WO2009080024A1 - Chewing-gum comprimé comprenant un mimétique de l'incrétine - Google Patents

Chewing-gum comprimé comprenant un mimétique de l'incrétine Download PDF

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Publication number
WO2009080024A1
WO2009080024A1 PCT/DK2007/050200 DK2007050200W WO2009080024A1 WO 2009080024 A1 WO2009080024 A1 WO 2009080024A1 DK 2007050200 W DK2007050200 W DK 2007050200W WO 2009080024 A1 WO2009080024 A1 WO 2009080024A1
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WO
WIPO (PCT)
Prior art keywords
tablet
compressed
chewing gum
tablet according
incretin mimetic
Prior art date
Application number
PCT/DK2007/050200
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English (en)
Inventor
Niels C. Kaarsholm
Carsten Andersen
Original Assignee
Fertin Pharma A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fertin Pharma A/S filed Critical Fertin Pharma A/S
Priority to PCT/DK2007/050200 priority Critical patent/WO2009080024A1/fr
Priority to PCT/DK2008/000444 priority patent/WO2009080032A1/fr
Publication of WO2009080024A1 publication Critical patent/WO2009080024A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is directed to compressed medicament-containing chewing gum compositions.
  • the present invention is directed to compressed chewing gum compositions comprising an incretin mimetic.
  • Such compositions are useful in the treatment of diabetes or ameliorating the symptoms of diabetes, in particular type II diabetes.
  • IDDM insulin-dependent diabetes
  • MIPDDM non-insulin-dependent diabetes
  • a few patients who appear to have type II diabetes may actually have a slowly progressive form of type I diabetes and eventually become dependent on insulin.
  • Most patients with type II diabetes can be treated without insulin. They are usually overweight and have the insulin resistance of obesity superimposed on the insulin resistance intrinsic to the disease.
  • Weight loss can restore normal glucose levels in the blood of these patients.
  • Their diabetes may develop when the impact of the combined insulin resistances exceeds the ability of their pancreatic beta cells to compensate.
  • Plasma insulin levels in such patients which are often higher than those in people of normal weight who do not have diabetes, are not appropriate to their obesity and hyperglycemia.
  • People with type II diabetes who are not obese may have a primary defect in insulin secretion in which elevations of plasma glucose levels cause not only insulin resistance but also the further deterioration of pancreatic beta cell functioning.
  • Patients with type II diabetes are generally treated with diet modifications and sulfonylureas and/or diguanides.
  • These patients tend to be resistant to insulin, thus high doses of insulin are administered, which in turn leads to hyperinsulinemia which can play a role in the development of atherosclerosis.
  • Incretin mimetics are insulinotropic molecules, in particular peptides, which are able to mimic the biological effect of GLP-I. Such anti-diabetic agents have been investigated for treatment of diabetes mellitus, in particular type II diabetes and in some cases also obesity. Due to the peptide nature of such incretin mimetics peroral administration is difficult due to enzymatic- and acid-catalyzed degradation of such molecules in the gastrointestinal system. Furthermore, incretin mimetics are typically too large for transdermal delivery. Incretin mimetics are therefore administered intravenously, subcutaneously, or by some other invasive route, which is not only cumbersome but also painful for the patient receiving therapy.
  • Incretin mimetics are aromatic peptidic compounds with a size up to about 100 amino acids, preferably up to about 75 amino acids, preferably up to about 50 amino acids, more preferably up to about 40 amino acids, and most preferably about 10-30 amino acids.
  • the buccal membrane potentially offers advantages over other routes of administration.
  • drugs administered through the buccal route has a rapid onset of action, reach high levels in the blood, avoid the first-pass effect of hepatic metabolism, and avoid exposure of the drug to the fluids of the gastrointestinal tract. Additional advantages include easy access to the membrane sites so that the drug can be applied, localized, and removed easily.
  • Controlled release characteristics are desirable in connection with buccal compositions in order to ensure efficient peptide uptake by the buccal membranes and to avoid that the majority of the peptides are swallowed and degraded without exerting their desired effects.
  • Some peptide compounds have an undesirable off-taste which is difficult to mask in connection with oral compositions intended for uptake by the buccal membranes.
  • Peptide compounds are generally relatively unstable and it is thus difficult to obtain compositions with good stability properties.
  • compositions with large peptide doses may increase the risk of getting overdosed since some patients may be able to take up the active compounds more efficiently than other patients.
  • compositions are easy and comfortable to use in order for the patients to comply with their medical regiments.
  • buccal administration of incretin mimetic peptides is disclosed in US 5,766,620.
  • Different types of delivering vehicles have been suggested herein, such as creams, gels, ointments, tablets, patches, and troches.
  • example 6 it is disclosed that tablets are placed inside the cheek and removed after 4.5 hours.
  • Compressed chewing gum tablets including the manufacturing thereof, are described in WO 04/004479, WO 04/004480, WO 04/068964, WO 04/068965 and WO 05/063038.
  • WO 2006/102752 discloses preparation of chewing gums comprising incretin mimetic, said method comprising forming a homogenous gum base comprising incretin mimetic.
  • the chewing gums are produced using conventional chewing gum procedures comprising heating of the gum base.
  • WO 2007/067964 discloses delivery of exendin peptides via the intranasal epithelium. Exendin is used in the treatment of insulin dependent diabetes mellitus. Exendin is traditionally administered to patients in need thereof by injection. Nasal administration is often perceived as unpleasant.
  • the present invention provides a compressed medicament-containing chewing gum composition suitable for the treatment of, or ameliorating the symptoms of, diabetes mellitus.
  • the present invention relates to a compressed chewing gum tablet comprising a first compressed module, wherein said tablet comprises at least one incretin mimetic and compressed chewing gum particles containing gum base.
  • the present invention relates to a compressed chewing gum tablet comprising a first compressed module, wherein said tablet comprises at least one human YY peptide and compressed chewing gum particles containing gum base, wherein said human peptide YY peptide has the following amino acid sequence: Tyr-Pro-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu- Asp-Ala-Ser-Pro-Glu-Glu-Leu- Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu- Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr (SEQ ID NO:8), wherein the C-terminus is optionally amidated and/or the N- terminus is optionally acetylated.
  • the YY peptide is especially suitable for use in treatment of obesity.
  • the present invention relates to a compressed chewing gum tablet comprising a first compressed module, wherein said tablet comprises at least one melanocortin-4 (MC-4) receptor antagonist and compressed chewing gum particles containing gum base.
  • MC-4 melanocortin-4
  • the present invention relates to a tablet according to the invention for use as a medicament.
  • the present invention relates to a tablet according to the invention for the treatment of, or ameliorating the symptoms of, diabetes mellitus.
  • the present invention relates to the use of a tablet according to the invention the manufacture of a medicament for the treatment of, or ameliorating the symptoms of, diabetes mellitus.
  • the present invention relates to method for the treatment of, or ameliorating the symptoms of, diabetes mellitus, said method comprising administering a tablet according to the invention to a patient in need thereof.
  • the present invention provides incretin mimetic, (MC-4) receptor antagonist and/or human YY peptide chewing gum compositions having desired characteristics.
  • compressed chewing gum tablets comprising incretin mimetic, (MC-4) receptor antagonist and/or human YY peptide may be said to be that the chewing experience of patients requiring administration of such compounds is more pleasant with the compressed chewing gum tablets.
  • the normal experience is that more patients prefer the experience of chewing the compressed chewing gum tablets of the invention over conventional chewing gums.
  • the compressed chewing gum tablets of the invention therefore facilitate correct and safe administration of such compounds mimetic compared to prior art formulations.
  • incretin mimetic refer both to incretin mimetics as well as (MC-4) receptor antagonist and human YY peptides. Throughout this document, 'Mncretin mimetic" thus refers to the therapeutically active peptide compounds.
  • Figure 1 illustrates a two-layer compressed tablet according to the invention.
  • Figure 2 illustrates a three layer compressed tablet according the invention.
  • the expression "taste-masking agent” relates to one or more agents or compounds which, optionally together, successfully mask or cover the (potential) bitter taste of the incretin mimetic, but which simultaneously provides the chewing gum with a good palatability.
  • the taste masking agent comprises a polyol sweetener.
  • 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.
  • gum base composition may be a gum base as defined above comprising one or more ingredients (e.g. sweetener, flavour, colouring agents, fillers, etc.) as described below.
  • ingredients e.g. sweetener, flavour, colouring agents, fillers, etc.
  • a chewing gum composition is the final formulation, which constitutes at least a part of the compressed chewing gum tablets ready for sale or use by the consumer.
  • a chewing gum composition may comprise an incretin mimetic, a taste masking agent, a pH controlling agent, sweetener and/or flavour and optionally other ingredients like colouring agents, enzymes, humectants, flavour enhancers, anti-caking agents etc.
  • the expression “chewing gum particles containing gum base” refers to particulated material of a 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 or powder.
  • 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.
  • the particles may also to be understood as macroparticles.
  • compressed chewing gum particles containing gum base refers to a portion of chewing gum particles which become compressed after mixed with, e.g., a taste masking agent, a pH controlling agent, sweeteners or flavours.
  • compressed chewing gum tablet denotes a ready-for-use chewing gum tablet comprising at least one incretin mimetic and compressed chewing gum particles containing gum base possibly mixed with a taste masking agent, a pH controlling agent, sweeteners, flavour or other ingredients and optionally coated.
  • a compressed chewing gum tablet may be 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.
  • 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.
  • insulin mimetic covers insulinotropic molecules, in particular peptides, which are able to mimic GLP-l's biological effects, such as glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, reduction of appetite and delay of food absorption.
  • GLP-l's biological effects such as glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, reduction of appetite and delay of food absorption.
  • simulated saliva is intended to mean an aqueous solution containing M S ⁇ rensen phosphate buffer and 8 g/l NaCI adjusted to pH 6.0 with phosphoric acid.
  • conjugated is intended to indicate a heterogeneous (in the sense of composite or chimeric) molecule formed by the covalent conjugation (or attachment) of one or more incretin mimetics to one or more non-peptide moieties.
  • covalently conjugated means that the incretin mimetic and the non-peptide moiety are either directly covalently joined to one another, or else are indirectly covalently joined to one another through an intervening moiety or moieties, such as a bridge, spacer, or linkage moiety or moieties.
  • a conjugated incretin mimetic is soluble at relevant concentrations and conditions, i.e. soluble in physiological fluids such as saliva.
  • conjugated incretin mimetics of the invention include alkylated, acetylated, glycosylated and/or PEGylated incretin mimetics.
  • the term “derivative” (of an incretin mimetic) is used synonymous with the term “conjugate”, i.e. a “derivative” (of an incretin mimetic) is intended to mean a heterogeneous molecule formed by the covalent conjugation (or attachment) of one or more incretin mimetics to one or more non- peptide moieties.
  • conjugative also covers amidated forms, acylated forms, and esterified forms of such incretin mimetics.
  • non-peptide moiety is intended to indicate a molecule that is capable of conjugating to an attachment group of the incretin mimetic, thereby giving rise to an incretin mimetic conjugate/incretin mimetic derivative.
  • Preferred examples of such molecules include polymer molecules, lipophilic compounds, sugar moieties or organic derivatizing agents. It will be understood that the non-peptide moiety is linked to the peptide through an attachment group of the peptide.
  • every reference to "a non-peptide moiety" attached to the incretin mimetic or otherwise used in the present invention shall be a reference to one or more non-peptide moieties attached to the incretin mimetic.
  • polymer molecule is defined as a molecule formed by covalent linkage of two or more monomers, wherein none of the monomers is an amino acid residue.
  • polymer may be used interchangeably with the term “polymer molecule”.
  • sugar moiety is intended to indicate a carbohydrate molecule attached by in vivo or in vitro glycosylation, such as N- or O-glycosylation.
  • N-glycosylation site has the sequence N-X-S/T/C, wherein X is any amino acid residue except proline, N is asparagine and S/T/C is either serine, threonine or cysteine, preferably serine or threonine, and most preferably threonine.
  • An "O- glycosylation site” is the OH-group of a serine or threonine residue.
  • modification covers substitution, insertion and deletion.
  • the terms “mutation” and “substitution” are used interchangeably herein.
  • the term “introduce” is primarily intended to mean substitution of an existing amino acid residue, but may also mean insertion of an additional amino acid residue.
  • the term “remove” is primarily intended to mean substitution of the amino acid residue to be removed for another amino acid residue, but may also mean deletion (without substitution) of the amino acid residue to be removed.
  • Compressed chewing gum tablets As indicated above, the present invention concerns a compressed chewing gum tablet comprising a first compressed module, wherein said tablet comprises at least one incretin mimetic and compressed chewing gum particles containing gum base.
  • the compressed chewing gum tablet comprises one compressed module, i.e. the above-mentioned "first compressed module” is the only compressed module present in the tablet.
  • the compressed module also contains the compressed chewing gum particles containing gum base.
  • the compressed module also contains the at least one incretin mimetic peptide.
  • the incretin mimetic peptide may be incorporated in the compressed chewing gum particles.
  • the incretin mimetic is present in the compressed module, but is located between the compressed chewing gum particles, i.e. the incretin mimetic does not form part of the compressed chewing gum particles.
  • the compressed module may further contain one or more components selected from the group consisting of tablet material, a taste masking agent, an absorption enhancer, a mucoadhesive agent, and combinations thereof.
  • the compressed module contains an absorption enhancer and/or a mucoadhesive agent.
  • the tablet further comprises a second compressed module.
  • the compressed chewing gum tablet of the invention comprises a first compressed module and a second compressed module, wherein the tablet comprises at least one incretin mimetic and compressed chewing gum particles containing gum base.
  • the compressed chewing gum tablet is one wherein the first compressed module and the second compressed module are cohered to each other.
  • the first compressed module is typically located on the top of the second compressed module as illustrated in Figure 1 which shows a compressed chewing gum tablet 10 containing two compressed modules, i.e. a first compressed module 11 and a second compressed module 12.
  • the two modules 11 and 12 are cohered (or adhered) to each other.
  • Different processes may be applied for obtaining sufficient adhesion between the modules as described in detail below.
  • the mutual adhering between the two modules is obtained by the compression of one module onto the other module.
  • the second compressed module contains the at least one incretin mimetic.
  • the incretin mimetic may be contained in the first compressed module and in the second compressed module.
  • the at least one incretin mimetic is contained in the second compressed module only, i.e. the first compressed module does not contain any incretin mimetic.
  • the incretin mimetic independently of whether the incretin mimetic is contained in the second compressed module only or if contained in both the first and the second compressed module, is preferably not contained within the compressed chewing gum particles containing gum base, i.e. it is preferred that the incretin mimetic does not form part of the compressed chewing gum particles.
  • a preferred embodiment of the invention concerns a compressed chewing gum tablet comprising a first compressed module and a second compressed module, wherein said tablet comprises at least one incretin mimetic and compressed chewing gum particles containing gum base, and wherein the second compressed module contains the at least one incretin mimetic.
  • the first compressed module does not contain any incretin mimetic.
  • this preferred embodiment corresponds to the situation where the first compressed module 11 does not contain any incretin mimetic and where the second compressed module 12 contains the at least one incretin mimetic.
  • the compressed chewing gum particles containing gum base may be present in the first compressed module and in the second compressed module.
  • the second compressed module does not contain gum base, i.e. the second compressed module does not contain compressed chewing gum particles containing gum base.
  • a particularly preferred embodiment of the invention concerns a compressed chewing gum tablet comprising a first compressed module and a second compressed module, wherein the first compressed module comprises chewing gum particles containing gum base, and wherein the second compressed module contains the at least one incretin mimetic.
  • the first compressed module does not contain any incretin mimetic and the second compressed module does not contain any chewing gum particles containing gum base.
  • this particular preferred embodiment corresponds to the situation where the first compressed module 11 does not contain any incretin mimetic, but contains compressed chewing gum particles containing gum base and where the second compressed module 12 contains the at least one incretin mimetic, but does not contain compressed chewing gum particles containing gum base.
  • the second compressed module comprises compressed tablet material. Accordingly, it is also preferred that the first compressed module does not contain tablet material. Examples of useful tablet material are given infra. As will be understood by the person skilled in the art, the above-disclosed principles concerning the structure and components of a compressed chewing gum tablet may be utilised to design a variety of different chewing gum tablets.
  • FIG. 5 One example of such an alternative design is a three-module chewing gum tablet as illustrated in Figure 2.
  • the compressed chewing gum tablet 20 shown in Figure 2 contains three compressed modules 21, 22 and 23.
  • the present invention concerns a compressed chewing gum tablet comprising a first, second and third compressed module, wherein said tablet 10 comprises at least one incretin mimetic and compressed chewing gum particles containing gum base.
  • the first and the third compressed module i.e. modules 21 and 23
  • the first and the third compressed module have the properties, and contains the features, discussed above in
  • the present invention concerns a compressed chewing gum composition
  • a compressed chewing gum composition comprising a first, a second and a third compressed module
  • first and third compressed module comprise chewing gum particles containing gum base
  • the second compressed module contains the at least one incretin mimetic.
  • the first and/or the third compressed module do not contain any incretin mimetic and the second compressed module does not contain any chewing gum particles containing gum base.
  • the first and/or the third compressed module do not contain any incretin mimetic and the second compressed module does not contain any chewing gum particles containing gum base.
  • second compressed module preferably comprises tablet material.
  • first compressed module 21 does not contain any incretin mimetic, but contains compressed chewing gum particles containing gum base; the second compressed module 22 contains the at least one incretin mimetic, but
  • the third compressed module 23 does not contain any incretin mimetic, but contains compressed chewing gum particles containing gum base.
  • the first and the third compressed module i.e. modules 35 21 and 23
  • the second compressed module i.e. module 22
  • the present invention concerns a compressed chewing gum composition
  • a compressed chewing gum composition comprising a first, a second and a third compressed module, wherein the first and third compressed module contain the at least one incretin mimetic, and wherein the second compressed module comprises chewing gum particles containing gum base.
  • the second compressed module does not contain any incretin mimetic and the first and/or third compressed modules do not contain any chewing gum particles containing gum base.
  • first and/or the third compressed module preferably contain tablet material.
  • this particular embodiment corresponds to the situation where the first compressed module 21 contains the at least one incretin mimetic, but does not contain compressed chewing gum particles containing gum base; the second compressed module 22 does not contain any incretin mimetic, but contains compressed chewing gum particles containing gum base; and the third compressed module 23 contains the at least one incretin mimetic, but does not contain compressed chewing gum particles containing gum base.
  • the tablet may, in addition to conventional chewing gum components, contain one or more components selected from the group consisting of tablet material, a taste masking agent, an absorption enhancer, a mucoadhesive agent, and combinations thereof. Such components are described in more detail infra, and may be present in the some or all of the above- mentioned compressed modules.
  • the compressed tablet contains a mucoadhesive agent and/or an absorption enhancer. While such components may be present in all or just some of the compressed modules, it is in general preferred that such components are located in the same compressed modules as the at least one incretin mimetic in order to obtain a co- release of such components.
  • incretin mimetic, the taste masking agent, the absorption enhancer, the mucoadhesive agent, and combinations thereof may encapsulated in the manner described infra, the encapsulated components being present in the modules as disclosed in the preceding paragraphs.
  • the 5 present inventors have found that a surprisingly high buccal bioavailability is achieved if certain well-defined release characteristics of the incretin mimetic are fulfilled.
  • the incretin mimetics may be designed to give a controlled release.
  • a particular preferred chewing gum tablet is a tablet wherein at least 10%, 10 20%, 30%, 40%, 50% or 60% of the incretin mimetic is released within 2, 3, 4, or 5 minutes as determined by LISP XXIX Paddle Method II using 500 ml simulated saliva at 37°C as the dissolution media and 50 rpm as the stirring rate.
  • the compressed chewing gum tablet may, as discussed above, comprise one or more taste masking agents.
  • taste masking agents As will be understood, the necessity of incorporating a taste masking agent in the chewing gum tablet is highly dependent on the chosen incretin mimetic and to what extent the incretin mimetic has an unpleasant taste when released from the chewing gum.
  • the incretin mimetic typically is released faster from a compressed chewing gum tablet than from a conventionally mixed chewing gum, it may be necessary to taste mask the (potential) unpleasant taste of the chosen incretin mimetic.
  • the taste masking agent and the incretin mimetic is preferably located
  • the taste masking agent does not form part of the compressed chewing gum particles containing gum base, i.e. the taste masking agent is located between the compressed chewing gum particles containing gum base. This has the advantage that the incretin mimetic and the taste masking agent are co-released from the
  • the term “co- release” means that when the incretin mimetic is released from the chewing gum during chewing, at least some taste masking agent is also released.
  • the taste-masking agent is one or more agents or compounds which, optionally together, successfully mask or cover the (potential) unpleasant taste of the incretin mimetic, but which simultaneously provides the chewing gum with a good palatability.
  • the taste masking agent is a polyol sweetener.
  • polyol sweeteners include sugars, in particular a sugar selected from the group consisting of dextrose, sucrose, maltose, fructose, lactose, and combinations thereof.
  • polyol sweeteners include sugar alcohols, in particular sugar alcohols selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, isomaltol, isomalt, erythritol, lactitol, maltodextrin, hydrogenated starch hydrolysates, and combinations thereof.
  • Polyol sweetener may be added in an amount of 0-75% by weight of the tablet.
  • poyol is present in an amount of 5-50%, more preferably 5-40%, more preferably 5-30%, more preferably 7-25%, more preferably 7-20%, and most preferably 10-20%.
  • the taste masking agent is a high intensity sweetener or a flavour.
  • Useful high intensity sweeteners may be selected from the group consisting of sucralose, neotame, aspartame, salts of acesulfame in particular the potassium salt of acesulfame (acesulfame K), 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.
  • the tablet of the invention comprises two or more taste masking agent, such as a polyol sweetener and a high intensity sweetener.
  • the polyol sweetener is typically present in an amount of from 90- 99.99% by weight of the total amount of taste masking agent, and the high intensity sweetener is present in an amount of from 0.01-10% by weight of the total amount of taste masking agent.
  • the polyol sweetener is present in an amount of from 95-99.99% by weight of the total amount of taste masking agent, and the high intensity sweetener is present in an amount of from 0.01-5% by weight of the total amount of taste masking agent.
  • the polyol sweetener is present in an amount of from 98-99.9% by weight of the total amount of taste masking agent, and the high intensity sweetener is present in an amount of from 0.1-2% by weight of the total amount of taste masking agent.
  • Suitable taste masking agents include salts of gluconate, such as sodium gluconate.
  • Examples of food acids suitable for use in connection with the present invention include citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, adipic acid and lactic acid, and mixtures thereof.
  • the chewing gum tablet of the invention further comprises a pH controlling agent.
  • Useful pH controlling agents include organic or mineral acids (acidulants), bases, and neutralizing agents. Specific examples of such pH controlling agents include, but is not limited to, ascorbic acid, fumaric acid, adipic acid, lactic acid, malic acid, citric acid, tartaric acid, propionic acid, phosphoric acid and combinations thereof.
  • the preferred ratio of pH controlling agents in relation to the amount of incretin mimetics is 1 :6, or more preferably 2:6 and most preferably about 2:4. In other preferred embodiments, the ratio is about 1 : 10.
  • the pH controlling agent and the incretin mimetic is preferably located within the same compressed module(s). Moreover, it is generally preferred that the pH controlling agent does not form part of the compressed chewing gum particles containing gum base, i.e. the pH controlling agent is located between the compressed chewing gum particles containing gum base.
  • the tablet of the invention may advantageously contain an absorption enhancer.
  • absorption enhancer As used herein, the term “absorption enhancer,” (or, analoguously, “penetration enhancer,” “permeation enhancer,” and the like) is intended to include enhancers that increase the flux of a drug across the mucosa and is limited only by functionality.
  • absorption enhancers may be selected from the group consisting of bile salts, cetomacrogols, chelating agents, citrates, cyclodextrins, detergents including steroidal detergents, enamine derivatives, fatty acids, lecithins, phospholipids, synthetic and natural surfactants including non-ionic surfactants.
  • Absorption enhancers according to the present invention may be selected from one or more of the following groups and sub-groups:
  • membrane penetration-enhancing agents e.g., o (i) a surfactant, o (N) a bile salt, o (iii) a phospholipid or fatty acid additive, mixed micelle, liposome, or carrier, o (iv) an alcohol, (v) an enamine, o (iv) an NO donor compound, o (vii) a long-chain amphipathic molecule, o (viii) a small hydrophobic penetration enhancer, o (ix) sodium or a salicylic acid derivative, o (x) a glycerol ester of acetoacetic acid, o (xi) a cyclodextrin or beta-cyclodextrin derivative, o (xii) a medium-chain fatty acid, o (xiii) a chelating agent, o (xiv) an amino acid or salt thereof, o (xv) an N-acet
  • modulatory agents of epithelial junction physiology such as o nitric oxide (NO) stimulators, 5 o chitosan, and chitosan derivatives;
  • NO o nitric oxide
  • Examples of compounds that can be used as enhancers according to the present invention include but are not limited to: CPC (Cetylpyridinium Chloride), Benzalkonium chloride, Sodium lauryl sulfate, Polysorbate 80, Cetyltrimethylammonium bromide, Laureth 9, Sodium salicylate, Sodium EDTA, EDTA, Aprotinin, Sodium taurocholate, Saponins, Bile salt derivatives, Fatty acids,
  • Sucrose esters Azone emulsion, Dextran sulphate, Linoleic acid, Labrafil,
  • Particularly preferred enahncers include: Polysorbate 80, Polysorbate 20, L- ⁇ - phosphatidylcholine Didecanoyl (DDPC), Polyethylene glycol, Cetyl alcohol, Polyvinylpyrolidone, Polyvinyl alcohol, Lanolin alcohol, Sorbitan monooleate, Methyl- ⁇ -cylodextrin, sodium lauryl sulfate og sodium glycocholate, isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate, sodium dodecyl sulfate, and sorbitan esters C 2 or C 3 alcohol, and C 3 or C 4 diol, DMSO, DMA, DMF, 1-n-dodecyl
  • pH control agents may also function as enhancers and/or pH control agents in tablets according to the present invention.
  • examples of such compounds include but are not limited to: Acetic acid, Adipic acid, Citric acid, Fumaric acid, Glucono- ⁇ -lactone, Gluconsyre, Lactic acid, Malic acid, Maleic acid, Tartaric acid, Succinic acid, Propionic acid, Ascorbic acid, Phosphoric acid, Sodium orthophosphate, Potassium orthophosphate, Calcium orthophosphate, Sodium diphosphate, Potassium diphosphate, Calcium diphosphate, Pentasodium triphosphate, Pentapotassium triphosphate, Sodium polyphosphate, Potassium polyphosphate, Carbonic acid, Sodium carbonate, Sodium bicarbonate, Potasium carbonate, Calcium carbonate, Magnesium carbonate, and Magnesium oxide.
  • mucoadhesive agents may also function as enhancers and/or mucoadhesives in tablets according to the present invention.
  • Exampls of such mucoadhesive compounds include but are not limited to: Carbopol 934+HPC, Maize + Carbopol 907, HPC (hydroxypropyl cellulose), Na-CMC, HPMC (hydroxypropylmethylcellulose), HEMA hydroxyethyl metacrylate, Carbopol 907 crosslinked with sucrose, Polyacrylic acids (PAA), Chitosans, Lectins, Polymetacrylate derivatives, Hyaluronic acid, P(AA-co-PEG) monomethylether monomethacrylate, PAA-PVP (Poly acrylic acid-poly vinyl pyrrilidone), PVP-PEG, methylcellulose, N-Trimethyl, Chitosans, PDMAEMA (poly(dimethyl-aminoethyl methacrylate), HEC Hydroxethyl Cellulose, Carb
  • the term “enhancer” encompasses a wide range of different compounds, and it even encompasses compounds that can also be grouped as mucoadhesive agents as well as pH control agents. This means that in some cases a mucoadhesive agent is used as an enhancer and sometimes as a mucoadhesive agent and in some cases a pH control agent is used as an enhancer and sometimes as a pH control agent.
  • absorption enhancers can be found in inter alia Rowe et al., Handbook of Pharmaceutical Excipients, Fourth Ed. Pharmaceutical Press, London, 2003, and in US 5,766,620.
  • the absorption enhancers disclosed from column 9, line 46, to column 11, line 4, of US 5,766,620 are hereby incorporated by reference.
  • the absorption enhancer and the incretin mimetic is preferably located within the same compressed module(s). Moreover, it is generally preferred that the absorption enhancer does not form part of the compressed chewing gum particles containing gum base, i.e. the absorption enhancer is located between the compressed chewing gum particles containing gum base.
  • the tablet of the invention may advantageously contain a mucoadhesive agent.
  • Mucoadhesive agents are well-known to the person skilled in the art and may, preferably, be a hydrophilic polymer or a hydrogel, in particular a hydrophilic polymer.
  • the mucoadhesive agent is a cellulose derivative, in particular a cellulose derivative selected from the group consisting of hydroxypropylcellulose (HPC), sodium carboxy methylcellulose (Na-CMC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), and combinations thereof.
  • HPC hydroxypropylcellulose
  • Na-CMC sodium carboxy methylcellulose
  • HPMC hydroxypropylmethylcellulose
  • MC methylcellulose
  • EC ethylcellulose
  • HEC hydroxyethylcellulose
  • mucoadhesive agents include, for example, cross- linked acrylic acid-based polymers, such as the Carbopols and Carbomers, e.g. Carbopol 934, Carbopol 907, Carbomer 940 and Carbomer 971; acrylic-acid based polymers, such as hydroxyethyl methacrylate, polyacrylic acid (PAA), polymethacrylate derivatives; monomethylether monomethacrylate (P(AA-co- PEG), poly acrylic acid-poly vinyl pyrrolidone (PAA-PVP); poly(dimethyl- aminoethyl methacrylate) (PDMAEMA); polymers of acrylic acid cross-linked with di-vinyl groups, such as Polycarbophil; AB block polymers of methyl methacrylate and PAA.
  • PAA polyacrylic acid
  • PAA-PVP monomethylether monomethacrylate
  • PAA-PVP poly acrylic acid-poly vinyl pyrrolidone
  • Still other examples include chitosan and its derivatives, such as N- trimethyl chitosans; pectins; lectin and its derivatives; hyaluronic acid; polyethylene oxide; polyethers; vinyl polymers; polymers of vinyl alcohols; dextrin; dextran; poly(methyl vinyl ether/maleic anhydride); polyvinylpyrrolidone (PVP); PVP-PEG; agar; gaur gum; tragacanth; sodium alginate; karaya gum; MEC and thiol group-containing polymers.
  • chitosan and its derivatives such as N- trimethyl chitosans; pectins; lectin and its derivatives; hyaluronic acid; polyethylene oxide; polyethers; vinyl polymers; polymers of vinyl alcohols; dextrin; dextran; poly(methyl vinyl ether/maleic anhydride); polyvinylpyrrolidone (PVP); PVP-PEG; agar
  • the mucoadhesive agent and the incretin mimetic is preferably located within the same compressed module(s). Moreover, it is generally preferred that the mucoadhesive agent does not form part of the compressed chewing gum particles containing gum base, i.e. the mucoadhesive agent is located between the compressed chewing gum particles containing gum base.
  • the chewing gum tablet material comprises water soluble ingredients as well as water insoluble ingredients - and it follows that the particular mixture of ingredients can be compressed into a tablet. In some embodiments, most or all of the water soluble ingredients form one separate module of the tablet and the water insoluble components form another separate module. In other embodiments, some or all of the water soluble material is mixed with the insoluble material.
  • the water soluble ingredients comprise conventional pharmaceutically acceptable excipients, such as glidants, lubricants, fillers, dry or wet binders, etc., used in the pharmaceutical industry in the manufacturing of standard tablets.
  • 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 incretin mimetic 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.
  • ingredients such as incretin mimetics, enhancers, mucoadhesive agents, pH controlling agents, emulsifiers, taste masking agents etc. usually also form part of the "water soluble ingredients".
  • the gum base contained in the compressed modules of the chewing gum tablet is typically present 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 or e.g. those described in the EP 1 474 993, EP 1 474 994 and EP 1 474 995, hereby incorporated by reference.
  • the chewing gum particles contain 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%, such as at least 80% or at least 90%, 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 tablet of the invention comprises a gum base which is essentially insoluble in water.
  • a useful gum base composition typically comprises 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 compressed module containing gum base may typically be made on the basis of gum base particles.
  • the gum base particles are made on the basis of a gum base.
  • the expression further refers to the water-insoluble part of the chewing gum tablet 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 tablet.
  • the chewing gum tablet comprises gum base in the range of 10-80% by weight of the chewing gum tablet, preferably in the range 20-70% by weight, and even more preferably in the range 30-60% by weight of the chewing gum tablet.
  • the gum base which is admixed with chewing gum ingredients (infra), 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 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. Food and Drug Administration, CFR, Title 21, Section 172,615, the Masticatory Substances, Synthetic, the contents of which are incorporated herein by reference for all purposes, such as polyisobutylene.
  • 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 tablet 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 softeners.
  • softener may be used interchangeably with term like “plasticizer” and “plasticizing agent”, 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 may also be considered to be plasticizers, and 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/text urizers may also include natural organic fibres such as fruit vegetable fibres, grain, rice, cellulose and combinations thereof.
  • the chewing gum tablet typically comprises further chewing gum ingredients.
  • chewing gum ingredients include, but is not limited to, bulk sweeteners, high intensity sweeteners, flavouring agents, cooling agents, warming agents, and combinations thereof.
  • 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; 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-l,6-sorbitol manufactured under the tradename PALATINIT by S ⁇ d Weg Zucker), maltodextrins; hydrogenated starch hydrolysates; hydrogenated hexoses; and hydrogenated disaccharides.
  • monosaccharides disaccharides, polysaccharides, sugar alcohols, and mixtures thereof
  • randomly bonded glucose polymers such as those polymers distributed under the tradename POLYDEXTROSE by Pfizer, Inc., Groton, Conn.
  • isomalt a race
  • the bulk sweetener may be selected from the group consisting of dextrose, sucrose, lactose, xylitol, mannitol, sorbitol, mannitol, maltitol, isomaltol or isomalt, erythritol, lactitol, and cyclodextrin.
  • the bulk sweetener is present in amount ranging from 10-70% by weight of the chewing gum tablet.
  • the bulk sweetener may be present in amount ranging from 30-70% by weight of the chewing gum tablet, such as in the range 35-65% by weight of the chewing gum tablet, e.g. in the range 40-60% by weight of the chewing gum tablet.
  • the bulk sweetener may be present in amount ranging from 20-55% by weight of the chewing gum tablet, such as in amount ranging from 30-50% by weight of the chewing gum tablet.
  • the chewing gum tablet 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 high intensity sweeteners can also be provided e.g. using another chewing gum component, such as a resinous compound, as the encapsulation agent. These encapsulation methods (spray drying, etc.) may also be employed in order to encapsulate e.g. peptides and/or enhancer.
  • the concentration of the high intensity 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 level of high intensity sweetener will typically vary from about 0.02% to 8% by weight of the chewing gum tablet.
  • the usage level of the encapsulated high intensity 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 ® ).
  • guar gum hydrolysates e.g. Sun Fiber ®
  • indigestible dextrins e.g. Fibersol ®
  • other low calorie-bulking agents can be used.
  • Flavouring agents may also be useful for the organoleptic properties of the chewing gum tablet.
  • 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., piperonal (vanilla, cream), vanillin (vanilla, cream), alpha-amyl cinnamaldehyde (spicy fruity flavours), butyraldehyde (butter, cheese), valeraldehyde (butter, cheese), citronellal (modifies, many types), decanal (citrus fruits), aldehyde C-8 (cititral
  • 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. Without being limited thereto, such physical forms include free forms, such as spray dried, powdered, beaded forms, encapsulated forms, and mixtures thereof.
  • 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 tablet.
  • Encapsulated flavours may be added to the final blend prior to compression.
  • Different methods of encapsulating flavours mixed into the gum base and flavours compressed 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 US 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- mercapto-
  • cooling agents are further described in the following US patents, all of which are incorporated in their entirety by reference hereto: US 4,230,688; US 4,032,661; US 4,459,425; US 4,136,163; and US 5,266,592.
  • the cooling agents are typically present in amounts from about 0.001& to about 10% by weight of the chewing gum tablet.
  • 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 tablet.
  • titanium dioxide may be incorporated in amounts up to about 2%, but preferably less than about 1%, by weight of the chewing gum tablet.
  • Colouring agents may also include natural food colours and dyes suitable for food, drug and cosmetic applications. These colouring agent are known as F.D.& C. dyes and lakes.
  • the materials acceptable for the foregoing uses are preferably water- insoluble.
  • Illustrative non-limiting examples include the indigoid dye known as F.D.& C. Blue No. 2, which is the disodium salt of 5,5-indigotindisulfonic acid.
  • 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].
  • a full recitation of all 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.
  • Compression adjuvants may also be added. These compounds facilitate compression of the gum into tablets. Suitable compression adjuvants include, but are not 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 above mentioned chewing gum ingredients may be pre-mixed into the gum base or be added to a portion of the chewing gum comprising no or a low amount of gum base.
  • the chewing gum comprises a center filling.
  • the chewing gum tablet may 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.
  • Food acids may enhance the perception of other ingredients in the compressed chewing gum tablet. If the taste masking agents comprise e.g. both food acids and flavouring agents, the perception of the flavouring agents may thus be enhanced by the presence of food acids.
  • taste masking agents such as e.g. food acids and flavouring agents
  • the release of taste masking agents do not always follow the same release profile upon chewing. Usually food acids tend to release rather quickly from the chewing gum upon chewing, while e.g. flavouring agents tend to remain in the chewing gum for a longer period. Consequently, if food acids are released from the chewing gum rather quickly, the perception of the other ingredients in the confectionary base may be significantly reduced, and the effects of the taste masking agents may thus be impaired.
  • Delayed release of food acids and flavouring agents may be accomplished by a method of encapsulating one or more food acids into an encapsulation material, and subsequently incorporating the encapsulation material in the compressed chewing gum tablet as discrete encapsulations for delivery of the taste masking agents upon chewing.
  • Another advantage of encapsulating food acids is that it may buffer food acids from other ingredients, and vice versa, which may be helpful in situations where the food acids and said ingredients may interact or react together in a manner that degrades the product if the food acid is not encapsulated.
  • the one or more flavouring agents may also be encapsulated separate from the one or more food acids, optionally with a different encapsulation material than the one or more food acids.
  • the one or more food acids and flavouring agents may however also be an advantage to encapsulate one or more food acids and one or more flavouring agents together in order to ensure their simultaneous release.
  • the one or more food acids and the one or more flavouring agents are encapsulated separately in encapsulation material having substantially the same release characteristics, optionally being encapsulated in identical encapsulation material.
  • the incretin mimetic may however also be encapsulated separately, optionally in encapsulation material having substantially the same release characteristics as the encapsulation material of the one or more food acids, optionally being encapsulated in identical encapsulation material. It is also envisioned that the incretin mimetic may be encapsulated together with one or more flavouring agents as well as one or more food acids. Alternatively, the incretin mimetic, the one or more flavouring agents, and the one or more food acids are encapsulated separately in encapsulation materials having substantially the same release characteristics, optionally identical release characteristics.
  • Encapsulating the incretin mimetic and/or absorption enhancers together or separately may also be advantageous for obtaining desired release characteristics. Encapsulation of incretin mimetic may in particular achieve slow or controlled release of the incretin mimetic in order to avoid excessive ingestion of the incretin mimetic via the gastrointestinal route. Encapsulation of the incretin mimetic and one or more absorption enhancers together may help to ensure better absorption through the buccal membrane since the two components are released simultaneously. Alternatively, the incretin mimetic and one or more absorption enhancers are encapsulated separately in encapsulation material having substantially the same release characteristics, optionally being encapsulated in identical encapsulation material.
  • the one or more mucoadhesive agents may however also be encapsulated separately, optionally in encapsulation material having substantially the same release characteristics as the encapsulation material of the one or more absorption enhancers, optionally being encapsulated in identical encapsulation material.
  • incretin mimetic may be encapsulated together with one or more absorption enhancers as well as one or more mucoadhesive agents.
  • the incretin mimetic, the one or more absorption enhancers, and the one or more mucoadhesive agents are encapsulated separately in encapsulation materials having substantially the same release characteristics, optionally identical release characteristics.
  • the incretin mimetic, one or more flavouring agents, and one or more absorption enhancers may also be envisioned encapsulating the incretin mimetic, one or more flavouring agents, and one or more absorption enhancers together. Alternatively, they are encapsulated separately in encapsulation material having substantially the same release characteristics, optionally being encapsulated in identical encapsulation material.
  • a particularly interesting option may be to encapsulate the incretin mimetic and the one or more absorption enhancers together, while the one or more flavouring agents are encapsulated separately from the incretin mimetic and the one or more absorption enhancers.
  • the encapsulation material of the incretin mimetic and the one or more absorption enhancers may have substantially the same release characteristics as the encapsulation material of the one or more flavouring agents.
  • incretin mimetic one or more food acids, one or more flavouring agents, one or more absorption enhancers, and one or more mucoadhesive agents separately or together. It may e.g. be envisioned encapsulating the incretin mimetic, one or more food acids, one or more flavouring agents, and one or more absorption enhancers together. Alternatively, they are encapsulated separately in encapsulation material having substantially the same release characteristics, optionally being encapsulated in identical encapsulation material.
  • a particularly interesting option may be to encapsulate the incretin mimetic and the one or more absorption enhancers together, while the one or more flavouring agents and the one or more food acids are encapsulated together, separate from the incretin mimetic and the one or more absorption enhancers.
  • the encapsulation material of the incretin mimetic and the one or more absorption enhancers may have substantially the same release characteristics as the encapsulation material of the one or more flavouring agents and the one or more food acids.
  • the encapsulation material may comprise at least one natural resin, such as at least one polyterpene resin, at least one hydrogenated resin, or at least one polymerised resin, or mixtures thereof.
  • the at least one polyterpene resin may comprise polymerised monoterpenes. It is envisioned that the at least one polyterpene resin may consist essentially of polymerised monoterpenes.
  • the at least one polyterpene resin may also comprise polymerised cyclic monoterpenes, and it envisioned that the at least one polyterpene resin may consist essentially of polymerised cyclic monoterpenes.
  • the at least one polyterpene resin may further comprise polymerised limonene.
  • the at least one polyterpene resin may consist essentially of polymerised limonene.
  • the at least one polyterpene resin may also comprise polymerised alpha-pinene.
  • the at least one polyterpene resin may consist essentially of polymerised alpha- pinene.
  • the at least one polyterpene resin may further comprise polymerised beta-pinene.
  • the at least one polyterpene resin may consist essentially of polymerised beta- pinene.
  • the at least one polyterpene resin may comprise styrenated polyterpene resin.
  • the encapsulation material may comprise a combination of two or more polyterpene resins.
  • the encapsulation material may comprise a combination of polymerised alpha-pinene and polymerised beta-pinene; a combination of polymerised alpha-pinene and polymerised limonene; a combination of polymerised alpha-pinene and styrenated polyterpene resin.
  • the at least one polyterpene resin comprises at least 50% by weight polymerised monoterpenes, preferably at least 75% by weight polymerised monoterpenes, even more preferably at least 95% by weight polymerised monoterpenes. In another embodiment of the invention, the at least one polyterpene resin comprises at least 50% by weight polymerised cyclic monoterpenes, preferably at least 75% by weight polymerised cyclic monoterpenes, even more preferably at least 95% by weight polymerised cyclic monoterpenes.
  • Natural resins comprised in the encapsulation delivery system may 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, pen
  • the compressed chewing gum tablet of the invention may comprise two or more different encapsulation materials, such as three or more different encapsulation materials.
  • the different encapsulation materials may have different release characteristics.
  • the encapsulation material may comprise at least one polyvinyl acetate.
  • the encapsulation material used to encapsulate one of the components discussed above as suitably being encapsulated may comprise at least one polyterpene resin and a second encapsulation material used to encapsulate another of the components discussed above as suitably being encapsulated may comprise at least one polyvinyl acetate.
  • the encapsulation material used to encapsulate one of the components discussed above as suitably being encapsulated may comprise at least one hydrogenated resin and a second encapsulation material used to encapsulate another of the components discussed above as suitably being encapsulated may comprise at least one polyvinyl acetate.
  • the encapsulation material used to encapsulate one of the components discussed above as suitably being encapsulated may comprise at least one polymerised resin and a second encapsulation material used to encapsulate another of the components discussed above as suitably being encapsulated may comprise at least one polyvinyl acetate.
  • the encapsulation component e.g. food acids
  • the encapsulation component may be encapsulated by first melting the encapsulation material, e.g. a natural resin, in e.g. a high shear mixer. A softening system may then be added to the molten polymer. The encapsulation component, e.g. food acids, may then be added to the resulting mixture and mixed, e.g. under high shear.
  • the resulting filled polymer melt is then cooled and formed to a suitable size, e.g. by means such as chopping, pulverizing, milling or grinding.
  • the encapsulated component may be stored in an air tight container with low humidity until it is to be employed in a compressed chewing gum tablet.
  • the method comprising the step of: a) mixing the at least one encapsulation component, e.g. food acids with at least one encapsulation material, e.g. a natural resin, b) converting the mixture of step a) to particles, thus obtaining the encapsulated component.
  • a) mixing the at least one encapsulation component e.g. food acids with at least one encapsulation material, e.g. a natural resin
  • encapsulation material e.g. a natural resin
  • Step a) may also involve mixing components such as a softening system and/or at least one elastomer with the at least one encapsulation component and the at least one encapsulation material.
  • the chewing gum tablet may comprise a coating applied onto the chewing gum tablet.
  • a suitable coating is preferably a 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 coatings of any composition including those currently used in coating of chewing gum, pharmaceutical products and confectioneries.
  • the chewing gum tablet comprises the coating in an amount in the range of 1- 80% by weight of the tablet, such as in an amount in the range of 10-50%, or 15- 45% by weight of the tablet.
  • the chewing gum tablet comprises the coating in an amount in the range of 20-40% by weight of the chewing gum tablet.
  • 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 tablets 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, incretin mimetics and/or other therapeutically active compounds.
  • 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 may act simultaneously as a sweetener and as a taste masking agent.
  • a syrup containing crystallizable sugar and/or polyol is applied onto the chewing gum tablet 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.
  • 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.
  • 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 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 compressed chewing gum tablet 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 center-filled chewing gum tabletss 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 gum tablets 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.
  • chewing gum particles containing gum base are provided.
  • Useful particles may be manufactured according to conventional methods e.g. as described in the EP 1 474 993, EP 1 474 994 and EP 1 474 995, hereby incorporated by reference.
  • the chewing gum particles may be in any suitable form. 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 tablet is a compressed chewing gum tablet.
  • the compression is preferably performed by applying pressure to the mixture of chewing gum particles, ingredients etc., 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 compressed chewing gum tablet comprising one compressed module, the method comprising the steps of: a) providing a portion comprising an active compound according to formula I, a portion comprising taste-masking agent, and chewing gum particles containing gum base; b) optionally providing one or more further chewing gum ingredients; c) dosing the portion comprising the compound according to formula I, the portion comprising taste-masking agent, 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 compressed chewing gum tablet is prepared by providing a portion comprising the compound according to formula I, a portion comprising taste- masking agent, and chewing gum particles containing gum base. Subsequent, the portions are individually dosed, i.e. the portions are individually loaded in the table machine, and compressed together under high pressure (typically when applying cooling) into a first 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 according to formula I, the portion comprising taste-masking agent and the chewing gum particles containing gum base.
  • the one and more chewing gum ingredients may also be added to the gum base in the extruder as described above.
  • the method comprising the steps of a) providing a portion comprising an active compound according to formula I, a portion comprising taste-masking agent, and chewing gum particles containing gum base; b) optionally providing one or more further chewing gum ingredients; c) mixing the portion comprising the compound according to formula I, the portion comprising taste-masking agent, 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 methods according to the invention furthermore comprise a step of coating the first compressed module with the above mentioned coatings.
  • the above methods furthermore comprises the steps of e) providing a portion comprising tablet material; f) contacting the first compressed module with the portion of step e), i.e. the tablet material; and g) compressing the portion of e) and the first compressed module to obtain a coherent compressed chewing gum tablet comprising a first and a second compressed module.
  • a further step of the present methods comprises a step of coating the coherent compressed chewing gum tablet of step g).
  • the method comprises a step of coating the coherent compressed chewing gum tablet.
  • a further aspect relates to a method of preparing a compressed chewing gum tablet 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 an active compound according to formula I and a portion comprising a taste-masking agent; 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 an active compound according to formula I and the portion comprising a taste- masking agent may be dosed individually or mixed together before dosed in the tablet machine.
  • a further step of the present method 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 two compressed modules, the method comprising the steps of a) providing chewing gum particles containing gum base and a portion comprising an active compound according to formula I, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising taste-masking agent; 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.
  • the portion comprising an active compound according to formula I and chewing gum particles comprising gum base may be dosed individually or mixed together before dosed in the tablet machine.
  • a further step of the present method 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 a taste-masking agent, and optionally portion(s) comprising one or more chewing gum ingredients; b) providing a portion comprising tablet material and optionally a portion comprising an active compound according to formula I; c) providing a portion comprising tablet material and a portion comprising an active compound 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.
  • the portion comprising a taste-masking agent and the chewing gum particles containing gum base may be dosed individually or mixed together before dosed in the tablet machine.
  • the method according to the invention furthermore comprises a step of coating the coherent compressed chewing gum tablet of step d).
  • a still further aspect relates to 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 active compound according to formula I, and optionally portion(s) comprising one or more chewing gum ingredients, b) providing a portion comprising tablet material and optionally a portion comprising a taste-masking agent, c) providing a portion comprising tablet material and a portion comprising a taste-masking agent, 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 method according to the invention furthermore comprises a step of coating the coherent compressed chewing gum tablet of step d).
  • a final aspect relates to 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 an active compound according to formula I and a portion comprising a taste-masking agent; c) providing a portion comprising tablet material and a portion comprising an active compound according to formula I and a portion comprising a taste- masking agent; 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.
  • the a portion comprising an active compound according to formula I and the portion comprising a taste-masking agent may be dosed individually or mixed together before dosed in the tablet machine.
  • the compressed chewing gum tablet of the invention comprises at least one incretin mimetic.
  • the incretin mimetic may be added at any time during the process of preparing the chewing gum. However, it is preferred that the incretin mimetic is added to the chewing gum subsequent to any significant heating or mixing. In other words, the incretin mimetic should preferably be added immediately prior to the compression of the final tablet. Referring to the process described infra, the adding of the incretin mimetic may be cautiously blended with pre-mixed gum base particles and further desired ingredients, immediately prior to the final compression of the tablet.
  • the incretin mimetic is selected from the group consisting of a glucagon-like peptide (GLP) and analogues and derivatives thereof; exendine 4 and analogues and derivatives thereof.
  • GLP glucagon-like peptide
  • incretin mimetic is replaced by human peptide YY and analogues and derivatives thereof, and/or a selective melanocortin-4 (MC-4) receptor antagonist.
  • the incretin mimetic is GLP-I, in particular GLP-I (7-37), and analogues and derivatives thereof.
  • GLP-I The amino acid sequence of GLP-I is given by Schmidt et al., Diabetologia 28; 704-707;1985.
  • Human GLP-I is a 37 amino acid residue peptide originating from preproglucagon which is synthesized, inter alia in the L-cells in the distal ileum, in the pancreas, and in the brain. Processing of preproglucagon to GLP-I (7-36)- amide, GLP-I (7-37) and GLP-2 occurs mainly in the L-cells.
  • GLP-I (7-37) Although the interesting pharmacological properties of GLP-I (7-37), and analogues thereof, have attracted much attention in recent years only little is known about the structure of these molecules.
  • the secondary structure of GLP-I in micelles has been described by Thorton, et al., Biochemistry 33;3532-3539; 1994, but in normal solution, GLP-I is considered a very flexible molecule.
  • the compressed chewing gum tablet comprises a peptide having the following amino acid sequence: H-A-E-G-T-F-T-S- D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-I-A-W-L-V-K-G-R-G (SEQ ID NO: 1), wherein the C- terminus is optionally amidated and/or the N-terminus is optionally acetylated.
  • SEQ ID NO: 1 is GLP-I (7-37) and, in a preferred embodiment, the C-terminus is amidated.
  • the compressed chewing gum tablet may comprise analogues, such as fragments, of GLP-I (7-37).
  • GLP-I (7-37) analogues to be used for the purposes described herein include [G37*]-SEQ ID NO: 1 (GLP-I (7-36)); [R36*+G37*]-SEQ ID NO: 1 (GLP-I (7-35)) and [G35* + R36*+G37*]-SEQ ID NO: 1 (GLP-I (7-34)), including C-terminus amidated forms thereof and/or N-terminus acylated forms thereof.
  • GLP-I (7-37) analogues include such analogues where the amino acid sequence of GLP-I (7-37) has been modified in one or more of positions 8, 22 and 34.
  • Specific examples of such analogues include H-A-E-G-T-F- T-S-D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-I-A-W-L-V-R-G-R-G (SEQ ID NO:5) ([K34R]- SEQ ID NO: 1), wherein the C-terminus is optionally amidated and/or the N- terminus is optionally acetylated; H-Aib-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K- E-F-I-A-W-L-V-R-G-R-G (SEQ ID NO:6) ([A8Aib] + [K34R]-
  • GLP-I analogues and derivatives are those described in Hoist J., Expert Opin. Emerg. Drugs, 9(l); 155-161;2004; RoNn R. et al., Am J. Physiol. Endocrinol. Metab., 283;E745-E752;2002; Deacon C, Diabetes, 53;2181- 2187;2004; Perry T., et al., Trends Pharmacol. ScL, 24(7);377-383;2003; HoIz G., et al., Curr. Med. Chem., 10(22);2471-2481;2003; Naslund E., et al., Regul.
  • GLP-I analogues and derivatives described in the above-mentioned reference are useful for the purposes described herein and are incorporated by reference.
  • any of the above- mentioned GLP-I analogues and derivatives, including GLP-I (7-37) itself, may be further modified by the SIP technology described in WO 99/46283.
  • the hexapeptide (Lys) 6 or (LyS) 6 -NH 2 is introduced at the C-terminus of GLP-I (7-37), including the analogues and/or derivatives thereof, and/or that the hexapeptide (Lys) 6 or Ac-(LyS) 6 is introduced at the N-terminus of GLP-I (7-37), including the analogues and/or derivatives thereof. 5
  • any of the above-mentioned GLP-I analogues, including GLP-I (7-37) itself, may be derivatized.
  • the above-mentioned GLP-I analogues, including GLP-I (7-37) itself are covalently attached to a non-peptide moiety, such as a polymer molecule, a0 lipophilic compound, a sugar moiety or an organic derivatizing agent. Specific examples of non-peptide moieties are described infra.
  • the incretin mimetic is exendin 4 and analogues and derivatives thereof.
  • Exendin 4 is a 395 amino acid residue peptide and its sequence is shown in US 5,424,286.
  • the compressed chewing gum tablet comprises a peptide having the following amino acid sequence: H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-0 S-S-G-A-P-P-S (SEQ ID N0:2), wherein the C-terminus is optionally amidated and/or the N-terminus is optionally acetylated.
  • SEQ ID N0:2 is exendin 4 and, in a preferred embodiment, the C-terminus is amidated.
  • the compressed chewing gum tablet may comprise analogues of exendin 4.
  • exendin 4 analogue to be used for the5 purposes described herein include exendin 3 having the following amino acid sequence: H-S-D-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P- S-S-G-A-P-P-S (SEQ ID NO:3) ([G2S] + [E3D]-SEQ ID NO:2), wherein the C- terminus is optionally amidated and/or the N-terminus is optionally acetylated.
  • any of the above-mentioned exendin 4 analogues and derivatives, including exendin 4 itself, may be further modified by the SIP technology described in WO 99/46283.
  • the hexapeptide (Lys) 6 or (LyS) 6 -NH 2 is introduced at the C-terminus of exendin 4, including analogues and/or derivatives thereof, and/or that the hexapeptide (Lys) 6 or Ac-(LyS) 6 is introduced at the N-terminus of exendin 4, including the analogues and/or derivatives thereof.
  • the exendin 4 analogue has the following amino acid sequence: H-S-D-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F- I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-S-K-K-K-K-K (SEQ ID NO:4) ([S39SKKKKKK]-SEQ ID NO:2), wherein the C-terminus is optionally amidated and/or the N-terminus is optionally acetylated. In a preferred embodiment, the C- terminus is amidated.
  • any of the above-mentioned exendin 4 analogues, including exendin 4 itself, may be derivatized.
  • the above-mentioned exendin 4 analogues, including exendin 4 itself are covalently attached to a non-peptide moiety, such as a polymer molecule, a lipophilic compound, a sugar moiety or an organic derivatizing agent. Specific examples of non-peptide moieties are described infra.
  • the incretin mimetic is human peptide YY and analogues and derivatives thereof.
  • Human peptide YY is a 36 amino acid residue regulatory gut hormone peptide present in endocrine cells in the intestine.
  • the sequence and function of human peptide YY have been described in inter alia Tatemoto, K. et al. BBRC 157;713; 1988; Hallden, G. and G. Aponte, J. Biol. Chem. 272; 12591; 1997); Murphy, KG. and SR. Bloom, Exp. Physiol. 89;507;2004; Batterham, R. et al. Nature 418;650;2002; Gribble, F. et al.
  • the compressed chewing gum tablet comprises a peptide having the following amino acid sequence: Tyr-Pro-Ile- Lys-Pro-Glu-Ala-Pro-Gly-Glu- Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala- Ser-Leu-Arg-His-Tyr-Leu- Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr (SEQ ID NO:8), wherein the C-terminus is optionally amidated and/or the N-terminus is optionally acetylated.
  • SEQ ID NO:8 is human peptide YY and, in a preferred embodiment, the C-terminus is amidated.
  • the compressed chewing gum tablet may comprise analogues of human peptide YY.
  • a human peptide YY analogue to be used for the purposes described herein include the human peptide (3-36) YY fragment having the following amino acid sequence: Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu- Asp-Ala-Ser-Pro- Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu- Asn-Leu-Val-Thr-Arg- Gln-Arg-Tyr (SEQ ID NO:9) ([Y1* + P2*]-SEQ ID NO:8), wherein the C-terminus is optionally amidated and/or the N-terminus is optionally acetyl
  • the C-terminus is amidated.
  • any of the above- mentioned human peptide YY analogues and derivatives, including human peptide YY itself, may be further modified by the SIP technology described in WO 99/46283.
  • the hexapeptide (Lys) 6 or (LyS) 6 -NH 2 is introduced at the C- terminus of human peptide YY, including the analogues and/or derivatives thereof, and/or that the hexapeptide (Lys) 6 or Ac-(LyS) 6 is introduced at the N-terminus of human peptide YY, including the analogues and/or derivatives thereof.
  • any of the above-mentioned human peptide YY analogues may be derivatized.
  • the above-mentioned human peptide YY analogues, including human peptide YY itself are covalently attached to a non-peptide moiety, such as a polymer molecule, a lipophilic compound, a sugar moiety or an organic derivatizing agent. Specific examples of non-peptide moieties are described infra.
  • the incretin mimetic is a selective melanocortin-4 (MC-4) receptor anatagonist, in particular ⁇ -MSH and analogues or derivatives thereof.
  • the compressed chewing gum tablet comprises a peptide having the following amino acid sequence: S-Y-S-M-E- H-F-R-W-G-K-P-V (SEQ ID NO:9), wherein the C-terminus is optionally amidated and/or the N-terminus is optionally acetylated.
  • SEQ ID NO:9 is ⁇ -MSH and, in a preferred embodiment, the C-terminus is amidated.
  • the compressed chewing gum tablet may comprise analogues of ⁇ - MSH.
  • ⁇ .MSH analogues to be used for the purposes described herein include the analogues disclosed in WO 07/022774. More particular, the analogues listed as SEQ ID NOs: 1-36 on page 64-65 of WO 07/022774, including amidated and acetylated forms thereof, are considered useful for the purposes described herein. Accordingly, each of the individual amino acid sequences listed as SEQ ID NOs: 1-36 on page 64-65 of WO 07/022774, including amidated and acetylated forms thereof, are hereby incorporated by reference.
  • any of the above-mentioned ⁇ -MSH analogues and derivatives, including ⁇ -MSH itself, may be further modified by the SIP technology described in WO 99/46283.
  • the hexapeptide (Lys) 6 or (LyS) 6 -NH 2 is introduced at the C- terminus of ⁇ -MSH, including the analogues and/or derivatives thereof, and/or that the hexapeptide (Lys) 6 or Ac-(LyS) 6 is introduced at the N-terminus of ⁇ - MSH, including the analogues and/or derivatives thereof.
  • the hexapeptide (Lys) 6 or Ac-(LyS) 6 is introduced at the N-terminus of ⁇ -MSH, including the analogues and/or derivatives thereof.
  • incretin mimetics are available for the purposes described herein. Moreover, in addition to the specifically disclosed amino acid sequences (SEQ ID NOs: 1-9), analogues and derivatives of these sequences are considered useful.
  • the tablet of the invention comprises an incretin mimetic, wherein said incretin mimetic is an analogue of the parent amino acid sequences selected from the group consisting of SEQ ID: 1, SEQ ID NO:2, SEQ ID NO.3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, including their C-terminus amidated form and/or their N-terminus acetylated form, wherein said analogue contains 1-10 amino acid modifications relative to the parent amino acid sequence.
  • the analogues contains 1-7, such as 1-5, e.g. 1-3 amino acid modifications relative to the parent amino acid sequence.
  • the incretin mimetic (such as any of the amino acid sequences selected from the group consisting of SEQ ID: 1, SEQ ID NO:2, SEQ ID NO.3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, including their C-terminus amidated form and/or their N-terminus acetylated form, and analogues thereof, is covalently conjugated to a non-peptide moiety.
  • non-peptide moieties examples include a polymer molecule, a lipophilic compound, a sugar moiety or an organic derivatizing agent.
  • the various non-peptide moieties are discussed in more detail in the paragraphs entitled “Sugar moiety”, “Lipophilic compound”, “Polymer molecule” and “Organic derivatizing agent”.
  • the peptide-based incretin mimetics may be prepared by methods known per se in the art.
  • the incretin mimetics may be prepared by standard peptide- preparation techniques, such as solution synthesis or Merrifield-type solid phase synthesis. A detailed description if such methods can be found in John Jones, The Chemical Synthesis of Peptides, Clarendon Press, Oxford, 1991; Bodanszky & Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag Berlin Heidelberg, 1994; and WO 99/46283.
  • Another possible strategy is to prepare two or more amino acid sequences separately by solution synthesis, solid phase synthesis, recombinant techniques, or enzymatic synthesis, followed by coupling of the two or more sequences by well-known segment condensation procedures, either in solution or using solid phase techniques or a combination thereof.
  • segment condensation procedures are described by, e.g., Liu et al., J. Am. Chem. Soc. 118;307-312; 1996 and Dawson et al., 1996, 226:776) and W. Kullmann, 1987, Enzymatic Peptide Synthesis, CRC Press, Boca Raton, FIa., pp. 41-59.
  • the peptide-based incretin mimetics may also be prepared by means of recombinant DNA-technology using general methods and principles known to the person skilled in the art (see, for example, J. Sambrook, E. F. Fritsch, and T. Maniatus, 1989, Molecular Cloning, A Laboratory Manual, 2d edition, Cold Spring Harbor, New York).
  • the compressed chewing gum tablet comprises, in addition to the at least one incretin mimetic, at least one additional therapeutically active compound.
  • the additional therapeutically active compound is an anti-diabetic compound.
  • anti-diabetic compounds include therapeutically active compounds selected from the group consisting of sulfonylureas, biguanides, meglitinides, thiazolidinediones, ⁇ -glucosidase inhibitors, metformin, and DPP-4 inhibitors.
  • sulfonylureas include the so-called first-generation agents tolbutamide (Orinase ® ), acetohexamide (Dymelor ® ), tolazamide (Tolinase ® ) and chlorpropamide (Diabinese ® ), as well as the so-called second-generation agents glipizide (Glucotrol ® ), glyburide (Diabeta ® ), glimepiride (Amaryl ® ) and gliclazide (Diamicron ® ).
  • biguanides include incretin mimetic (Glucophage ® ), phenformin and buformin.
  • a particular preferred biguanide is incretin mimetic.
  • meglitinides include repaglinide (Prandin ® ) and nateglinide (Starlix ® ).
  • thiazolidinediones include rosiglitazone (Avandia ® ), pioglitazone (Actos ® ) and troglitazone (Rezulin ® ).
  • ⁇ -glucosidase inhibitors examples include miglitol (Glyset ® ) and acarbose (precose ® ).
  • DPP-4 inhibitors include vildagliptin (Galvus ® ) and sitagliptin.
  • incretin mimetic is preferred.
  • the additional therapeutically active compound and the incretin mimetic is preferably located within the same compressed module(s). Moreover, it is generally preferred that the additional therapeutically active compound does not form part of the compressed chewing gum particles containing gum base, i.e. the additional therapeutically active compound is located between the compressed chewing gum particles containing gum base.
  • the tablet of the invention is useful for the treatment of, or ameliorating the symptoms of, diabetes mellitus, in particular diabetes mellitus type II and/or obesity.
  • the amount of incretin mimetic being transferred from the tablet to the blood stream is about 1- 25% of the amount in the tablet.
  • the remaining 75-99% of the peptide in the tablet is either retained in the chewing gum and/or swallowed and digested.
  • Preferably about 2-15% of the peptide is transferred to the blood stream, more preferably 3-10%, and most preferably 5-8%.
  • the premixture is mixed dry in a conventional dry mixer.
  • each layer including the premixture is mixed dry in a conventional dry mixer and formed into a tablet in a tablet machine:
  • Chewing gum mixture I is passed to a standard tablet pressing machine comprising dosing apparatus (e.g. P 3200 C, available from Fette GmbH, Germany) and compressed to form a first compressed module. Subsequently, mixture II is filed into the tablet pressing machine and compressed onto the first module to form a chewing gum tablet having two compressed modules.
  • dosing apparatus e.g. P 3200 C, available from Fette GmbH, Germany
  • the content of exenatide is 100 meg per piece. If a tablet with 10 mg exenatide is desired, 0,2 gram of exenatide is added in the mixture for the second layer and the sorbitol content is reduced with 0,1 gram.
  • the apparatus is composed of a temperature controlled chewing chamber with two horizontal pistons and one vertical piston.
  • a chewing gum tablet is placed in the chamber and 20 ml of a phosphate buffer equilibrated to 37 ° C is added.
  • the two horizontal pistons move towards each other and press the chewing gum between them before returning to the starting point.
  • the vertical piston move down and press the chewing gum down, resulting in a better and reproducible chewing of the gum.
  • the cycle rate is set to 60 per minute. At 5, 10, 20 and 30 minutes a sample is removed from the reservoir and the content of exenatide is determined.
  • the chewing gum tablets obtained in example 1 are packed in commercial packages (blister packs, Duma bottles and aluminium bags) and stored for up to 3 months at conditions 40°C/75% RH and 21°C/55% RH.
  • the amount of exenatide is measured at the beginning of the storage (initial amount) and after 1, 2 and 3 months.
  • the chewing gum tablets obtained in example 1 are distributed to six healthy volunteers.
  • the volunteers have fasted for 12 hours prior to tablet distribution.
  • the volunteers are chewing the tablets for twenty minutes.
  • Blood glucose levels as well as blood exanatide levels are measured continuously from blood samples taken at 0, 5, 10, 15, 30, 45, 60, 120, 180, 240 and 360 minutes.

Abstract

Cette invention concerne des compositions de chewing-gum comprimé contenant un médicament. L'invention concerne en particulier des compositions de chewing-gum comprimé comprenant un mimétique de l'incrétine. Ces compositions sont utiles dans le traitement du diabète ou l'atténuation des symptômes du diabète, en particulier le diabète de type II.
PCT/DK2007/050200 2007-12-20 2007-12-20 Chewing-gum comprimé comprenant un mimétique de l'incrétine WO2009080024A1 (fr)

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PCT/DK2008/000444 WO2009080032A1 (fr) 2007-12-20 2008-12-19 Chewing-gum comprimé comprenant un petit peptide à action systémique

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WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2015070875A1 (fr) * 2013-11-15 2015-05-21 Fertin Pharma A/S Gomme à mâcher convenant aux diabétiques
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
EP3381299A1 (fr) * 2011-02-18 2018-10-03 Biolingus IP LLC Procédé pour la préparation de produits comprenant des actifs stabilisés et compositions les comprenant
CN114891071A (zh) * 2020-12-08 2022-08-12 鸿绪生物科技(嘉善)有限公司 新型多肽及其治疗用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP3381299A1 (fr) * 2011-02-18 2018-10-03 Biolingus IP LLC Procédé pour la préparation de produits comprenant des actifs stabilisés et compositions les comprenant
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2015070875A1 (fr) * 2013-11-15 2015-05-21 Fertin Pharma A/S Gomme à mâcher convenant aux diabétiques
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
CN114891071A (zh) * 2020-12-08 2022-08-12 鸿绪生物科技(嘉善)有限公司 新型多肽及其治疗用途

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