WO2009006892A1 - Gomme à mâcher médicamenteuse stable comprenant un antioxydant - Google Patents

Gomme à mâcher médicamenteuse stable comprenant un antioxydant Download PDF

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Publication number
WO2009006892A1
WO2009006892A1 PCT/DK2007/050093 DK2007050093W WO2009006892A1 WO 2009006892 A1 WO2009006892 A1 WO 2009006892A1 DK 2007050093 W DK2007050093 W DK 2007050093W WO 2009006892 A1 WO2009006892 A1 WO 2009006892A1
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Prior art keywords
chewing gum
antioxidant
compressed
gum
formula
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PCT/DK2007/050093
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English (en)
Inventor
Carsten Andersen
My Ly Lao
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Fertin Pharma A/S
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Priority to PCT/DK2007/050093 priority Critical patent/WO2009006892A1/fr
Publication of WO2009006892A1 publication Critical patent/WO2009006892A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention is directed to medicament-containing chewing gums.
  • the present invention is directed to chewing gums, which effectively stabilise compounds according to formula I contained therein and it is directed to methods for preparing such chewing gums.
  • R2 may be selected from the group consisting of a -CH 2 OH group, a -COOH group and a -CONH 2 group;
  • Ari and Ar 2 are independently an aromatic or heteroaromatic ring with 5 or 6 atoms in the ring, said heteroaromatic ring having 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said ring being unsubstituted or substituted with Ci -4 alkyl, preferably methyl or tertiary butyl, Ari and Ar 2 preferably being unsubstituted phenyl or phenyl substituted with Ci -4 alkyl, preferably methyl or tertiary butyl; and
  • Xi and X 2 may independently be selected from the group consisting of a hydrogen atom, a halogen atom, a straight-chain or branched Ci-C 4 alkoxy group or a trifluoromethyl group; as well as pharmaceutically acceptable salts, geometrical isomers, enantiomers, diastereomers and mixtures thereof.
  • Ci -4 -alkoxy is intended to mean Ci -4 -alkyl-oxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • cetirizine which in its dihydrochloride form marketed under the tradename Zyrtec ® , the (S)-enantiomer thereof, levocetirizine, in its dihydrochloride form marketed under the trade name Xyzal ® and efletirizine in its dihydrochloride form.
  • US 2005/0038039 discloses an oral pharmaceutical composition containing two separate formulations: a first formulation, which contains an active compound according to the above formula I and which first formulation does not contain polyols having a molecular weight of less than 300 g/mol in a molar ratio between the polyol and active compound of formula I above 10; and a second formulation, which contains one or more polyol(s) with a molecular weight of less than 3000 and which second formulation is free of any drug.
  • the present inventors realized that the stability loss of the active agent in medicated chewing gum could not be explained by reaction with polyols as suggested in the prior art. It was thus surprising when the inventors found that the loss of stability was due to an oxidation of compounds according to formula I caused by other chewing gum ingredients. Without being bound by theory, it is contemplated that the gum base plays a major role in the reduction of stability of compounds according to formula I in chewing gum.
  • an object of the present invention is to provide chewing gums containing one or more active compound(s) according to formula I wherein the stability of the compound(s) according to formula I is improved. It is furthermore an object of the invention to provide methods for producing the stable chewing gum containing the compound(s) according to formula I.
  • the present invention provides a chewing gum comprising one or more active compounds selected from 2-[4-(diphenylmethyl)-l-piperazine] derivatives having the general formula I:
  • R 2 may be selected from the group consisting of a -CH 2 OH group, a -COOH group and a -CONH 2 group;
  • Ari and Ar 2 are independently an aromatic or heteroaromatic ring with 5 or 6 atoms in the ring, said heteroaromatic ring having 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said ring being unsubstituted or substituted with Ci -4 alkyl, preferably methyl or tertiary butyl, Ari and Ar 2 preferably being unsubstituted phenyl or phenyl substituted with Ci -4 alkyl, preferably methyl or tertiary butyl; and
  • Xi and X 2 may independently be selected from the group consisting of a hydrogen atom, a halogen atom, a straight-chain or branched Ci-C 4 alkoxy group or a trifluoromethyl group; as well as pharmaceutically acceptable salts, geometrical isomers, enantiomers, diastereomers and mixtures thereof; an antioxidant and a gum base.
  • the invention relates to a method of preparing a chewing gum comprising one or more active compound(s) according to formula I, the method comprising the steps of: a) providing one or more active compound(s) according to formula I, a gum base, and an antioxidant; b) mixing the compound(s) according to formula I, the gum base and the antioxidant, and thus obtaining a mixture; and c) shaping the mixture to obtain the chewing gum.
  • the present invention provides a method of preparing a chewing gum comprising one or more active compound(s) according to formula I, the method comprising the steps of: a) providing one or more active compound(s) according to formula I and a gum base comprising an antioxidant; b) mixing the compound(s) according to formula I and the gum base, thus obtaining a mixture; and c) shaping the mixture to obtain the chewing gum.
  • the present invention provides a method of preparing a chewing gum comprising one or more active compound(s) according to formula I, the method comprising the steps of: a) providing a pre-mix comprising one or more active compound(s) according to formula I and an antioxidant; b) mixing the pre-mix with a gum base to obtain a mixture; and c) shaping the mixture to obtain the chewing gum.
  • a further aspect of the present invention provides a method of preparing a chewing gum comprising one compressed module, the method comprising the steps of: a) providing a portion comprising one or more active compound(s) according to formula I, a portion comprising an antioxidant, and chewing gum particles containing gum base; b) optionally providing one or more further chewing gum ingredients; c) dosing the portion comprising the compound(s) according to formula I, the portion comprising an antioxidant, and the chewing gum particles containing gum base, and optionally the one or more further chewing gum ingredients; and d) compressing a) and b) after dosing, to obtain a first compressed module.
  • a method of preparing a chewing gum comprising the steps of: a) providing a portion of powdered pre-mix comprising one or more active compound(s) according to formula I and an antioxidant; b) providing chewing gum particles containing gum base; and c) compressing a) and b) to obtain a chewing gum comprising a compressed module.
  • a method of preparing a chewing gum comprising two compressed modules, the method comprising the steps of: a) providing chewing gum particles containing gum base and a portion comprising an antioxidant, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising tablet material and a portion comprising one or more active compound(s) according to formula I; c) compressing a), to obtain a first compressed module; d) contacting the first compressed module with b); e) compressing b) and the first compressed module, to obtain a coherent compressed chewing gum comprising a first compressed module and a second compressed module.
  • a still further aspect relates to a method of preparing a chewing gum comprising three compressed modules, the method comprising the steps of: a) providing chewing gum particles containing gum base, a portion comprising an antioxidant, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising tablet material and a portion comprising one or more active compound(s) according to formula I; c) providing a further portion comprising tablet material and a portion comprising one or more active compound(s) according to formula I; and d) locating b) and c) on opposite sites of a) following a sequence of one or more compressing step(s), to obtain a coherent compressed chewing gum tablet comprising a first compressed module and a second compressed module and a third compressed module.
  • An even further aspect of the present invention relates to a method for improving the stability of one or more active compound(s) according to formula I in a chewing gum comprising : a) introducing an oxidation-inhibiting/reducing amount of an antioxidant to a chewing gum comprising one or more active compound(s) according to formula I and a gum base; b) mixing the antioxidant, the compound(s) according to formula I and the gum base to obtain a chewing gum mixture, and c) shaping the mixture to obtain the chewing gum; wherein the stability of the compound(s) according to formula I is improved by at least 10% when stored for 1 month at a temperature of 40 0 C and a humidity of 75% RH compared to a chewing gum not comprising an antioxidant stored under the same conditions.
  • Another aspect of the invention relates to the use of an antioxidant in the preparation of a medicated chewing gum comprising one or more active compound(s) according to formula I for improving the stability of said compound.
  • the present invention relates to the use according to claim 59, wherein the stability of said compound is improved by at least 10% when stored for 1 month at a temperature of 40 0 C and a humidity of 75% RH compared to a medicated chewing gum comprising one or more active compound(s) according to formula I not comprising an antioxidant stored under the same conditions.
  • a final aspect relates to the use of an oxidation-inhibiting/reducing amount of an antioxidant for the preparation of a chewing gum comprising one or more active compound(s) according to formula I, wherein at least 80 % of the initial amount of said compound is left after storage for 1 month at a temperature of 40 0 C and a humidity of 75% RH.
  • Figs. Ia-Ib illustrate a two-layer compressed tablet according to an embodiment of the invention
  • Figs. 2a-2b illustrate a three layer compressed tablet according to an embodiment of the invention
  • Figs. 3a-3b illustrate a further two layer compressed tablet according to an embodiment of the invention
  • Figs. 4a-4b illustrate a further two layer compressed tablet according to an embodiment of the invention
  • Figs. 5a-5b illustrate a further two layer compressed tablet according to an embodiment of the invention.
  • antioxidant is used in its traditional meaning and relates to any substance that reduces oxidative damage (damage due to oxygen) such as that caused by free radicals.
  • Free-radicals are unstable, highly reactive molecules (ions), which become chemically stable, free-radicals by snatching electrons from other molecules in the chewing gum, such as the active medicament, and thus causing an oxidative damage.
  • Antioxidants prevent such oxidative damage by donating electrons to free-radicals.
  • useful antioxidants may be natural or artificial, and may further be divided into lipophilic and hydrophilic antioxidants.
  • lipophilic antioxidants relates to antioxidants which are soluble in fats, oils and lipids but are not soluble in an aqueous medium
  • hydrophilic antioxidants relates to antioxidants which normally are soluble in an aqueous medium.
  • the term “gum base” refers in general to a commercially available gum base suitable for production of chewing gum. Such gum bases normally comprise one or more elastomeric compounds which may be of synthetic or natural origin, one or more resinous compounds which may be of synthetic or natural origin and softening compounds.
  • the term "gum base composition” as used herein may be a gum base as defined above comprising one or more ingredients (e.g. sweetener, flavour, colouring agents, fillers etc.) as described below.
  • a chewing gum composition is the final formulation, which constitutes at least a part of the chewing gum ready for sale or use by the consumer.
  • a chewing gum composition may comprise one or more active compound(s) according to formula I, an antioxidant, sweetener and/or flavour and optionally other ingredients like colouring agents, enzymes, humectants, flavour enhancers, anticaking agents etc.
  • compressed chewing gum tablets denote a ready for use chewing gum tablet, e.g. comprising compressed particles containing gum base possibly mixed with one or more active compound(s) according to formula I, an antioxidant, sweeteners, flavour or other ingredients and optionally coated.
  • a compressed chewing gum tablet is produced by an initial conventional mixing of the gum base with e.g. water-insoluble ingredients such as elastomers and resins, followed by a granulation or the like of the obtained gum base mix.
  • the obtained particles containing gum base may then be mixed with further chewing gum ingredients, such as one or more active compound(s) according to formula I, an antioxidant, sweeteners and flavours.
  • the final mix may then be compressed under high pressure (typically when applying cooling) into to a compressed chewing gum tablet or a compressed module.
  • the expression “chewing gum particles containing gum base” refers to particulated material of chewing gum composition and is to be understood as any form of chewing gum particles containing a certain amount of gum base, as described in detail below.
  • the chewing gum particles may be in any suitable form such as pellets, granules, agglomerates, powder. Thus, in some embodiments, the particles have been particulated prior to application.
  • Particulation may be in any form of "building up” particles from smaller primary particles into macro particles or in any form of "building down” from larger substances into macro particles. Any form of particulation may be applied, such as granulation, pelletizing, agglomeration, or any other suitable means for particulation, as described below. Thus, the particles may also to be understood as macroparticles.
  • the components of the chewing gum composition are described in detail below. More details regarding the composition of compressed chewing gum and methods of preparing it may be found in WO 2004/068964, WO 2004/004480, and WO 2004/004479. The contents of these three publications are incorporated herein by reference for all uses.
  • compressed chewing gum particles containing gum base refers to a portion of chewing gum particles which become compressed after mixed with e.g. one or more active compound(s) according to formula I, an antioxidant, sweeteners or flavours.
  • the present invention relates to a medicated chewing gum with an effective amount of one or more active compound(s) according to formula I, having a stability of the active medicament during production, storage and chewing which allows the chewing gum to be a suitable carrier for said medicament.
  • a stability of the active medicament during production, storage and chewing which allows the chewing gum to be a suitable carrier for said medicament.
  • an oxidation caused by chewing gum ingredients is the reason of the diminishing stability of the active medicament observed during production, storage and chewing, it was possible to provide a method for counteracting this instability.
  • this increased stability is achieved by incorporating an effective amount of an antioxidant in the chewing gum.
  • the present invention provides a chewing gum comprising one or more active compounds selected from 2-[4-(diphenylmethyl)-l-piperazine] derivatives having the general formula I:
  • R 2 may be selected from the group consisting of a -CH 2 OH group, a -COOH group and a -CONH 2 group;
  • Ari and Ar 2 are independently an aromatic or heteroaromatic ring with 5 or 6 atoms in the ring, said heteroaromatic ring having 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said ring being unsubstituted or substituted with Ci -4 alkyl, preferably methyl or tertiary butyl, Ari and Ar 2 preferably being unsubstituted phenyl or phenyl substituted with Ci -4 alkyl, preferably methyl or tertiary butyl; and
  • Xi and X 2 may independently be selected from the group consisting of a hydrogen atom, a halogen atom, a straight-chain or branched Ci-C 4 alkoxy group or a trifluoromethyl group; as well as pharmaceutically acceptable salts, geometrical isomers, enantiomers, diastereomers and mixtures thereof;
  • the active compound(s) according to formula I may be added at any time during the process of preparing the chewing gum. However, it is presently preferred that the active compounds are added to the chewing gum subsequent to any significant heating or mixing. In compressed chewing gums, the active compound(s) should preferably be added immediately prior to the compression of the final tablet. Referring to the process described below, the adding of active compounds may be cautiously blended with pre-mixed gum base particles and further desired ingredients, immediately prior to the final compression of the tablet.
  • the active compounds according to formula I are preferably orally active and selective histamine Hi-receptor antagonists.
  • the one or more active compound(s) according to formula I are so selected that Xi is a hydrogen atom, X 2 is a halogen atom, and Ri is -CH 2 CH 2 -O- CH 2 -COOH.
  • the active compound according to formula I is a salt, e.g. a dihydrochloride salt.
  • the active compound(s) according to formula I are selected from the group consisting of buclizine, cetirizine, chlorcyclizine, cinnarizine, cyclizine, hydroxyzine, levocetirizine, meclozine, efletirizine and oxatomide, as well as any pharmaceutically acceptable salts, geometrical isomers, enantiomers, diastereomers and mixtures thereof.
  • Useful active compounds according to formula I may be selected from the group consisting of cetirizine, the dihydrochloride salt of cetirizine, levocetirizine, the dihydrochloride salt of levocetirizine, efletirizine, and the dihydrochloride salt of efletirizine.
  • the active compound according to formula I is cetirizine, i.e. 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl] piperazin-1- yl]ethoxy]acetic acid having the following formula II:
  • the chewing gum comprises the compound(s) according to formula I, e.g. cetirizine or cetirizine dihydrochloride, in an amount in the range of 0.1 - 50 mg, preferably in the range of 1 - 30 mg, and even more preferably in the range of 5-25 mg.
  • antioxidants have occasionally been used in chewing gums the purpose of such an addition has been to protect chewing gum ingredients containing carbon—carbon double bonds, such as fats, oils, unsaturated elastomers and elastomer plasticizers, which are a subject to deterioration through oxidation during storage.
  • the presence of an antioxidant in a chewing gum comprising one or more active compound(s) according to the formula I results in an improved chemical stability of the active compound during production, storage and chewing compared to a compound according to formula I which is present in a chewing gum not comprising an antioxidant.
  • the chewing gum is one wherein the stability of the compound(s) according to formula I is improved by at least 10% by weight when stored for 1 month at a temperature of 40 0 C and a humidity of 75% RH compared to a chewing gum not comprising an antioxidant and stored under the same conditions.
  • the chewing gum is one wherein the stability of the compound(s) is improved by at least 20% by weight, such as at least 30%, including at least 40%, such as at least 50%, e.g. at least 60%, including at least 80% by weight when stored for 1 month at a temperature of 40 0 C and a humidity of 75% RH compared to a chewing gum not comprising an antioxidant and stored under the same conditions.
  • the chewing gum is one wherein at least 80% of the initial amount of the compound(s) according to formula I is left after storage for 1 month at a temperature of 40 0 C and a humidity of 75% RH.. In a particular interesting embodiment of the invention at least 85%, preferably at least 90%, most preferably at least 95%, most preferably 99% of the initial amount of the compound(s) according to formula I is left after storage for 1 month, for 2 months or even for 3 months at a temperature of 40 0 C and a humidity of 75% RH.
  • the chewing gum is one wherein the antioxidant comprises a lipophilic antioxidant.
  • a lipophilic antioxidant may in accordance with the invention be selected from the group consisting of buthylhydroxytoluen (BHT), butylhydroxyanisol (BHA), tocopherols including alpha, beta, gamma and delta (dl-alfa) tocopherols, tert-butylhydroxyquinone (TBHQ), alkylgallates (e.g. propylgallate), betacarotene, vitamin A, ascorbylpalmitate, ascorbylstearate, phospholipids, and mixtures thereof.
  • BHT buthylhydroxytoluen
  • BHA butylhydroxyanisol
  • TBHQ tert-butylhydroxyquinone
  • alkylgallates e.g. propylgallate
  • betacarotene vitamin A
  • ascorbylpalmitate ascorbylstearate
  • phospholipids and mixtures thereof
  • the lipophilic antioxidant is buthylhydroxytoluen (BHT) or butylhydroxyanisol (BHA), or a mixture thereof.
  • the chewing gum according to the invention is one wherein the antioxidant comprises two or more lipophilic antioxidants.
  • the antioxidant comprises two or more lipophilic antioxidants.
  • examples of such combinations of lipophilic antioxidants are a mixture of buthylhydroxytoluen (BHT) and butylhydroxyanisol (BHA) and optionally propyl gallate, a mixture of tocopherols and phospholipids, and a mixture of ascorbyl palmitate and alpha tocopherol.
  • the antioxidant both comprises a hydrophilic and a lipophilic antioxidant.
  • a hydrophilic antioxidant citric acid and the lipophilic antioxidant TBHQ.
  • the chewing gum is one wherein the antioxidant comprises a hydrophilic antioxidant.
  • a hydrophilic antioxidant may be selected from the group consisting of citric acid, tartaric acid, glycine, ascorbic acid (vitamin C), sodium ascorbate (vitamin C), calcium ascorbate (vitamin C), salts of sulphur dioxide, including those derived from bisulphite, metabisulphite and sulphite (e.g. sodium sulfite, sodium metabisulphite, potassium-metabisulfit), fumaric acid, malic acid, propionic acid, tartaric acid, phosphoric acid and salts thereof, monothioglycerol, and mixtures thereof.
  • antioxidants useful in the methods of the present invention are selected from the group consisting of spices or extracts like clove, oregano, sage, vanilla, ginger, mace, pepper, rosemary, and mixture thereof.
  • One advantage of the present invention is that the antioxidant can be located at different places in the chewing gum and in relation to the compound(s) according to formula I. As shown in the below examples, this is achieved by several different methods, resulting in different types of chewing gums, but all with an effective amount of antioxidant. This leaves the chewing gum industry with a high flexibility in the production of different kinds of medicated chewing gum, without compromising the stability of the active compound.
  • Gum base plays a major role in the reduction of the stability of the compound(s) according to formula I in the chewing gum.
  • Gum base is produced through a blend of raw materials which can be categorized in different classes such as elastomers, resins, softeners, emulsifiers, fats, waxes and filler materials, and thus, is a very diverse, insoluble, non-nutritive masticatory composition containing free radicals which may snatch electrons from the active medicament, and thus causing an oxidative damage of the medicament.
  • the gum base comprises the antioxidant or at least a part of the antioxidant.
  • the gum base comprises at least 50% by weight of the total amount of antioxidant, such as at least 60% by weight, including at least 70% by weight, e.g. at least 80% by weight or at least 90% by of the total amount of antioxidant.
  • the gum base products on the marked which inherently comprise a suitable amount of an antioxidant. Such commercial products may also be useful in the chewing gum according to the invention.
  • the gum base is a water insoluble composition used as a support for the edible and water soluble portion of the chewing gum (sugar, glucose, polyols, flavours and the compound(s) according to formula I), a lipophilic antioxidant can be used with benefit in the gum base.
  • the gum base comprises a lipophilic antioxidant.
  • a lipophilic antioxidant blends well with the lipophilic gum base and is therefore advantageously mixed into the gum base.
  • a hydrophilic antioxidant also can be comprised in the gum base in order to stabilise the compound(s) according to formula I present in the gum base.
  • the gum base in the chewing gum comprises a lipophilic or a hydrophilic antioxidant.
  • the antioxidant is presence in the chewing gum as a pre-mixture of an antioxidant and one or more active compound(s) according to formula I.
  • the weight ratio between lipophilic or hydrophilic antioxidant and the compound(s) according to formula I in the pre-mixture is at least 1: 13, such as at least 1 : 10, including as at least 1 :9, e.g. at least 1 :8, including at least 1 :6, such as at least 1 :5.
  • the weight ratio between lipophilic or hydrophilic antioxidant and the compound(s) according to formula I in the pre-mixture is at least 1 : 170, such as at least 1 : 150, including as at least 1 : 100, e.g. at least 1 :50, including at least 1:25, such as at least 1 :20.
  • the pre-mixture and/or the gum base comprises a hydrophilic antioxidant. It is contemplated that the hydrophilic antioxidant surrounds or encapsulates the compound(s) according to formula I resulting in an effective protection against oxidations when present in the water insoluble part of the chewing gum.
  • the antioxidant is added to the chewing gum as a composition or pre-mixture comprising said antioxidant and a flavour and/or a colouring agent.
  • a composition or pre-mixture comprising said antioxidant and a flavour and/or a colouring agent.
  • useful flavour and colouring agents are described below.
  • the chewing gum according to the invention may be processed into different shapes such as a stick, a core, a tablet, a slab, a bead, a pellet, a tape, a ball or a center-filled chewing gum.
  • the chewing gum may also be a compressed chewing gum or a compressed chewing gum tablet comprising a compound according to formula I, an antioxidant and one or more compressed module(s) comprising compressed chewing gum particles containing gum base.
  • Such a chewing gum tablet may in accordance with the invention be processed into in a number of different shapes such as a stick, a core, a tablet, a slab, a bead, a pellet, a tape, or a ball.
  • a useful embodiment of the present invention is one wherein the chewing gum comprises a first compressed module comprising compressed chewing gum particles containing gum base.
  • One advantage of compressing the chewing gum particles containing gum base and one or more active compound(s) according to formula I as described herein is that the active compound is released faster than from conventionally mixed chewing gum.
  • the chewing gum is one wherein the first compressed module is on top of a second compressed module.
  • Figure Ia and Ib illustrates such a chewing gum according to the invention.
  • the illustrated chewing gum 10 comprises two chewing gum modules 11 and 12.
  • each module is simply comprised by a layer.
  • the multi-module chewing gum may in this embodiment be regarded as a two-layer or a two-module chewing gum 10.
  • the two modules 11 and 12 are adhered to each other. Different processes may be applied for the purpose as described below.
  • the mutual adhering between the two modules is obtained by the compression of one module 11 onto the other module 12.
  • the illustrated chewing gum 10 may for example comprise a non-gum base- containing module 11 and a gum base-containing module 12.
  • the chewing gum is one wherein the second compressed module, i.e. the module 11, comprises compressed tablet material. Examples of useful tablet material are described below.
  • the second compressed module i.e. the module 11, comprises compressed chewing gum particles containing gum base and optionally one or more further chewing gum ingredients.
  • Figure 2a illustrates a cross-section of a compressed chewing gum according to the invention and figure 2b illustrates the chewing gum from above.
  • an embodiment of the present invention is one wherein the first compressed module is on top of a second compressed module on top of a third compressed module, or described in another manner, the first module is located between two outer modules.
  • the illustrated chewing gum tablet 20 in figure 2a may in one embodiment comprises a three-module chewing gum of which the lowest module or third module 23 comprises compressed tablet material, and the modules 21 and 22 are as described above in figure 1.
  • the compressed chewing gum tablet 20 is one wherein the third compressed module 23 comprises compressed chewing gum particles containing gum base and optionally one or more further chewing gum ingredients.
  • the modules 21 and 22 may be as described above in figure 1.
  • the compressed chewing gum tablet is one wherein said first, second and/or third compressed module comprises compressed chewing gum particles containing gum base and one or more further chewing gum ingredients.
  • the chewing gum 20 comprises three modules, wherein the first compressed module 22 comprises compressed chewing gum particles containing gum base and one or more further chewing gum ingredients, and where said module is located between two compressed outer modules 21 and 23 comprising compressed tablet material.
  • FIG 3a illustrates a cross-section of a compressed chewing gum 30 according the invention and illustrated in figure 3b from above.
  • the illustrated chewing gum 30 comprises a module 32 comprising compressed chewing gum particles containing gum base and optionally one or more further chewing gum ingredients upon which a second module 31 is arranged.
  • the module 31 may comprise compressed tablet material or compressed chewing gum particles containing gum base and one or more further chewing gum ingredients.
  • FIG 4a illustrates a cross-section of a further compressed multi-modular chewing gum 40 according to the invention and illustrated in figure 4b from above.
  • the chewing gum 40 differs somewhat from the other described chewing gums in the sense that the chewing gum comprises a module 42 comprising compressed chewing gum particles containing gum base and optionally one or more further chewing gum ingredients forming a gum centre.
  • the module 42 is encapsulated by a surrounding module 41.
  • the module 41 may comprise compressed tablet material or compressed chewing gum particles containing gum base and one or more further chewing gum ingredients.
  • Figure 5a illustrates a cross-section of a compressed multi-modular chewing gum 50 according to the invention and illustrated in figure 5b from above.
  • a module 52 comprising compressed chewing gum particles containing gum base a certain concentration and optionally one or more further chewing gum ingredients
  • the other module 51 comprises compressed tablet material.
  • the chewing gum module 51 may comprise a content of compressed chewing gum particles containing gum base differing from that of the content of module 52, thereby facilitating a chewing gum providing at least two different release profiles in one piece.
  • the observed increased stability of the active compound according to formula I may be achieved by placing the compound(s) and the antioxidant together or separate in different compressed modules of the chewing gum according to the invention.
  • the chewing gum of the present invention is one comprising a first and a second compressed module, wherein the first compressed module comprises compressed chewing gum particles containing gum base, one or more active compound(s) according to formula I, and an antioxidant.
  • the second compressed module may preferable not comprise gum base, or only comprise at most 1% gum base, such as at the most 0.5% gum base by weight of the second compressed module.
  • the second module may further comprise tablet material. Examples of useful tablet materials are described below.
  • the chewing gum is one comprising a first and a second compressed module, wherein the first compressed module comprises compressed chewing gum particles containing gum base, and one or more active compound(s) according to formula I, and the second compressed module comprises the antioxidant.
  • the second compressed module may further comprise tablet material.
  • the chewing gum is one comprising a first and a second compressed module, wherein the first compressed module comprises compressed chewing gum particles containing gum base, and an antioxidant, and the second compressed module comprises one or more active compound(s) according to formula I.
  • the second module may further comprise tablet material.
  • the chewing gum is one comprising a first and a second compressed module, wherein the first compressed module comprises compressed chewing gum particles containing gum base, and the second compressed module comprises one or more active compound(s) according to formula I and an antioxidant.
  • the second compressed module may further comprise tablet material.
  • the chewing gum comprises a first, a second and a third compressed module, wherein the first compressed module comprises compressed chewing gum particles containing gum base, and the second compressed module may comprise one or more active compound(s) according to formula I and the third compressed module may comprise an antioxidant.
  • the chewing gum is one, wherein the first compressed module comprises further an antioxidant and the compressed modules comprising compressed tablet material comprises one or more active compound(s) according to formula I.
  • the compound(s) according to formula I and the antioxidant are compressed together with the chewing gum particles containing gum base.
  • this process is described in detail below.
  • the second compressed module not comprises gum base, or only comprise at most 1% gum base, such as at the most 0.5% gum base by weight of the second compressed module, it may be useful to incorporate compressed chewing gum particles containing gum base in the second module of the chewing gum.
  • the weight ratio, in the chewing gum, between the compound(s) according to formula I and the antioxidant is at least 1 :2, such as at least 1 : 1, including at least 1:0.5, e.g. at least 1 :0.2, such as at least 1 :0.16, including at least 1 :0.12, e.g. at least 1 :0.1, such as at least 1 :0.08, including at least 1 :0.06, e.g. at least 1 :0.05, such as at least 1 :0.04, including at least 1 :0.02, or at least 1:0.01.
  • the chewing gum is one wherein the weight ratio between the compound(s) according to formula I and the antioxidant is in the range of 1 :2-1 :0.2, such as in the range of 1 : 1 - 1 :0.2, including in the range of 1 :0.2 - 1 :0.01, such as in the range of 1 :0.2 - 1 :0.02, including in the range of 1 :0.16 - 1 :0.08, such as in the range of 1 :0.1 -1 :0.05, including in the range of 1 :0.12 - 1 :0.10, such as in the range 1:0.2 - 1 :0.08, including in the range of 1 :0.06 - 1 :0.04, such as in the range of 1 :0.08 - 1 :0.04, or in the range 1:0.1 - 1 :0.02.
  • the amount of the antioxidant useful in the chewing gum according to the invention may also be expressed as an amount by weight of the chewing gum or by weight of the gum base. Accordingly, in preferred embodiments, the antioxidant is presence in an amount in the range of 0.005 - 2% by weight of the uncoated chewing gum, such as in the range of 0.5-2%, including in the range 0.1 - 1%, such as in the range of 0.01 to 1%, e.g. range of 0.01-0.5%, such as in the range 0.01-0.2%, including in the range 0.01-0.1%, such as in the range of 0.1 - 1%, including in the range of 0.1-0.5%, e.g. in the range 0.1-0.2%, such as in the range 0.1-0.1%, including in the range of 0.2-1%, e.g. in the range 0.5-1% or in the range 0.7-1% by weight of the uncoated chewing gum.
  • the antioxidant is presence in an amount in the range of 0.005 - 2% by weight of the gum base, such as in the range of 0.5-2%, including in the range 0.1 - 1%, such as in the range of 0.01 - 1%, including in the range of 0.01-0.5% by weight of the gum base, preferably in the range 0.01-0.2% and even more preferred in the range 0.01-0.1%, such as in the range of 0.1 - 1%, preferably in the range of 0.1-0.5%, preferably in the range 0.1-0.2% and even more preferred in the range of 0.2-1%, preferably in the range 0.5-1% and even more preferred in the range 0.7-1% by weight of the chewing gum.
  • the chewing gum according to the invention is one wherein the antioxidant is presence in an amount of at least 0.005% by weight of the gum base, such as at least 0.05%, including at least 0.02%, e.g. at least 0.1%, such as at least 0.5%, including at least 1%, such as at least 1.1% by weight of the gum base, including at least 1.2 by weight of the gum base, e.g. at least 1.5% by weight of the gum base, such as at least 1.8% by weight of the gum base, including at least 2% by weight of the gum base.
  • the chewing gum according to the invention is one wherein the antioxidant is presence in an amount of at least 25 ppm, such as at least 50 ppm, including at least 100 ppm, such as at leat 200 ppm, including at least 250 ppm, such as at least 500 ppm, including at least 1000 ppm, such as at least 5000 ppm or at least 10000 ppm.
  • the chewing gum according to the invention is one wherein the antioxidant is presence in an amount of at least 1 mg/g gum base, such as at least 1.5 mg/g gum base, e.g. at least 1.7 mg/g gum base, including at least 2.0 mg/g gum base, e.g. at least 2.3 mg/g gum base, or at least 2.5 mg/g gum base.
  • the chewing gum particles containing gum base are one wherein the antioxidant is presence in an amount of at least 1 mg/g gum base, such as at least 1.5 mg/g gum base, e.g. at least 1.7 mg/g gum base, including at least 2.0 mg/g gum base, e.g. at least 2.3 mg/g gum base, or at least 2.5 mg/g gum base.
  • said gum base when having compressed modules comprising gum base, said gum base is typically in the form of compressed gum base particles.
  • the manufacturing of gum base particles is described below. However, the particles may be manufactured according to conventional methods such as those described in the EP 1 474 993, EP 1 474 994 and EP 1 474 995, which are hereby incorporated by reference.
  • the chewing gum particles comprise gum base.
  • the chewing gum particles may have any form of chewing gum particles containing a certain amount of gum base.
  • the content of gum base in the particles may vary.
  • the amount of gum base in the chewing gum particles is rather high, such in the range of 40-99% by weight of the chewing gum particles.
  • the amount of gum base in the chewing gum particles is in the range of 40-90% by weight of the chewing gum particles, such as in the range of 40-80% by weight, including in the range of 40- 70% by weight, e.g. in the range of 40-50% by weight, such as in the range of 50-85% by weight, including in the range of 50-75% by weight, e.g. in the range of 50-55% by weight of the chewing gum particles.
  • the amount of gum base in the chewing gum particles is lower, such as in the range of 15-60% by weight of the chewing gum particles.
  • Other useful amounts may vary in the range of 20-60% by weight of the chewing gum particles, such as in the range of 20-50% including in the range of 20-40% by weight, e.g. in the range of 30-55% by weight, such as in the range of 30-45% by weight of the chewing gum particles.
  • the remaining content of the chewing gum particles may comprise one or more of the below described chewing gum ingredients.
  • the particles are made entirely of gum base, substantially without conventional chewing gum ingredients.
  • the chewing gum ingredients may be applied in the compression process, such as by adding the chewing gum ingredients together with the gum base particles for compression.
  • the particles are made of chewing gum, substantially without further needs for chewing gum ingredients in the compression process.
  • intermediate solutions may be applicable, such as a varying amount of chewing gum ingredients in the chewing gum particles or in the compression process.
  • chewing gum particles may be applied at least a certain amount of high intensity sweetener and/or flavour and/or colour to the chewing gum particles in some embodiments of the invention, such as in case the chewing gum particles substantially consist of gum base.
  • the average particle size of the particles is in the range of 50-2000 ⁇ m measured as the longest dimension of the particle, preferably in the range of 100-1500 ⁇ m, and even more preferred in the range of 200-1300 ⁇ m.
  • the chewing gum tablet is one wherein at least 70% of the particles have a particle size in the range of 50-2000 ⁇ m measured as the longest dimension of the particle, preferably in the range of 100- 1500 ⁇ m, and even more preferred in the range of 200-1300 ⁇ m.
  • the chewing gum comprises one or more active compound(s) according to formula I, an antioxidant and a gum base.
  • the gum base may be used as such or it may be particulated and used as particles containing gum base as described above.
  • a useful gum base composition comprise one or more elastomeric compounds which may be of synthetic or natural origin, one or more resinous compounds which may be of synthetic or natural origin, fillers, softening compounds and minor amounts of miscellaneous ingredients such as antioxidants and colorants, etc.
  • One advantage of the present invention is that there is no need to adjust the content of other chewing gum ingredients in order to maintain the desired texture. Furthermore, a very interesting observation is that no disintegration of the chewing gum occurs upon chewing.
  • the expression further refers to the water-insoluble part of the chewing gum which typically constitutes 10 to 99% by weight including the range of 20-99% by weight of the total chewing gum composition, such as the range of 30-99% by weight of the total chewing gum composition.
  • the chewing gum composition comprises gum base in the range of 10-80% by weight of the chewing gum composition, preferably in the range 20-70% by weight, and even more preferably in the range 30-60% by weight of the chewing gum composition.
  • the chewing gum base which is admixed with chewing gum ingredients as defined below, can vary substantially depending on the particular product to be prepared and on the desired masticatory and other sensory characteristics of the final product.
  • typical ranges (weight %) of the above gum base components are: 5 to 50% by weight elastomeric compounds, 5 to 55% by weight elastomer plasticizers, 0 to 50% by weight filler/texturiser, 5 to 35% by weight softener and 0 to 1% by weight of miscellaneous ingredients such as antioxidants, colorants, etc.
  • the gum base of the chewing gum comprises an elastomer.
  • Natural elastomers may include natural rubber such as smoked or liquid latex and guayule as well as natural gums such as jelutong, lechi caspi, massaranduba balata, sorva, perillo, rosindinha, massaranduba chocolate, chicle, nispero, gutta hang kang, and combinations thereof.
  • Useful synthetic elastomers include, but are not limited to, synthetic elastomers listed in U.S.
  • polyisobutylene e.g. having an average molecular weight in the range of about 10,000 to 1,000,000 including the range of 50,000 to 80,000
  • isobutylene-isoprene copolymer butyl elastomer
  • styrene-butadiene copolymers e.g. having styrene-butadiene ratios of about 1 :3 to 3: 1
  • PVA polyvinyl acetate
  • polyvinyl acetates having a average molecular weight in the range of 2,000 to 90,000 such as the range of 3,000 to 80,000 including the range of 30,000 to 50,000, where the higher molecular weight polyvinyl acetates are typically used in bubble gum base, polyisoprene, polyethylene, vinyl acetate-vinyl laurate copolymer e.g. having a vinyl laurate content of about 5 to 50% by weight such as 10 to 45% by weight of the copolymer and combinations hereof.
  • synthetic elastomers include, but are not limited to, polyisobutylene and styrene-butadiene, polyisobutylene and polyisoprene, polyisobutylene and isobutylene-isoprene copolymer (butyl rubber) and a combination of polyisobutylene, styrene-butadiene copolymer and isobutylene isoprene copolymer, and all of the above individual synthetic polymers in admixture with polyvinyl acetate, vinyl acetate-vinyl laurate copolymers, respectively and mixtures thereof.
  • the gum base comprises at least one elastomer in an amount in the range of 3-80% by weight of the gum base, preferably in an amount in the range of 4-60% by weight of the gum base, and even more preferred in the range of 5- 40% by weight of the gum base, such as in the range of 8-20% by weight of the gum base.
  • Particularly interesting elastomeric or resinous polymer compounds which advantageously can be used in accordance with the present invention include polymers which, in contrast to currently used elastomers and resins, can be degraded physically, chemically or enzymatically in the environment after use of the chewing gum, thereby giving rise to less environmental pollution than chewing gums based on non-degradable polymers, as the used degradable chewing gum remnants will eventually disintegrate and/or can be removed more readily by physical or chemical means from the site where it has been dumped.
  • the gum base of the chewing gum according to the invention comprises one or more resins contributing to obtain the desired masticatory properties and acting as plasticizers for the elastomers of the gum base.
  • the resin may be a natural resin and/or it may be a synthetic resin.
  • useful resins include, but are not limited to, natural rosin esters, often referred to as ester gums including as examples glycerol esters of partially hydrogenated rosins, glycerol esters of polymerised rosins, glycerol esters of partially dimerised rosins, glycerol esters of tally oil rosins, pentaerythritol esters of partially hydrogenated rosins, methyl esters of rosins, partially hydrogenated methyl esters of rosins and pentaerythritol esters of rosins.
  • natural rosin esters often referred to as ester gums including as examples glycerol esters of partially hydrogenated rosins, glycerol esters of polymerised rosins, glycerol esters of partially dimerised rosins, glycerol esters of tally oil rosins, pentaerythritol esters of
  • resinous compounds include synthetic resins such as terpene resins derived from alpha- pinene, beta-pinene, and/or d-limonene, natural terpene resins; and any suitable combinations of the foregoing.
  • synthetic resins such as terpene resins derived from alpha- pinene, beta-pinene, and/or d-limonene, natural terpene resins; and any suitable combinations of the foregoing.
  • the choice of resins will vary depending on the specific application, and on the type of elastomer(s) being used.
  • the gum base comprises at least one resin in an amount in the range of 10-90% by weight of the gum base, preferably in the range of 20-80% by weight, even more preferred in the range of 30-70% by weight of the gum base, such as in the range of 40-60% by weight of the gum base.
  • the gum base comprises at least one resin in the range of 3-80% by weight of the gum base, preferably in an amount in the range of 4-60% by weight of the gum base, and even more preferred in the range of 5-40% by weight of the gum base, such as in the range of 8-20% by weight of the gum base.
  • the gum base may furthermore comprise one or more softener.
  • softener may be used interchangeably with plasticizers and plasticizing agents, and is used for ingredients, which softens the gum or chewing gum formulation and encompass wax, fat, oil, emulsifiers, surfactants, solubilizers etc.
  • the softeners may also include sucrose polyesters, such as glycerin, lecithin, and combinations thereof.
  • Aqueous sweetener solutions such as those containing sorbitol, hydrogenated starch hydrolysates, corn syrup and combinations thereof, may also be used as softeners and binding agents in the chewing gum according to the invention.
  • the gum base comprises an emulsifier, which aid in dispersing any immiscible components into a single stable system.
  • the emulsifiers useful in this invention include glyceryl monostearate, lecithin, fatty acid monoglycerides, diglycerides, propylene glycol monostearate, and the like, and mixtures thereof.
  • the emulsifier may be employed in an amount in the range of 1- 15% by weight of the gum base, and preferably in the range 5-10% by weight of the gum base.
  • emulsifiers include anionic, cationic, amphoteric or non- ionic emulsifiers can be used.
  • Suitable emulsifiers include lecithins, polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid esters, fatty acid salts, mono and diacetyl tartaric acid esters of mono and diglycerides of edible fatty acids, citric acid esters of mono and diglycerides of edible fatty acids, saccharose esters of fatty acids, polyglycerol esters of fatty acids, polyglycerol esters ofinteresterified castor oil acid (E476), sodium stearoyllatylate, sodium lauryl sulfate and sorbitan esters of fatty acids and polyoxyethylated hydrogenated castor oil (e.g.
  • CREMOPHOR block copolymers of ethylene oxide and propylene oxide (e.g. products sold under trade names PLURONIC and POLOXAMER), polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, sorbitan esters of fatty acids and polyoxyethylene steraric acid esters.
  • Particularly suitable emulsifiers are polyoxyethylene stearates, such as for instance polyoxyethylene (8) stearate and polyoxyethylene (40) stearate, the polyoxyethylene sorbitan fatty acid esters sold under the trade name TWEEN, for instance TWEEN 20 (monolaurate), TWEEN 80 (monooleate), TWEEN 40 (monopalmitate), TWEEN 60 (monostearate) or TWEEN 65 (tristearate), mono and diacetyl tartaric acid esters of mono and diglycerides of edible fatty acids, citric acid esters of mono and diglycerides of edible fatty acids, sodium stearoyllactylate, sodium laurylsulfate, polyoxyethylated hydrogenated castor oil, blockcopolymers of ethylene oxide and propyleneoxide and polyoxyethylene fatty alcohol ether.
  • the emulsifiers may either be a single compound or a combination of several compounds.
  • plasticizers Some emulsifier, also referred to as plasticizers, to provide a variety of desirable textures and consistency properties. Because of the low molecular weight of these components, the plasticizers are able to penetrate the fundamental structure of the gum base making it plastic and less viscous.
  • Useful plasticizers include lanolin, palmitic acid, oleic acid, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glyceryl lecithin, glyceryl monostearate, propylene glycol monostearate, acetylated monoglyceride, glycerine, and the like, and mixtures thereof.
  • the softener used in the gum base of the chewing gum of the invention is a fat.
  • the fat may e.g. include partially or fully hydrogenated vegetable or animal fats, such as partially or fully hydrogenated coconut oil, partially or fully hydrogenated palm oil, partially or fully hydrogenated palm kernel oil, partially or fully hydrogenated rapeseed oil, partially or fully hydrogenated castor oil, partially or fully hydrogenated maize oil, partially or fully hydrogenated cottonseed oil, partially or fully hydrogenated olive oil, partially or fully hydrogenated sunflower oil, partially or fully hydrogenated safflower oil, partially or fully hydrogenated sesame oil, partially or fully hydrogenated soybean oil, partially or fully hydrogenated beef tallow, and partially or fully hydrogenated lard, and any mixture thereof and any derivative thereof.
  • the gum base comprises a fat in an amount in the range of 1-15% by weight of the gum base, and preferably in the range 5-10% by weight of the gum base.
  • the gum base may furthermore comprise a wax.
  • a wax When a wax is present in the gum base, it softens the polymeric elastomer mixture and improves the elasticity of the gum base.
  • the waxes employed will have a melting point below about 60 0 C, and preferably between about 45°C and about 55°C.
  • the low melting wax may be a paraffin wax.
  • the wax may be present in the gum base in an amount from about 6% to about 10%, and preferably from about 7% to about 9.5% by weight of the gum base.
  • waxes having a higher melting point may be used in the gum base in amounts up to about 5%, by weight of the gum base.
  • high melting waxes include beeswax, vegetable wax, candelilla wax, canauba wax, most petroleum waxes, and the like, and mixtures thereof.
  • waxes include natural and synthetic waxes, hydrogenated vegetable oils, petroleum waxes such as polyurethane waxes, polyethylene waxes, paraffin waxes, microcrystalline waxes, fatty waxes, sorbitan monostearate, tallow, propylene glycol, mixtures thereof, and the like, may also be incorporated into the gum base.
  • petroleum waxes such as polyurethane waxes, polyethylene waxes, paraffin waxes, microcrystalline waxes, fatty waxes, sorbitan monostearate, tallow, propylene glycol, mixtures thereof, and the like, may also be incorporated into the gum base.
  • Anhydrous glycerin may also be employed as a softening agent, such as the commercially available United States Pharmacopeia (L)SP) grade.
  • Glycerin is a syrupy liquid with a sweet warm taste and has a sweetness of about 60% of that of cane sugar. Because glycerin is hygroscopic, the anhydrous glycerin may be maintained under anhydrous conditions throughout the preparation of the chewing gum composition.
  • the gum base comprises at least one resin in an amount in the range of 10-90% by weight of the gum base, at least one elastomer in an amount in the range of 4-60% by weight of the gum base, and an emulsifier in an amount in the range of 1-15% by weight.
  • the gum base comprises at least one resin in an amount in the range of 30-70% by weight of the gum base, at least one elastomer in an amount in the range of 5-40% by weight of the gum base, and an emulsifier in an amount in the range of 5-10% by weight of the gum base.
  • the gum base of the chewing gum according to the invention comprises a filler.
  • the fillers/text urizers may include magnesium and calcium carbonate, sodium sulphate, ground limestone, silicate types such as magnesium and aluminium silicate, kaolin, clay, aluminium oxide, silicium oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, and combinations thereof.
  • the fillers/texturizers may also include natural organic fibres such as fruit vegetable fibres, grain, rice, cellulose and combinations thereof.
  • the chewing gum comprises one or more further chewing gum ingredients.
  • a chewing gum ingredient may be selected from the group consisting of at least a bulk sweetener, a high intensity sweetener, a flavouring agent, a cooling agent, a warming agent, a colouring agent, a binding agent, a pH-regulating agent and an active ingredient.
  • the at least one chewing gum ingredient is a bulk sweetener.
  • the bulk sweetener may be selected from the group consisting of monosaccharides, disaccharides, polysaccharides, sugar alcohols, and mixtures thereof; dextrose, sucrose, lactose, xylitol, mannitol, sorbitol, mannitol, maltitol, isomaltol or isomalt, erythritol, lactitol, cyclodextrin randomly bonded glucose polymers such as those polymers distributed under the tradename POLYDEXTROSE ® by Pfizer, Inc., Groton, Conn.; isomalt (a racemic mixture of alpha-D-glucopyranosyl-l,6-mannitol and alpha-D-glucopyranosyl-1,6- sorbitol manufactured under the tradename PALATINIT ® by S ⁇ d Weg Zucker), malto
  • the bulk sweetener is present in amount ranging from 10-70% by weight of the chewing gum.
  • the bulk sweetener may be present in amount ranging from 30-70% by weight of the chewing gum, such as e.g. in the range 35-65% by weight of the chewing gum, and in the range 40-60% by weight of the chewing gum.
  • the bulk sweetener may be present in amount ranging from 20-55% by weight of the chewing gum, such as e.g. in amount ranging from 30-50% by weight of the chewing gum.
  • the chewing gum according to the invention further comprises a high intensity sweetener.
  • a high intensity sweetener may be selected from the group consisting of sucralose, neotame, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones e.g. NHDC, thaumatin, monellin, stevioside, Twinsweet (aspartame-acesulfame salt) and combinations thereof.
  • encapsulation may be applied for the purpose of stabilizing the ingredients. Techniques such as wet granulation, wax granulation, spray drying, spray chilling, fluid bed coating, coascervation, encapsulation in yeast cells and fiber extrusion may be used to achieve the desired release characteristics. Encapsulation of sweetening agents can also be provided e.g. using another chewing gum component, such as a resinous compound, as the encapsulation agent.
  • usage level of the artificial sweetener will vary considerably depending e.g. on factors such as potency of the sweetener, rate of release, desired sweetness of the product, level and type of flavour used and cost considerations.
  • the active level of artificial sweetener may vary from about 0.02 to 8% by weight.
  • the usage level of the encapsulated sweetener will be proportionally higher.
  • Combinations of sugar and/or non-sugar sweeteners can be used in the chewing gum formulation processed in accordance with the invention. Additionally, the softener may also provide additional sweetness such as with aqueous sugar or alditol solutions.
  • a low calorie bulking agent can be used.
  • low calorie bulking agents include polydextrose, Raftilose, Raftilin, Inuline, fructooligosaccharides (NutraFlora ® ), palatinose oligosaccharided; guar gum hydrolysates (e.g. Sun Fiber ® ) or indigestible dextrins (e.g. Fibersol ® ).
  • other low calorie-bulking agents can be used.
  • Flavouring agents may also be useful for the organoleptic properties in the chewing gum according to the invention.
  • the flavouring agents which may be used include those flavouring agents known to the skilled artisan, such as natural and artificial flavouring agents. These flavouring agents may be chosen from synthetic flavour oils and flavouring aromatics and/or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, and so forth, and combinations thereof.
  • Non-limiting representative flavour oils include spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice, oil of sage, mace, oil of bitter almonds, and cassia oil.
  • Also useful flavouring agents are artificial, natural and synthetic fruit flavours such as vanilla, and citrus oils including lemon, orange, lime, grapefruit, and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. These flavouring agents may be used in liquid or solid form and may be used individually or in admixture.
  • Commonly used flavouring agents include mints such as peppermint, menthol, spearmint, artificial vanilla, cinnamon derivatives, and various fruit flavouring agents, whether employed individually or in admixture.
  • flavouring agents include aldehydes and esters such as cinnamyl acetate, cinnamaldehyde, citral diethylacetal, dihydrocarvyl acetate, eugenyl formate, p-methylamisol, and so forth may be used.
  • any flavouring agent or food additive such as those described in Chemicals Used in Food Processing, publication 1274, pages 63-258, by the National Academy of Sciences, may be used. This publication is incorporated herein by reference.
  • aldehyde flavouring agents include, but are not limited to, acetaldehyde (apple), benzaldehyde (cherry, almond), anisic aldehyde (licorice, anise), cinnamic aldehyde (cinnamon), citral, i.e. alpha-citral (lemon, lime), neral, i.e. beta-citral (lemon, lime), decanal (orange, lemon), ethyl vanillin (vanilla, cream), heliotrope, i.e.
  • trans-2 berry fruits
  • tolyl aldehyde cherry, almond
  • veratraldehyde vanilla
  • 2,6-dimethyl-5- heptenal i.e. melonal (melon)
  • 2,6-dimethyloctanal green fruit
  • 2-dodecenal citrus, mandarin
  • cherry, grape, strawberry shortcake and mixtures thereof.
  • the flavouring agent may be employed in either liquid form and/or dried form.
  • suitable drying means such as spray drying the oil may be used.
  • the flavouring agent may be absorbed onto water soluble materials, such as cellulose, starch, sugar, maltodextrin, gum arabic and so forth or may be encapsulated. The actual techniques for preparing such dried forms are well-known.
  • the flavouring agents may be used in many distinct physical forms well-known in the art to provide an initial burst of flavour and/or a prolonged sensation of flavour.
  • such physical forms include free forms, such as spray dried, powdered, beaded forms, encapsulated forms, and mixtures thereof.
  • the amount of flavouring agent employed herein may be a matter of preference subject to such factors as the type of final chewing gum, the individual flavour, the gum base employed, and the strength of flavour desired. Thus, the amount of flavouring may be varied in order to obtain the result desired in the final product and such variations are within the capabilities of those skilled in the art without the need for undue experimentation.
  • the flavouring agent is generally present in amounts from about 0.02% to about 5% by weight, and more specifically from about 0.1% to about 2% by weight, and even more specifically, from about 0.8% to about 1.8%, by weight of the chewing gum.
  • encapsulated flavours may be added to the final blend and optionally prior to compression.
  • Different methods of encapsulating flavours mixed into the gum base and flavours into the chewing gum may e.g. include spray drying, spray cooling, film coating, coascervation, double emulsion method (extrusion technology) or prilling.
  • Materials to be used for the above-mentioned encapsulation methods may e.g.
  • gelatine examples include gelatine, wheat protein, soya protein, sodium caseinate, caseine, gum arabic, modified starch, hydrolyzed starches (maltodextrines), alginates, pectin, carregeenan, xanthan gum, locus bean gum, chitosan, bees wax, candelilla wax, camauba wax, hydrogenated vegetable oils, zein and/or sucrose.
  • cooling agents are mentioned in U.S. Patent No. 6,627,233, the contents of which are incorporated herein by reference for all purposes.
  • Particular examples of cooling agents include: menthol, xylitol, menthane, menthone, menthyl acetate, menthyl salicylate, N,2,3-trimethyl-2-isopropyl butanamide (WS-23), substituted p-menthanes, substituted p-menthane-carboxamides (e.g., N-ethyl-p-menthane- 3-carboxamide (FEMA 3455)), acyclic carboxamides, substituted cyclohexanamides, substituted cyclohexane carboxamides, substituted ureas and sulphonamides, and substituted menthanols (all from Wilkinson Sword); hydroxymethyl and hydroxyethyl derivatives of p-menthane (from Lever Bros.); menthyl succinate; 2-
  • cooling agents are further described in the following U.S. patents, all of which are incorporated in their entirety by reference hereto: U.S. Pat. Nos. 4,230,688 and 4,032,661 to Rowsell et al.; 4,459,425 to Amano et al.; 4,136,163 to Watson et al.; and 5,266,592 to Grub et al.
  • the cooling agents are typically present in amounts of about 0.001 to about 10% by weight of the chewing gum composition.
  • Useful warming agents may be selected from a wide variety of compounds known to provide the sensory signal of warming to the user. These compounds offer the perceived sensation of warmth, particularly in the oral cavity, and often enhance the perception of flavours, sweeteners and other organoleptic components.
  • useful warming compounds include vanillyl alcohol n-butylether (TK-1000) supplied by Takasago Perfumary Company Limited, Tokyo, Japan, vanillyl alcohol n-propylether, vanillyl alcohol isopropylether, vanillyl alcohol isobutylether, vanillyl alcohol n-aminoether, vanillyl alcohol isoamyleather, vanillyl alcohol n-hexyleather, vanillyl alcohol methylether, vanillyl alcohol ethyleather, gingerol, shogaol, paradol, zingerone, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin
  • Whiteners and colouring agents may be used in amounts effective to produce the desired colour.
  • the colouring agents may include pigments which may be incorporated in amounts up to about 6%, by weight of the chewing gum.
  • titanium dioxide may be incorporated in amounts up to about 2%, and preferably less than about 1%, by weight of the chewing gum.
  • the colourants may also include natural food colours and dyes suitable for food, drug and cosmetic applications. These colourants are known as F.D.& C. dyes and lakes.
  • the materials acceptable for the foregoing uses are preferably water-soluble.
  • Illustrative nonlimiting examples include the indigoid dye known as F.D.& C. Blue No. 2, which is the disodium salt of 5,5-indigotindisulfonic acid.
  • the dye known as F.D.& C. Green No. 1 comprises a triphenylmethane dye and is the monosodium salt of 4-[4-(N-ethyl-p-sulfoniumbenzylamino) diphenylmethylene]- [l-(N-ethyl-N-p— sulfoniumbenzyl)-delta-2,5-cyclohexadieneimine].
  • F.D.& C. colourants and their corresponding chemical structures may be found in the Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Edition, in volume 5 at pages 857-884, which text is incorporated herein by reference.
  • Useful pH-regulating agents, acidity regulators, or pH control agents are additives which may be added to the chewing gum to change or maintain pH (acidic, alkaline or pH neutral). They can be organic or mineral acids (acidulants), bases, neutralizing agents, or buffering agents. Examples of useful compounds include ascorbic acid, fumaric acid, adipic acid, lactic acid, malic acid, citric acid, tartaric acid, propionic acid, phosphoric acid and combinations thereof.
  • Compression adjuvants may also be added. These compounds facilitate compression of the gum into tablets. Suitable compression adjuvants include, but are limited to, glidants, lubricants, wetting agents, diluents, humectants. More specifically, useful compression adjuvants include silicon dioxide, magnesium stearate, calcium stearate, behenic acid, talc and similar substances which can be used to limit the tendency of the gum tablets to stick to the presses.
  • the second and/or third compressed module of the chewing gum may comprise tablet material.
  • tablette material is in the present context used for the above described chewing gum ingredients when these are used in a compressed module comprising tablet material.
  • further useful tablet materials include, but are not limited to, conventional pharmaceutical acceptable excipients such as a glidant, a lubricant, a filler substance, and a dry or wet binder.
  • useful glidants and lubricants are stearic acid, metallic stearates, talc, colloidal silica, sodium stearyl fumarate and alkyl sulphates.
  • a dry binder such as e.g. sorbitol, isomalt, or mixtures thereof may be used.
  • the dry binder provides the effect of binding a material and thereby providing a powder that can be compressed into a tablet.
  • a wet binder is an excipient that in combination with water facilitates a powder to be compressed into tablets.
  • a wet binder must, at least to some extent, be soluble in water.
  • wet binders are PVP (polyvinylpyrrolidone), HPMC (hydroxymethylpropylcellulose) or gelatine.
  • a filler substance may be any pharmaceutically acceptable substance that does not interact with the active compound according to formula I or with other excipients.
  • Useful filler substances include sorbitol, mannitol, dextrins, maltodextrins, inositol, erythritol, isomalt, lactitol, maltitol, mannitol, xylitol, low- substituted hydroxypropylcellulose, starches or modified starches (e.g potato starch, maize starch, rice starch, pre-gelatinised starch), polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, agar (e.g.
  • sodium alginate carboxyalkylcellulose, dextrates, gelatine, gummi arabicum, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysaccharides e.g. dextran, soy polysaccharide, sodium carbonate, and sodium chloride.
  • the chewing gum may comprise a coating applied onto the chewing gum centre.
  • a suitable coating is any coating that results in extended storage stability of the compressed chewing gum products as defined above, relative to a chewing gum of the same composition that is not coated.
  • suitable coating types include hard coatings, soft coatings, film coatings and sealing coating of any composition including those currently used in coating of chewing gum, pharmaceutical products and confectioneries.
  • the chewing gum comprises the coating in an amount in the range of 1-80% by weight of the chewing gum, such as in an amount in the range of 10-50%, or 15- 45% by weight of the chewing gum.
  • the chewing gum comprises the coating in an amount in the range of 20-40% by weight of the chewing gum.
  • the coating comprises one or more active compound(s) according to formula I.
  • the coating may e.g. comprise one or more active compound(s) according to formula I in an amount in the range of 1- 30 mg, and preferably in the range of 5-20 mg.
  • the coating comprises one or more active compound(s) according to formula I an amount in the range of 1-10% by weight of the coating.
  • the coating may be a hard coating, which term is used in the conventional meaning of that term including sugar coatings and sugar-free (or sugarless) coatings and combinations thereof.
  • the objects of hard coating are to obtain a sweet, crunchy layer, which is appreciated by the consumer, and to protect the composition for various reasons.
  • a typical process of providing the composition with a protective sugar coating the gum centers are successively treated in suitable coating equipment with aqueous solutions of crystallizable sugar such as sucrose or dextrose, which, depending on the stage of coating reached, may contain other functional ingredients, e.g. fillers, colours, etc.
  • the sugar coating may contain further functional or active compounds including flavour compounds, pharmaceutically active compounds and/or polymer degrading substances.
  • sorbitol, maltitol, mannitol, xylitol, erythritol, lactitol, isomalt and tagatose which are obtained by industrial methods by hydrogenation of D-glucose, maltose, fructose or levulose, xylose, erythrose, lactose, isomaltulose and D-galactose, respectively.
  • polyols in the coating is that they act simultaneously as a sweetener and as a masking agent for the bitter taste of one or more active compound(s) according to formula I.
  • a syrup containing crystallizable sugar and/or polyol is applied onto the chewing gum and the water it contains is evaporated off by blowing with warm, dry air. This cycle may be repeated several times, typically 10 to 80 times, in order to reach the swelling required.
  • swelling refers to the increase in weight of the products, as considered at the end of the coating operation by comparison with the beginning, and in relation to the final weight of the chewing gum.
  • a sealing coating of e.g. shellac, ethyl cellulose, zein, acrylic compounds or carnauba wax or the like may be applied over the hard coating, if desired, in order to seal the crunchy coating to reduce the exposure of the coating to atmospheric moisture.
  • the coating may be a soft coating.
  • a soft coating is applied using conventional methods and may advantageously consist of a composition of a sugar or any of the above non-cariogenic, sugar-less sweetening compounds and a starch hydrolysate.
  • the chewing gum tablet comprises a film coating.
  • the film coating may be obtained by subjecting the composition to a film coating process and which therefore comprises one or more film-forming polymeric agents and optionally one or more auxiliary compounds, e.g. plasticizers, pigments and opacifiers.
  • a film coating is a thin polymer-based coating applied to a composition of any of the above forms. The thickness of such a film coating is usually between 20 and 100 ⁇ m.
  • the film coating is obtained by passing the composition through a spray zone with atomized droplets of the coating materials in a suitable aqueous or organic solvent vehicle, after which the material adhering to the composition is dried before the next module of coating is received. This cycle is repeated until the coating is complete.
  • suitable film-coating polymers include edible cellulose derivatives such as cellulose ethers including methylcellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC).
  • Other useful film-coating agents are acrylic polymers and copolymers, e.g. methylacrylate aminoester copolymer or mixtures of cellulose derivatives and acrylic polymers.
  • Useful polymers may include: cellulose acetate phtalate (CAP), polyvinyl acetate phtalate (PVAP), shellac, metacrylic acid copolymers, cellulose acetate trimellitate (CAT) and HPMC.
  • CAP cellulose acetate phtalate
  • PVAP polyvinyl acetate phtalate
  • shellac metacrylic acid copolymers
  • CAT cellulose acetate trimellitate
  • HPMC hydroxypropyl methylcellulose
  • the film-coating layer of the chewing gum tablet comprise a plasticizing agent having the capacity to alter the physical properties of a polymer to render it more useful in performing its function as a film forming material.
  • plasticizers will be to make the polymer softer and more pliable as the plasticizer molecules interpose themselves between the individual polymer strands thus breaking down polymer-polymer interactions.
  • Most plasticizers used in film coating are either amorphous or have very little crystallinity.
  • suitable plasticizers include polyols such as glycerol, propylene glycol, polyethylene glycol, e.g. the 200-6000 grades hereof, organic esters such as phtalate esters, dibutyl sebacate, citrate esters and triacetin, oils/glycerides including castor oil, acetylated monoglycerides and fractionated coconut oil.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, e.g. the 200-6000 grades hereof
  • organic esters such as phtalate esters, dibutyl sebacate, citrate esters and triacetin
  • oils/glycerides including castor oil, acetylated monoglycerides and fractionated coconut oil.
  • film-forming polymer (s) and plasticizing agent (s) for the film coating of the composition is made with due consideration for achieving the best possible barrier properties of the coating in respect of dissolution and diffusion across the film of moisture and gasses.
  • the film coating of the chewing gum tablet may also contain one or more colorants or opacifiers.
  • colorants or opacifiers include organic dyes and their lakes, inorganic colouring agents, e.g. titanium oxide and natural colours such as e.g. beta-carotene.
  • film coatings may contain one or several auxiliary substances such as flavours and waxes or saccharide compounds such as polydextrose, dextrins including maltodextrin, lactose, modified starch, a protein such as gelatine or zein, a vegetable gum and any combination thereof.
  • the coating typically comprises one or more layers.
  • the number of layers of the coating may be in the range of 1-100 layers, such as 3-75 layers, 10-60 layers, and 20-40 layers.
  • the coating comprises for example comprise a wax layer.
  • the outermost layer of the coating is a wax layer.
  • a chewing gum according to the present invention has typically a weight in the range of 0.1-10 g, such as in the range of 0.5-5 g or in the range of 0.75-2.5 g, preferably in the range of 0.8-2 g, and even more preferred in the range of 1-1.5 g.
  • Compressed chewing gums according to the invention have typically a weight in the range of 0.5-3.0 g, such as in the range of 0.75-2.5 g or in the range of 0.8-2.0 g, preferably in the range of 1.0-1.5 g.
  • Center-filled chewing gums normally have weights in the range of 0.5-5 g, preferably in the range of 1-4 g, and even more preferred in the range of 2-3 g.
  • Typical weights for bead shaped chewing gums are in the range of 0.1-0.6 g, preferably in the range of 0.2-0.5 g, and even more preferred in the range of 0.3-0.4 g.
  • a chewing gum comprising one or more active compound(s) according to formula I.
  • medicated chewing gums are prepared by sequentially adding the various chewing gum ingredients to a commercially available kneading kettles or mixer known in the art in order to produce a homogeneous chewing gum composition.
  • the kneading kettles are heated to a temperature of 30-80 0 C, typically approx. 50-60 0 C.
  • the mixing process starts with mixing and melting the gum base for 1- 20 min, typically approx. 10 minutes.
  • the gum base may also be melted before adding. All or a part of the bulk sweetener(s) may be added and mixed at the same time together with the gum base.
  • sweeteners and antioxidant are added and following mixing for further 1-20 minutes, typically approx. 5-10 minutes.
  • Adding and mixing of the active ingredient may be at the same time as the sweeteners and antioxidant or added separately in the following step and mixed for further 10-30 min., typically approx. 20 min.
  • Flavours are added together or separately in additional steps and mixed for further 1-15 minutes, typically 5-10 minutes.
  • the adding and mixing of flavours may also take place in the beginning of the mixing process, i.e. before the admixture of sweetener and antioxidant. It is also possible to add flavours in two or more portions during the mixing process.
  • Total mixing time to produce a homogeneous gum mass with the chewing gum components may take from 14 to 95 minutes, typically 45 to 55 minutes.
  • the mixer When mixing is completed, the mixer is tipped, and the gum mass is taken out into rolling bins, carts, onto trays or the like.
  • the chewing gum mass Before forming the chewing gum core, the chewing gum mass must be cooled until the right texture of the gum mass is achieved.
  • the temperature of the gum mass is 30-80 0 C, typically 50-65 0 C.
  • the temperature of the gum mass In order to form the chewing gum cores, the temperature of the gum mass must be reduced to 30-50 0 C by cooling at room temperature or in a cooled place/room (controlled temperature and moisture) or through a cooling tunnel to achieve a quicker cooling of the gum mass.
  • the forming of the chewing gum cores may take place by extrusion through a specially formed nozzle, or after extrusion by means of rollers, punching machines, tentering wheels and the like.
  • the chewing gum core may be formed into cores suitable shape, e.g. rectangular pellets/tablets, sticks, balls, cubes, cylinders, and many other shapes.
  • the chewing gum mass is frequently powdered with e.g. icing sugar, talc, corn flour, and the like.
  • the formed chewing gum cores can be hardened and cooled to room temperature in a cooling tunnel or the cooling may take place on trays at a store room for semi-manufactured products at a controlled temperature and moisture condition.
  • the formed and cooled chewing gum cores may be coated and polished before the packing.
  • the coating of the chewing gum cores may take place in a tilted, round, horizontally placed cylindrical coating kettle that rotate during the coating and polishing process.
  • the coating kettle may be made from copper, stainless steel or fiberglass-reinforced polyester, and are often equipped with piping systems that supply and exhaust air and dose the coating suspension, powder sweetener, flavours, wax, talc etc.
  • Coaters with perforated drum like the Dria-coater or Fluid bed coaters may also be used for coating of the product
  • the coating suspension is produced and heated up to 75°C depending on the sweetener; when xylitol is used, the suspension is heated up to about 70 0 C.
  • Cores of chewing gum are first separated in the rotating coating kettles.
  • the coating suspension with xylitol is added in small portions to the kettle and dispersed evenly over the surfaces of the cores after some time to smooth out.
  • Powder may be added in connection with each or some of the suspension portions.
  • the operation is repeated until the specified weight has reached a weight of typically about 1.1 g to 1.2 g. Dose and smooths the surfaces of the tablets with xylitol suspension until the tablet weight is 1.3 g.
  • the coat weight may be up to 500 mg, but typically 200 to 300 mg is preferred.
  • Flavour(s) might be added during coating of the chewing gum product, either together with a small dosage of the coating suspension or by it self.
  • High potency sweetener(s) may also be added in the coat, either added in the formulation of the produced coating suspension or together with a small dose the coating suspension or by it self.
  • the high potency sweeteners are added in the formulation of the coating suspension to achieve a more homogeneous distribution of the sweeteners.
  • the polishing may also take place in rotating kettles in which a polishing suspension or polishing powder is added to the coated cores in one or more portion(s).
  • the polishing suspension often consists of wax, emulsifier, coating agent, gum arabic, water, etc.
  • the polishing powder often consists of wax only, or of wax mixed with emulsifiers, gum Arabic or talc, etc.
  • a method of preparing a chewing gum comprising one or more active compound(s) according to formula I, the method comprising the steps of a) providing one or more active compound(s) according to formula I, a gum base, and an antioxidant, b) optionally providing one or more further chewing gum ingredients, c) mixing the compound(s) according to formula I, the gum base and the antioxidant, and optionally the one or more further chewing gum ingredients, and thus obtaining a mixture, and d) shaping the mixture to obtain the chewing gum.
  • the optionally further chewing gum ingredients may be selected from the group consisting of a bulk sweetener, a high intensity sweetener, a flavouring agent, a cooling agent, a warming agent, a colouring agent, a binding agent, a pH-regulating agent and an active ingredient.
  • the antioxidant is added as a composition or a pre- mixture comprising said antioxidant and a flavour and/or colouring agent as discussed above.
  • a flavour and/or colouring agent examples include any suitable flavour and/or colouring agent.
  • Such commercial composition may be useful and convenient in the method according to the invention, as the amount of antioxidant in such commercial composition also has an effect on the compound(s) according to formula I. It will be understood that such a composition comprising the antioxidant and a flavour and/or colouring agent also can be prepared by the chewing gum manufacturer.
  • a method of preparing a chewing gum comprising one or more active compound(s) according to formula I, the method comprising the steps of a) providing one or more active compound(s) according to formula I and a gum base comprising an antioxidant, b) optionally providing one or more further chewing gum ingredients, c) mixing the compound(s) according to formula I and the gum base, and optionally the one or more further chewing gum ingredients, and thus obtaining a mixture, and d) shaping the mixture to obtain the chewing gum.
  • a composition comprising the gum base and at least one antioxidant, may be used with advantage in the present method.
  • Such composition may be commercially available where the antioxidant is added in order to improve or extend the shelf life of the gum base by delaying oxidation.
  • the inventors of the present inventions have shown, that such commercial composition may be useful and convenient in the method according to the invention, as the amount of antioxidant in such commercial composition also have a stabilising effect on the compound(s) according to formula I. It will be understood that such a composition comprising the antioxidant and a gum base also can be prepared by the chewing gum manufacturer.
  • a method of preparing a chewing gum comprising one or more active compound(s) according to formula I, the method comprising the steps of a) providing a pre-mix comprising one or more active compound(s) according to formula I and an antioxidant, b) optionally providing one or more further chewing gum ingredients, c) mixing the pre-mix with a gum base and optionally the one or more further chewing gum ingredients, to obtain a mixture, and d) shaping the mixture to obtain the chewing gum.
  • the antioxidant comprised in the pre-mix is added as a composition comprising said antioxidant and a flavour and/or colouring agent.
  • the antioxidant is a lipophilic or a hydrophilic antioxidant.
  • the above methods may comprise a step of coating the chewing gum.
  • chewing gums comprising compressed modules, such as one or multiple compressed modules. Initially, chewing gum particles containing gum base are provided.
  • the chewing gum particles may be in any suitable form according to the invention. As described above, in some embodiments, the particles have been particulated prior to application. Particulation may be in any form of "building up” particles from smaller primary particles into macro particles or in any form of "building down” from larger substances into macro particles. Any form of particulation may be applied, such as granulation, pelletizing, agglomeration, or any other suitable means for particulation.
  • Granulation may be applied in some embodiments as a means for particulation, resulting in granules.
  • Granules should be understood in its broadest content.
  • the granules may be a result of a total chewing gum manufacture, where the chewing gum after production is comminuted into smaller particles, optionally under cooling conditions such as with a coolant or physical cooling, where after these particles are pressed together, optionally using at least some further processing aids.
  • the comminuted particles may be achieved by grinding, milling, or any other suitable processing means.
  • the chewing gum particles are provided by a method where the particles are obtained through grinding of the prepared chewing gum composition. More specifically, such a method comprises the steps of a) mixing of a soft basic gum base with at least one sweetener and, optionally, at least one other chewing gum ingredient, at a temperature of between 35 and 75°C; b) cooling of the mixture thus obtained to a temperature of between 0 and -40 0 C and, preferably, between -10 and -40 0 C; c) grinding and subsequent screening of the mixture thus obtained to a particle size of less than 10 mesh; and d) optional mixing of the powder thus obtained with at least one anti-agglutination agent.
  • Agglomeration may also be applied in some other embodiments as a means for particulation, resulting in agglomerates.
  • Pelletizing may be applied in some other embodiments as a means for particulation, resulting in pellets.
  • the pellets may be partly manufactured as a result of an extruding process.
  • the pellets are pelletized in an underwater process, whereby gum base are pressed through dies in a die plate, meaning openings of a certain diameter, into a cooling media and thereupon dried.
  • the pellets are pelletized in a strand pelletizing process with cool air.
  • the chewing gum particles containing gum base are provided by a method comprising at least the steps of a) feeding a gum base into an extruder; b) pressurizing the gum base in the extruder; c) extruding the gum base through a die means; and d) cutting the extruded gum base in a liquid filled chamber.
  • the provided chewing gum particles are made entirely of a gum base, substantially without conventional chewing gum ingredients.
  • the chewing gum ingredients may be applied in the compression process, such as by adding the chewing gum ingredients together with the gum base particles for compression.
  • Chewing gum ingredients e.g. flavours and sweeteners, may with advantage be added to the gum base in order to obtain a gum base composition in the extruder immediately before the composition is extruded through the die means into the water filled chamber where the extruded and cut chewing gum composition is immediately cooled to low temperatures.
  • intermediate solutions may be applicable, such as a varying amount of chewing gum ingredients in the chewing gum particles or in the compression process. It may be preferred to apply at least a certain amount of high intensity sweetener and/or flavour and/or colour to the chewing gum particles in some embodiments of the invention, such as in case the chewing gum particles substantially consist of gum base.
  • the ingredients are only subjected to elevated temperatures during the extrusion, such as only during the latter part thereof, and the short duration of the extrusion and the quick cooling in the water prevents or reduces decomposition of fragile flavours components, and thus preserving a maximum of the components. This is especially important for natural flavours in order to maintain the full natural taste of the flavour.
  • the chewing gum is a chewing gum comprising one or more compressed module(s), i.e. a compressed chewing gum.
  • the compression is preferably performed by applying pressure to the mixture of e.g. chewing gum particles and chewing gum ingredients, whereby the bulk volume is reduced and the amount of air is decreased. During this process energy is consumed. As the components of the mixture come into closer proximity to each other during the volume reduction process, bonds may be established between the components. The formation of bonds is associated with a reduction in the energy of the system as energy is released. Volume reduction takes place by various mechanisms and different types of bonds may be established between the components depending on the pressure applied and the properties of the components.
  • a method of preparing a chewing gum comprising one or a first compressed module, the method comprising the steps of: a) providing a portion comprising one or more active compound(s) according to formula I, a portion comprising an antioxidant, and chewing gum particles containing gum base; b) optionally providing one or more further chewing gum ingredients; c) dosing the portion comprising the compound(s) according to formula I, the portion comprising antioxidant, and the chewing gum particles containing gum base, and optionally the one or more further chewing gum ingredients; and d) compressing a) and b) after dosing, to obtain a first compressed module.
  • the chewing gum is prepared by providing a portion comprising the compound(s) according to formula I, a portion comprising an antioxidant, and chewing gum particles containing gum base. Subsequent, the portions are individually dosed, i.e. the portions are individually loaded in the tablet machine, and compressed together under high pressure (typically when applying cooling) into a compressed module. Any tablet pressing machine may be used which is capable of pressing tablets comprising particles containing chewing gum base.
  • one or more chewing gum ingredients may, as described above, may be provided and compressed together in step d) with the portion comprising the compound(s) according to formula I, the portion comprising antioxidant and the chewing gum particles containing gum base.
  • the one and more chewing gum ingredients may also be added to the gum base composition in the extruder as described above.
  • the method comprising the steps of: a) providing a portion comprising one or more active compound(s) according to formula I, a portion comprising antioxidant, and chewing gum particles containing gum base; b) optionally providing one or more further chewing gum ingredients; c) mixing the portion comprising the compound(s) according to formula I, the portion comprising antioxidant, and the chewing gum particles containing gum base, and optionally the one or more further chewing gum ingredients, thus obtaining a mixture, and d) compressing the mixture, to obtain a first compressed module.
  • the portions of the chewing gum components are mixed before the loading of the tablet machine.
  • the above methods according to the invention furthermore comprise a step of coating the first compressed module with the above mentioned coatings.
  • the above methods furthermore comprise the steps of e) compressing a portion comprising tablet material to obtain a second compressed module; f) contacting the first compressed module with the second compressed module, to obtain a coherent compressed chewing gum tablet comprising a first and a second compressed module.
  • Useful tablet materials are mentioned above.
  • the method comprises a step of coating the coherent compressed chewing gum tablet.
  • a method of preparing a chewing gum comprising one or more active compound(s) according to formula I, the method comprising the steps of a) providing a portion of powdered pre-mix comprising one or more active compound(s) according to formula I and an antioxidant; b) providing chewing gum particles containing gum base; and c) compressing a) and b) to obtain a chewing gum comprising a compressed module.
  • further chewing gum ingredients selected from the above-mentioned ingredients, may be added during the above step a and/or b.
  • a further aspect relates to a method of preparing a chewing gum according to the invention comprising two compressed modules, the method comprising the steps of: a) providing chewing gum particles containing gum base and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising one or more active compound(s) according to formula I and a portion comprising an antioxidant; c) compressing a) to obtain a first compressed module; d) contacting the first compressed module with b); and e) compressing b) and the first compressed module to obtain a coherent compressed chewing gum tablet comprising a first compressed module and a second compressed module.
  • the portion comprising one or more active compound(s) according to formula I and the portion comprising an antioxidant may be dosed individually or mixed together before dosed in the tablet machine.
  • a method of preparing a chewing gum according to the invention comprising two compressed modules, the method comprising the steps of: a) providing chewing gum particles containing gum base and a portion comprising one or more active compound(s) according to formula I, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising an antioxidant; c) compressing a) to obtain a first compressed module; d) contacting the first compressed module with b); e) compressing b) and the first compressed module, to obtain a coherent compressed chewing gum tablet comprising a first compressed module and a second compressed module.
  • a method of preparing a chewing gum according to the invention comprising two compressed modules, the method comprising the steps of: a) providing chewing gum particles containing gum base and a portion comprising an antioxidant, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising one or more active compound(s) according to formula I; c) compressing a) to obtain a first compressed module; d) contacting the first compressed module with b); e) compressing b) and the first compressed module, to obtain a coherent compressed chewing gum tablet comprising a first compressed module and a second compressed module.
  • a method of preparing a chewing gum according to the invention comprising two compressed modules, the method comprising the steps of: a) providing chewing gum particles containing gum base and a portion comprising an antioxidant, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising tablet material and a portion comprising one or more active compound(s) according to formula I; c) compressing a) to obtain a first compressed module; d) contacting the first compressed module with b); e) compressing b) and the first compressed module, to obtain a coherent compressed chewing gum tablet comprising a first compressed module and a second compressed module.
  • a further step of the above methods comprises a step of coating the coherent compressed chewing gum tablet of step e).
  • chewing gum particles containing gum base and optionally one or more chewing gum ingredients are further provided in step b), and subsequent compressed to obtain a second compressed module prior to contacting the first portion.
  • a tablet material is further provided in step b).
  • a method of preparing a compressed chewing gum tablet according to the invention comprising three compressed modules, the method comprising the steps of: a) providing chewing gum particles containing gum base, a portion comprising an antioxidant, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising tablet material and a portion comprising one or more active compound(s) according to formula I; c) providing a portion comprising tablet material and optionally a portion comprising one or more active compound(s) according to formula I; d) locating b) and c) on opposite sites of a) following a sequence of one or more compressing step(s), to obtain a coherent compressed chewing gum tablet comprising a first compressed module and a second compressed module and a third compressed module.
  • a method of preparing a compressed chewing gum tablet according to the invention comprising three compressed modules, the method comprising the steps of: a) providing chewing gum particles containing gum base, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising tablet material and a portion comprising one or more active compound(s) according to formula I and a portion comprising an antioxidant; c) providing a portion comprising tablet material and optionally a portion comprising one or more active compound(s) according to formula I and a portion comprising an antioxidant; d) locating b) and c) on opposite sites of a) following a sequence of one or more compressing step(s), to obtain a coherent compressed chewing gum tablet comprising a first compressed module and a second compressed module and a third compressed module.
  • the portion comprising one or more active compound(s) according to formula I and the portion comprising an antioxidant may be dosed individually or mixed together before dose
  • the above methods according to the invention furthermore comprise a step of coating the coherent compressed chewing gum tablet of step d).
  • the antioxidant is a lipophilic or a hydrophilic antioxidant.
  • useful lipophilic antioxidants may be selected from the group consisting buthylhydroxytoluen (BHT), butylhydroxyanisol (BHA), tocopherols including alpha, beta, gamma and delta (dl-alfa) tocopherols, ascobylpalmitate, tertbutylhydroxyquinone (TBHQ), alkylgallates (e.g. propylgallate), betacarotene, vitamin A, ascorbylpalmitate, ascorbylstearate, phospholipids, and mixtures thereof.
  • Useful hydrophilic antioxidants may be selected from the group consisting of citric acid, tartaric acid, glycine, ascorbic acid (vitamin C), hydroquinones, sodium ascorbate (vitamin C), calcium ascorbate (vitamin C), salts of sulphur dioxide, including those derived from bisulphite, metabisulphite and sulphite (e.g. sodium sulfite, sodium metabisulphite, potassium-metabisulfit), fumaric acid, malic acid, propionic acid, tartaric acid, phosphoric acid and salts thereof, monothioglycerol, and mixtures thereof.
  • sulphur dioxide including those derived from bisulphite, metabisulphite and sulphite (e.g. sodium sulfite, sodium metabisulphite, potassium-metabisulfit), fumaric acid, malic acid, propionic acid, tartaric acid, phosphoric acid and salts thereof, monothioglycerol, and mixture
  • the antioxidant is added to the chewing gum in an amount in order to obtain a weight ratio, in the chewing gum, between the compound(s) according to formula I and the antioxidant which is at least 1 :2, such as at least 1 : 1, including at least 1 :0.5, e.g. at least 1 :0.2, such as at least 1 :0.16, including at least 1 :0.12, e.g. at least 1 :0.1, such as at least 1 :0.08, including at least 1 :0.06, e.g. at least 1 :0.05, such as at least 1 :0.04, including at least 1 :0.02, or at least 1 :0.01.
  • the weight ratio between the compound(s) according to formula I and the antioxidant in the chewing gum is in the range of 1 :2-1 :0.2, such as in the range of 1 : 1 - 1 :0.2, including in the range of 1 :0.2 - 1 :0.01, such as in the range of 1 :0.2 - 1 :0.02, including in the range of 1 :0.16 - 1 :0.08, such as in the range of 1 :0.1 -1 :0.05, including in the range of 1 :0.12 - 1 :0.10, such as in the range 1 :0.2 - 1 :0.08, including in the range of 1 :0.06 - 1 :0.04, such as in the range of 1 :0.08 - 1 :0.04, or in the range 1 :0.1 - 1 :0.02.
  • the antioxidant is added to the chewing gum in such an amount in order to obtain an amount in the chewing gum in the range of 0.005 - 2% by weight of the uncoated chewing gum, such as in the range of 0.5-2%, including in the range 0.1 - 1%, such as in the range of 0.01 to 1%, e.g. range of 0.01-0.5%, such as in the range 0.01-0.2%, including in the range 0.01-0.1%, such as in the range of 0.1 - 1%, including in the range of 0.1-0.5%, e.g. in the range 0.1-0.2%, such as in the range 0.1-0.1%, including in the range of 0.2-1%, e.g. in the range 0.5-1% or in the range 0.7-1% by weight of the uncoated chewing gum.
  • the antioxidant is added to the chewing gum in order to be presence in an amount in the range of 0.005 - 2% by weight of the gum base, such as in the range of 0.5-2%, including in the range 0.1 - 1%, such as in the range of 0.01 - 1%, including in the range of 0.01-0.5% by weight of the gum base, preferably in the range 0.01-0.2% and even more preferred in the range 0.01-0.1%, such as in the range of 0.1 - 1%, preferably in the range of 0.1-0.5%, preferably in the range 0.1-0.2% and even more preferred in the range of 0.2-1%, preferably in the range 0.5-1% and even more preferred in the range 0.7-1% by weight of the chewing gum.
  • the antioxidant is added to the chewing gum in order to be presence in an amount in the range of at least 0.005% by weight of the gum base, such as at least 0.05%, including at least 0.02%, e.g. at least 0.1%, such as at least 0.5%, including at least 1%, such as at least 1.1% by weight of the gum base, including at least 1.2 by weight of the gum base, e.g. at least 1.5% by weight of the gum base, such as at least 1.8% by weight of the gum base, including at least 2% by weight of the gum base.
  • the antioxidant is added to the chewing gum in order to be presence in an amount of at least 25 ppm, such as at least 50 ppm, including at least 100 ppm, such as at leat 200 ppm, including at least 250 ppm, such as at least 500 ppm, including at least 1000 ppm, such as at least 5000 ppm or at least 10000 ppm.
  • the antioxidant is added to the chewing gum according to the methods of the invention in an amount of at least 1 mg/g gum base, such as at least 1.5 mg/g gum base, e.g. at least 1.7 mg/g gum base, including at least 2.0 mg/g gum base, e.g. at least 2.3 mg/g gum base, or at least 2.5 mg/g gum base.
  • An interesting aspect of the present invention relates to a method for improving the stability of a chewing gum comprising one or more active compound(s) according to formula I, comprising the steps of adding an antioxidant to said chewing gum.
  • antioxidants examples include buthylhydroxytoluen (BHT), butylhydroxyanisol (BHA), tocopherols including alpha, beta, gamma and delta (dl-alfa) tocopherols, tertbutylhydroxyquinone (TBHQ), alkylgallates (e.g. propylgallate), betacarotene, vitamin A, ascorbylpalmitate, ascorbylstearate, phospholipids, and mixtures thereof. Under some circumstances it may be useful to use a combination or mixture of two, such as three, four, five or six, antioxidants. Examples of such mixtures are described above.
  • hydrophilic antioxidants examples include citric acid, tartaric acid, glycine, ascorbic acid (vitamin C), hydroquinones, sodium ascorbate (vitamin C), calcium ascorbate (vitamin C), salts of sulphur dioxide, including those derived from bisulphite, meta bisulphite and sulphite (e.g. sodium sulfite, sodium metabisulphite, potassium-metabisulfit), fumaric acid, malic acid, propionic acid, phosphoric acid and salts thereof, monothioglycerol, and mixtures thereof.
  • sulphur dioxide including those derived from bisulphite, meta bisulphite and sulphite (e.g. sodium sulfite, sodium metabisulphite, potassium-metabisulfit), fumaric acid, malic acid, propionic acid, phosphoric acid and salts thereof, monothioglycerol, and mixtures thereof.
  • a method for improving the stability of one or more active compound(s) according to formula I in a chewing gum comprising a) introducing an oxidation-inhibiting/reducing amount of an antioxidant to a chewing gum comprising one or more active compound(s) according to formula I and a gum base; b) mixing the antioxidant, the compound(s) according to formula I and the gum base to obtain a chewing gum mixture, and c) shaping the mixture to obtain the chewing gum; wherein the stability of the compound(s) according to formula I is improved by at least 10%, such as at least 20%, preferably at least 30%, more preferably at least 50% when stored for 1 month at a temperature of 40 0 C and a humidity of 75% RH compared to a chewing gum not comprising an antioxidant stored under the same conditions.
  • the stability of the compound(s) according to formula I is increased when an oxidation-inhibiting/reducing amount of an antioxidant is added during the production of the chewing gum according to the invention.
  • the expression "oxidation-inhibiting/reducing amount” refers to an amount of one of the above-mentioned antioxidants which is capable of reducing the oxidation of the active compound by at least 10% when stored for 1 month at a temperature of 40 0 C and a humidity of 75% RH.
  • such oxidation-inhibiting/reducing amount of an antioxidant is 1 mg/g gum base, such as 1.5 mg/g gum base, such as 1.7 mg/g gum base, e.g. 2.0 mg/g gum base or such as 2.5 mg/g gum base.
  • the oxidation-inhibiting/reducing amount of an antioxidant is in the range of 0.005 - 2% by weight of the gum base, such as in the range of 0.5-2%, including in the range 0.1 - 1%, such as in the range of 0.01 - 1%, including in the range of 0.01-0.5% by weight of the gum base, preferably in the range 0.01-0.2% and even more preferred in the range 0.01- 0.1%, such as in the range of 0.1 - 1%, preferably in the range of 0.1-0.5%, preferably in the range 0.1-0.2% and even more preferred in the range of 0.2- 1%, preferably in the range 0.5-1% and even more preferred in the range 0.7-1% by weight of the chewing gum.
  • the oxidation-inhibiting/reducing amount of an antioxidant is at least 0.005% by weight of the gum base, such as at least 0.05%, including at least 0.02%, e.g. at least 0.1%, such as at least 0.5%, including at least 1%, such as at least 1.1% by weight of the gum base, including at least 1.2 by weight of the gum base, e.g. at least 1.5% by weight of the gum base, such as at least 1.8% by weight of the gum base, including at least 2% by weight of the gum base.
  • the oxidation-inhibiting/reducing amount of an antioxidant is at least 25 ppm, such as at least 50 ppm, including at least 100 ppm, such as at leat 200 ppm, including at least 250 ppm, such as at least 500 ppm, including at least 1000 ppm, such as at least 5000 ppm or at least 10000 ppm.
  • the antioxidant is capable of reducing the oxidation of the active compound by at least 10% when stored for 1 month at a temperature of 40 0 C and a humidity of 75% RH, such as at least 20%, including at least 30%, e.g. at least 40%, including at least 50%, such as at least 60%, e.g. at least 70%, including at least 80%.
  • a further aspect of the present invention relates to the use of an antioxidant in the preparation of a medicated chewing gum comprising one or more active compound(s) according to formula I for improving the stability of said compound.
  • an antioxidant in the preparation of a medicated chewing gum comprising one or more active compound(s) according to formula I for improving the stability of said compound. Examples of useful lipophilic and hydrophilic antioxidants are mentioned above.
  • the stability of said compound is improved by at least 10% when stored for 1 month at a temperature of 40 0 C and a humidity of 75% RH compared to a medicated chewing gum comprising one or more active compound(s) according to formula I not comprising an antioxidant stored under the same conditions, such as such as at least 20%, e.g. at least 30%, including at least 40%, such as at least 50%, e.g. at least 60%, including at least 80%.
  • a still further aspect relates to the use of an oxidation-inhibiting/reducing amount of an antioxidant for the preparation of a chewing gum comprising one or more active compound(s) according to formula I, wherein at least 80% of the initial amount of said compound is left after storage for 1 month at a temperature of 5 40 0 C and a humidity of 75% RH, such as such as at least 85%, e.g. at least 90%, including at least 95%, such as at least 98% is left after storage.
  • Chewing gums comprising cetihzine 0
  • Examples of fourteen different chewing gums are presented, each having a different combination of type and/or amount of gum base, bulk sweetener, antioxidant, active compound, other ingredients and flavours.
  • the combinations of the ingredients in the different chewing gum are shown in the below tables 1.1 to5 1.4.
  • the chewing gum components are mixed in a mixer with strong horizontally placed Z-blades, which processes the components into a homogeneous gum mass.
  • the mixer is heated to a temperature of approx. 50-60 0 C.
  • the mixing0 process starts with mixing and melting the gum base for 3 minutes.
  • the bulk sweetener maltitol is then added and mixed for 4 minutes. Subsequent, the solubiliser cremophor is added and the mixture is mixed for further 3 minutes. In the next step the sweeteners TwinSweet ® , acesulfame K, the active ingredient Cetirizine di hydrochloride and BHT are added and the mixture is mixed for further 6 minutes. The grape and menthol flavours are then added and mixed for further 5 minutes. Total mixing time to produce a homogeneous gum mass with the chewing gum components is 20 minutes.
  • the gum mass is taken out onto trays and rolled out to a 1-2 cm thick sheet.
  • the chewing gum mass is then cooled for approx. 15- 20 minutes until the right texture of the gum mass is achieved.
  • the chewing gum core is formed into approx. 1 g/piece rectangular tablets by the rolling and scoring line.
  • the chewing gum mass is powdered with talc.
  • the formed chewing gum cores are then cooled to room temperature and hardened on trays at controlled temperature and moisture conditions.
  • the formed and cooled chewing gum cores are then coated and polished with a coating suspension in a round stainless steel coating kettle that rotate during the coating and polishing process.
  • the coating suspension has the following composition:
  • Titanium dioxide 0.9 %
  • the coating suspension is produced by mixing and heated up to 70 0 C.
  • Cores of chewing gum are first separated manually before adding them into the coating kettle. Xylitol suspension is added in portions to the kettle and dispersed even over the surface of the cores after some time to smooth out. The operation is repeated until the tablet weight is reached about 1.3 g Flavour (0.25 % of the total weight of the uncoated cores) is added during coating of the chewing gum product together with a small dosage of the coating suspension, when the tablet weight is between 1.2 g and 1.3 g.
  • polishing also takes place in rotating kettles in which carnauba wax (0.1 % of total weight of the uncoated cores) is added to the coated cores in one portion. Polishing is done until a shinning surface is achieved, typically for 10-20 minutes.
  • Chewing gum comprising cetihzine and different types and amounts of antioxidants
  • the chewing gums were prepared by the same process as described in Example 1.
  • the type and amount of the chewing gum ingredients in the different chewing gums are shown in Tables 2.1 and 2.2.
  • the chewing gums were stored up to 3 months at conditions 40°C/75% RH or 21°C/55% RH. Samples stored at 40°C/75% RH are packed in aluminium bags and samples stored at 21°C/55% RH are packed in plastic bags. The amount of cetirizine was measured at the beginning of the storage (initial amount) and after 1, 2 and 3 months. The results are shown in the below tables 2.4 and 2.5.
  • cetirizine containing chewing gum formulations with the antioxidants BHA or BHT have a better stability compared to formulation without antioxidant.
  • BHA is a better antioxidant than BHA at concentration levels of 400 and 600 ppm
  • the opposite is shown at 40°C/75%RH at concentration level of 800 ppm where BHA is a better antioxidant than BHT.
  • Compressed chewing gum comprising cetihzine and antioxidants
  • Different types of compressed chewing gum tablets comprising cetirizine, antioxidant and chewing gum particles containing gum base are prepared.
  • the cetirizine and/or the antioxidant are located in or between the chewing gum particles containing gum base.
  • the chewing gum tablet is manufactured from a commercially available gum base (Danfree, available from Gumlink A/S, Vejle, Denmark) supplemented with about 15% by weight elastomer, about 20% by weight natural resin, about 20% by weight PVA, about 20% by weight filler, about 5% emulsifier, and about 20% by weight fat.
  • Such mixture is in the following referred to as the "gum base"
  • the gum base is feed to an extruder (Leistrits ZSE/BL 360 kw 104, available from GALA GmbH, Germany) and flavour is added and mixed to the gum base in the extruder.
  • the resulting gum base composition is extruded to a granulator comprising a die plate and liquid filled chamber (A5 PAC 6, available from GALA GmbH, Germany) connected to a water system comprising water supply for the granulator and centrifugal dryer (TWS 20, available from GALA GmbH, Germany).
  • the granulator produces chewing gum particles containing gum base.
  • the preparation of chewing gum particles is described in details in EP1474993, EP147994 and EP147995.
  • the chewing gum particles containing gum base are subsequently mixed with cetirizine, and/or antioxidant and/or other chewing gum ingredients.
  • Method I The gum base is feed to an extruder (Leistrits ZSE/BL 360 kw 104, available from GALA GmbH, Germany) and cetirizine, antioxidant and/or flavour are added and mixed to the gum base in the extruder.
  • the resulting gum base composition is extruded to a granulator comprising a die plate and liquid filled chamber (A5 PAC 6, available from GALA GmbH, Germany)
  • Method II Cetirizine and/or antioxidant may also be incorporated into the particles by adding them during the manufacturing of the gum base. Cetirizine and/or antioxidant are added during the mixing of the gum base ingredients preferably in the end of mixing.
  • the gum base can subsequent be particulated by extrusion, pelletizing, milling, grinding or any other methods
  • the mixture Before pressing, the mixture is passed through a standard horizontal vibration sieve removing particles larger than 2.6 mm.
  • the mixture is subsequently passed to a standard tablet pressing machine comprising dosing apparatus (e.g. P 3200 C, available from Fette GmbH, Germany) and pressed into compressed chewing gum tablets having one compressed module.
  • the filling depth is approximately 7.5 mm and the diameter 7.0 mm.
  • the tablets are pre-compressed to 5.0 mm and then main compressed to 3.2 mm using a pressing pressure of 33.0 - 33.6 kN. There are 61 punches on the rotor, and the rotor speed used is 11 rpm.
  • the individual compressed tablets have a weight of approx. 1.5 g.
  • Chewing gums having two compressed modules may be prepared as follows: 2 g of a portion comprising cetirizine and/or antioxidant located in the chewing gum particles containing gum base or a potion comprising cetirizine and/or antioxidant located between the chewing gum particles containing gum base is filed into the tablet pressing machine and compressed onto the above first module to form a chewing gum having two compressed modules.
  • tablet material containing cetirizine may be used instead of chewing gum particles comprising gum base. Examples of such tablet materials are described above.

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Abstract

La présente invention concerne des gommes à mâcher contenant un médicament, les gommes à mâcher comprenant un ou plusieurs composés actifs selon la formule I, tels que la cétirizine, et un antioxydant qui stabilise efficacement le composé actif, ainsi que des procédés de préparation d'une telle gomme à mâcher répondant à la formule générale (I) : choisie parmi des dérivés de la 2-[4-(diphénylméthyl)-1-pipérazine] dans laquelle R1 est pris dans le groupe consistant en -CH2CH2-O-CH2-R2, -CH2CH=CH-Ar1, CH2-Ar2 et R2 peut être choisi dans le groupe consistant en un groupe -CH2OH, un groupe -COOH et un groupe -CONH2; Ar1 et Ar2 sont indépendamment un noyau aromatique ou hétéroaromatique avec 5 ou 6 atomes dans le noyau, ledit noyau hétéroaromatique comportant 1, 2 ou 3 hétéroatomes choisis dans le groupe consistant en azote, oxygène et soufre, ledit noyau étant non substitué ou substitué par un alkyle en C1-4, de préférence un méthyle ou butyle tertiaire, et Ar2 étant, de préférence, un phényle non substitué ou un phényle substitué par un alkyle en C1-4, de préférence un méthyle ou un butyle tertiaire; et X1 et X2 peuvent être indépendamment choisis dans le groupe consistant en un atome d'hydrogène, un atome d'halogène, un groupe alcoxy en C1-C4 à chaîne droite ou ramifiée ou un groupe trifluorométhyle. L'invention concerne aussi des sels de qualité pharmaceutique, des isomères géométriques, des énantiomères, des diastéréomères et des mélanges de ceux-ci.
PCT/DK2007/050093 2007-07-11 2007-07-11 Gomme à mâcher médicamenteuse stable comprenant un antioxydant WO2009006892A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110064783A1 (en) * 2008-05-26 2011-03-17 Birgitte Bang-Madsen Flavor Impregnation Of A Chewing Gum Core
WO2014086358A1 (fr) * 2012-12-07 2014-06-12 Gumlink A/S Comprimés

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WO2003084511A1 (fr) * 2002-04-04 2003-10-16 Pfizer Products Inc. Tablette a macher sapide
WO2004004479A1 (fr) * 2002-07-02 2004-01-15 Gumlink A/S Gomme a macher comprimee
WO2004028265A1 (fr) * 2002-09-24 2004-04-08 Gumlink A/S Chewing gum a faible teneur en eau
WO2004052367A1 (fr) * 2002-12-06 2004-06-24 Ucb Farchim, S.A. Comprime a base d'efletirizine et de pseudoephedrine
WO2006000232A1 (fr) * 2004-06-29 2006-01-05 Fertin Pharma A/S Chewing-gum liberant un alcaloide du tabac
WO2006124366A2 (fr) * 2005-05-18 2006-11-23 Mcneil-Ppc, Inc. Aromatisant pour chewing gums contenant un medicament
WO2007144902A1 (fr) * 2006-06-12 2007-12-21 Jubliant Organosys Limited Formulation sous forme de comprimé à mâcher bicouche

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084511A1 (fr) * 2002-04-04 2003-10-16 Pfizer Products Inc. Tablette a macher sapide
WO2004004479A1 (fr) * 2002-07-02 2004-01-15 Gumlink A/S Gomme a macher comprimee
WO2004028265A1 (fr) * 2002-09-24 2004-04-08 Gumlink A/S Chewing gum a faible teneur en eau
WO2004052367A1 (fr) * 2002-12-06 2004-06-24 Ucb Farchim, S.A. Comprime a base d'efletirizine et de pseudoephedrine
WO2006000232A1 (fr) * 2004-06-29 2006-01-05 Fertin Pharma A/S Chewing-gum liberant un alcaloide du tabac
WO2006124366A2 (fr) * 2005-05-18 2006-11-23 Mcneil-Ppc, Inc. Aromatisant pour chewing gums contenant un medicament
WO2007144902A1 (fr) * 2006-06-12 2007-12-21 Jubliant Organosys Limited Formulation sous forme de comprimé à mâcher bicouche

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110064783A1 (en) * 2008-05-26 2011-03-17 Birgitte Bang-Madsen Flavor Impregnation Of A Chewing Gum Core
WO2014086358A1 (fr) * 2012-12-07 2014-06-12 Gumlink A/S Comprimés

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