use of the coated chewing gum according to the invention will reduce the urge to smoke or use tobacco by reaching a t max , of nicotine in venous blood of the subject after about 3-15 minutes when said nicotine in any form is released from the at least one coating layer.
• a use of a coated chewing gum product according to the invention is also disclosed for delivering nicotine in any form to a subject.
• the delivering of nicotine in any form results in a t max of nicotine in venous blood of the subject after about 5-20 minutes.
• the delivering of nicotine in any form results in a t max of nicotine in venous blood of the subject after about 3-15 minutes when said nicotine in any form released from the at least one coating layer is absorbed.
• 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.
• the method comprises the steps of
• the method may in specific embodiments further comprise
• the nicotine is selected from the group consisting of a nicotine salt, the free base form of nicotine, a nicotine derivative, such as a nicotine cation exchanger, a nicotine inclusion complex or nicotine in any non-covalent binding; nicotine bound to zeolites; nicotine bound to cellulose or starch microspheres; and mixtures thereof.
• the at least one coating layer may in some embodiments be buffered by the use a buffer selected from the group consisting of a carbonate buffer, such as the carbonate, bicarbonate, sesquicarbonate of an alkali metal, e.g., potassium, sodium; or ammonium; sodium glycinate, alkali metal phosphate, sodium or potassium glycerophosphate, trisodium or tripotassium citrate, and mixtures thereof wherein the at least one coating layer is buffered in such a way that upon administration of the gum the pH of the saliva is increased by 0.3-4 pH units.
• the buffering may be transient.
• the at least one coating layer is buffered in such way that upon administration of the gum the pH of the saliva is increased by 0.5-2 pH units.
• the core/pellet composition may be formed simply by mixing, rolling and scoring or compression of the chewing gum base with at least one of the forms of nicotine, 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.
• the mixing is preferably conducted at a suitably elevated temperature depending on the viscosity of the gum core used. The increase in temperature decreases the viscosity of the gum and thereby enables the nicotine and other additives to be evenly and intimately distributed within the core/pellet of the chewing gum.
• Example 5 describes the mixing, rolling and scoring as well as the compression of gum cores. In principle, this procedure may be applied for coated chewing gum products up to at least 10 mg unit formula.
• the gum is extruded into a thick sheet, which is rolled by multiple sets of calender rolls to the correct thickness.
• the scoring rolls usually two sets, cut the gum into the correct size.
• the sheets are then transferred to a conditioned area on trays, where the sheets are cooled to make them brittle enough to be broken.
• the conditioned gum sheets are then passed through a breaker, which is a rotating drum that parts the sheets into separate pieces of gum along the scores.
• 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.
• the provision of the at least one chewing gum core in step a) above comprises the further steps of
• the provision of the chewing gum core in step a) is obtained by direct compressing of the ingredients.
• compositions of additives according to the invention are made simultaneously, according to known procedures in the art for formulating the buffers.
• the buffer system it may be convenient to add the buffer system/s either with the liquid part or with he solid part of the composition.
• buffering systems available as fine powders, it may, of course, be most convenient to add those powders with the solid, powdered part of other additives.
• the coating of the at least one chewing gum core with at least one layer of the at least one buffered coating comprises the steps of
• the product may then be analysed and further wrapped.
• the coated chewing gum product according to the invention may be used in therapy.
• Said therapy may be a treatment of a disease selected from the group consisting of Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerous colitis and post-smoking-cessation weight control.
• the nicotine may also be used for the production of a chewing gum product according to the invention for the treatment of a disease selected from the group consisting of Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerous colitis and post-smoking-cessation weight control.
• a disease selected from the group consisting of Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerous colitis and post-smoking-cessation weight control.
• a chewing gum product for the production of a nicotine containing chewing gum product according to the invention for the treatment of a disease selected from the group consisting of Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, and ulcerous colitis.
• 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 bioanalys for the determination of nicotine or its metabolites in the plasma of a subject.
• This example describes without limiting the invention a sugar coating, wherein the coating is buffered and wherein the nicotine is in the coating.
• the objective of this example is to provide a sugar coated chewing gum, wherein the coating is buffered and wherein the nicotine is in the coating.
• the nicotine is in the amount of 1, 2, 4 or 5 mg, respectively.
• This example describes without limiting the invention a film coated chewing gum, wherein the coating is buffered and wherein the nicotine is in the coating.
• the objective of this example is to provide a film coated chewing gum, wherein the coating is buffered and wherein the nicotine is in the coating.
• the nicotine is in the amount of 1, 2, 4 or 5 mg, respectively.
• This example describes without limiting the invention a press coated chewing gum, wherein the coating is buffered and wherein the nicotine is in the coating.
• the objective of this example is to provide a press coated chewing gum, wherein the coating is buffered and wherein the nicotine is in the coating.
• the nicotine is in the amount of 1, 2, 4 or 5 mg, respectively.
• NRC or NCC 2 mg unit 4 mg unit formula (mg) Component NRC NCC NRC NCC Xylitab 100 a 727 720 717 703 HPMC, 3cPs 238 238 238 Sodium carbonate 15 15 30 30
• NCC — 17.1 — 34.2 (corresponding to — 2 — 4 nicotine free base)
• This example describes without limiting the invention a melt coated chewing gum, wherein the coating is buffered and wherein the nicotine is in the coating.
• the objective of this example is to provide a melt coated chewing gum, wherein the coating is buffered and wherein the nicotine is in the coating.
• the nicotine is in the amount of 1, 2, 4 or 5 mg, respectively.
• NHT 1 mg unit 2 mg unit 4 mg unit 5 mg unit Component formula formula formula formula formula formula Hydrogenated 176 176 176 176 176 176 vegetable oil, type II, (Akopol E) Cocoa, alkalized 198 197 192 191 Aspartame 2.4 2.4 2.4 2.4 Sodium carbonate 15 20 30 40 Lecithin 4 4 4 4 Nicotine hydrogen 3.1 6.2 12.3 15.4 tartrate, (corresponding to 1 2 4 5 nicotine base, mg)
• the objective of this example is to provide a core suitable for a chewing gum product according to the invention.
• the nicotine is incorporated as the free base (NFB), nicotine ⁇ -cyclodextrin complex (NCC), nicotine hydrogen tartrate (NHT) or as a nicotine resin complex (NRC).
• the amount of nicotine in each fomula unit, i.e., per tablett core, is 1, 2, 4, or 6 mg.
• the core is formed by a mixing, rolling and scoring process or by a compression process.
• A. Manufactured by Tablet Compression Process 6 mg 4 mg 2 mg 1 mg unit formula unit formula unit formula unit formula (mg) (mg) (mg) (mg) Active ingredients Nicotine resin complex 20% 30 20 10 5 Other ingredients Chewing gum base for 500 500 500 500 compression a Xylitol 191 211 221 226 Sorbitol 100 100 100 100 100 100 100 100 Sodium carbonate anhydr. 40 30 20 10 Sodium bicarbonate — — 10 20 Magnesium stearate 15 15 15 15 15 Talcum 15 15 15 15 15 15 Magnesium oxide 5 5 5 5 5 Acesulfame K 2 2 2 2 Aspartame 2 2 2 2 2 2
• the sheets are then transferred to a conditioned area on trays, where the sheets are cooled to make them brittle enough to be broken.
• the conditioned gum sheets are then passed through a breaker, which is a rotating drum that parts the sheets into separate pieces of gum along the scores.
• Chewing gums produced by compression i.e., tabletted gums are made out of a special gum base.
• 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.

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