WO2009080033A1

WO2009080033A1 - Compressed chewing gum comprising metformin

Info

Publication number: WO2009080033A1
Application number: PCT/DK2008/000445
Authority: WO
Inventors: Heidi Ziegler Bruun; Carsten Andersen
Original assignee: Fertin Pharma A/S
Priority date: 2007-12-20
Filing date: 2008-12-19
Publication date: 2009-07-02
Also published as: WO2009080025A1

Abstract

The present invention relates to compressed medicament-containing chewing gum compositions. In particular, the present invention is directed to compressed chewing gum compositions comprising metformin. Such compositions are useful in the treatment of diabetes or ameliorating the symptoms of diabetes, in particular diabetes type II.

Description

COMPRESSED CHEWING GUM COMPRISING METFORMIN

Field of the invention

The present invention is directed to compressed medicament-containing chewing gum compositions. In particular, the present invention is directed to compressed chewing gum compositions comprising metformin. Such compositions are useful in the treatment of diabetes or ameliorating the symptoms of diabetes, in particular type II diabetes.

Background of the invention

Diabetes mellitus afflicts nearly 15 million people in the United States. About 15 percent have insulin-dependent diabetes (IDDM; type I diabetes), which is believed to be caused by autoimmune destruction of pancreatic islet beta cells. In such patients, insulin therapy is essential for life. About 80% of patients have non-insulin-dependent diabetes (NIDDM; type II diabetes), a heterogeneous disorder characterized by both impaired insulin secretion and insulin resistance. 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, however, 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, especially early in the disease, 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. Unfortunately, about 11-36% of patients with type II diabetes fail to respond well to diet and sulfonylurea therapy after one year of treatment. Within 5-7 years, about half of patients with type II diabetes receiving sulfonylurea treatment need to start insulin therapy. 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.

Metformin is a compound in the biguanide class of anti-diabetic compounds.

Compounds other than metformin belonging to the class are e.g. phenformin and buformin. Such anti-diabetic agents have been investigated for treatment of diabetes mellitus, in particular type II diabetes, as well as for treatment of obesity. Biguanide anti-diabetics are typically administered orally, which may give rise to gastrointestinal side effects (e.g. anorexia, nausea, bloating, occasional diarrhoea, and vomiting etc).

WO 2006/102752 discloses preparation of chewing gums comprising metformin, for buccal administration through the oral mucosal membrane, said method comprising forming a homogenous gum base comprising metformin. The chewing gums are produced using conventional chewing gum procedures comprising heating of the gum base.

Compressed chewing gum tablets, including the manufacturing thereof, are inter alia described in WO 04/004479, WO 04/004480, WO 04/068964, WO 04/068965 and WO 05/063038, all of which are incorporated herein by reference.

Summary of the invention

The present inventors have realises that oral formulations of metformin often have a bitter aftertaste resulting in loss of appetite in the patient and therefore see the need for means and methods for delivering metformin by an alternative administration route to patients in need thereof. Traditionally there has been very little work evaluating membranes of the oral cavity as sites of drug administration. However, the buccal membrane potentially offers advantages over other routes of administration. For example, 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.

The present inventors have identified a number of problems associated with buccal administration of metformin:

• Controlled release characteristics are desirable in connection with buccal compositions in order to ensure efficient metformin uptake by the buccal membranes and to avoid that the majority of the metformin is swallowed, resulting in gastrointestinal side effects.

• Metformin may give rise to a bitter aftertaste, which is difficult to mask in connection with oral compositions intended for uptake by the buccal membranes.

• Efficient uptake of metformin by the buccal membranes may be advantageous in order to avoid preparing expensive compositions with large doses.

• Compositions with large metformin 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.

• It is essential that the compositions are easy and comfortable to use in order for the patients to comply with their medical regiments.

The present inventors have found that compressed chewing gum tablets according to the present invention containing metformin are unexpectedly superior to conventional chewing gums containing metformin. Said metformin-containing compressed chewing gum tablet can solve a number of the problems described herein.

Thus, the present invention provides a compressed medicament-containing chewing gum composition suitable for the treatment of, or ameliorating the symptoms of, diabetes mellitus.

Accordingly, in a first aspect the present invention relates to a compressed chewing gum tablet comprising a first compressed module, wherein said tablet comprises at least one metformin and compressed chewing gum particles containing gum base.

In a further aspect, the present invention relates to a tablet according to the invention for use as a medicament.

In a still further aspect, the present invention relates to a tablet according to the invention for the treatment of, or ameliorating the symptoms of, diabetes mellitus. In yet another aspect, 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. In a related aspect, 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.

Other aspects of the present invention will be apparent from the below description and the appended claims.

It will appear in the following that the present invention provides metformin chewing gum compositions having desired characteristics.

Brief description of the figures

Figure 1 illustrates a two-layer compressed tablet according to the invention.

Figure 2 illustrates a three layer compressed tablet according to the invention. Detailed description of the invention

Definitions and nomenclature

In the context of the present application and invention the following definitions apply:

In the present context, the term "gum base" refers in general to a commercially available gum base suitable for production of chewing gum. Such gum bases normally comprise one or more elastomeric compounds which may be of synthetic or natural origin, one or more resinous compounds which may be of synthetic or natural origin and softening compounds.

The term "gum base composition" as used herein may be a gum base as defined above comprising one or more ingredients (e.g. metformin, sweetener, flavour, colouring agents, fillers, etc.) as described below.

The term "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 gum base, metformin, 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.

Thus, the expression "chewing gum particles containing gum base", also referred to "chewing gum particle", 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. Thus, in some embodiments, the particles have been particulated prior to application. Particulation may be in any form of "building up" particles from smaller primary particles into macro particles or in any form of "building down" from larger substances into macro particles. Any form of particulation may be applied, such as granulation, pelletizing, agglomeration, or any other suitable means for particulation, as described below. Thus, the particles may also to be understood as macroparticles.

Furthermore, the expression "compressed chewing gum particles containing gum base" refers to a portion of chewing gum particles which become compressed after being mixed with, e.g., a taste masking agent, a buffering agent, sweeteners or flavours.

The expression "compressed chewing gum tablet" denotes a ready-for-use chewing gum tablet comprising at least one metformin and compressed chewing gum particles containing gum base possibly mixed with a taste masking agent, sweeteners, flavour or other ingredients and optionally coated. As described in detail below, 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 composition. 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 a compressed chewing gum tablet or a compressed module.

The term "metformin" covers metformin base, i.e. N, N- dimethylimidodicarbonimidic diamide, as well as pharmaceutically acceptable salts thereof, such as the p-chlorophenoxyacetate, embonate, and hydrochloride salts thereof, in particular the hydrochloride salt thereof. Other pharmaceutically acceptable salts of metformin base are salts formed with food acids, such as citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, adipic acid and lactic acid, and mixtures thereof. In a preferred embodiment of the invention, the compressed chewing gum tablet contains metformin hydrochloride. In another preferred embodiment, the compressed chewing gum tablet contains metformin base.

The term "food acid" pertains to acids that are safe to use in food products. The food acids are typically mono-, di-, or tri-carboxylic acids. The food acid, that is, the at least one food acid may e.g. be selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, succinic acid, ascorbic acid, adipic acid and lactic acid, and mixtures thereof. Phosphoric acid may also be a food acid according to the present invention.

The term "pH controlling agent" is intended to mean an agent which, when added to the particles of the compressed chewing gum tablets of the invention creates a "micro-pH" around each particle when water is adsorbed to the particles or when water is added in small amounts to the particles. 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.

When referring to "substantially all" of a particular component in the compressed chewing gum tablets of the present invention being contained in a particular part of the tablets, it is intended to mean that the component in question is not present in other parts of the tablets. However, "substantially all" of said component being located in a particular part of the tablets also means that trace amounts or the like may be found in other parts of the tablets without significantly altering the properties of the tablets in terms of release characteristics of metformin etc.

When used in the present context, the term "simulated saliva" is intended to mean an aqueous solution containing phosphate buffer and 8 g/l NaCI adjusted to pH 6.0 with phosphoric acid.

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 metformin and compressed chewing gum particles containing gum base.

One advantage of compressed chewing gum tablets containing metformin over conventional chewing gums containing metformin may be said to be that the chewing experience of patients requiring administration of metformin 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.

A more pleasant chewing experience will result in better patient compliance with their medical regimens, which in turn will result in a better treatment. The compressed chewing gum tablets of the invention therefore facilitate correct and safe administration of metformin compared to prior art formulations.

Different types of compressed chewing gum tablets In one embodiment of the present invention, 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.

In the embodiment where the tablet contains only one compressed module, the compressed module also contains the compressed chewing gum particles containing gum base. The compressed module also contains the at least one metformin. The metformin may be incorporated in the compressed chewing gum particles. However, it is currently preferred that the metformin is present in the compressed module, but is located between the compressed chewing gum particles, i.e. the metformin does not form part of the compressed chewing gum particles.

Furthermore, in the embodiment where the tablet contains only one compressed module, 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. In a preferred embodiment of the invention, the compressed module contains an absorption enhancer and/or a mucoadhesive agent. A detailed description of the above-mentioned components is provided infra.

In another, and currently preferred, embodiment of the invention, the tablet further comprises a second compressed module. Thus, according to this embodiment of the invention, 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 metformin and compressed chewing gum particles containing gum base.

According to this embodiment of the invention, the compressed chewing gum tablet is one wherein the first compressed module and the second compressed module are cohered to each other. Thus, 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. As illustrated in Figure 1, 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. However, according to a preferred embodiment of the invention, the mutual adhering between the two modules is obtained by the compression of one module onto the other module.

In an interesting embodiment of the invention, the second compressed module contains the at least one metformin. Thus, according to this embodiment of the invention, the metformin may be contained in the first compressed module and in the second compressed module. However, in a preferred embodiment of the invention the at least one metformin is contained in the second compressed module only, i.e. the first compressed module does not contain any metformin. As explained above, the metformin, independently of whether the metformin 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 metformin does not form part of the compressed chewing gum particles.

Thus, 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 metformin and compressed chewing gum particles containing gum base, and wherein the second compressed module contains the at least one metformin. Preferably, the first compressed module does not contain any metformin. Referring to Figure 1, it will be understood that this preferred embodiment corresponds to the situation where the first compressed module 11 does not contain any metformin and where the second compressed module 12 contains the at least one metformin.

The compressed chewing gum particles containing gum base may be present in the first compressed module and in the second compressed module. However, in a further, and even more preferred, embodiment of the invention, 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.

Thus, 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 metformin. Preferably, the first compressed module does not contain any metformin and the second compressed module does not contain any chewing gum particles containing gum base. Again, referring to Figure 1, it will be understood that this particular preferred embodiment corresponds to the situation where the first compressed module 11 does not contain any metformin, but contains compressed chewing gum particles containing gum base and where the second compressed module 12 contains the at least one metformin, but does not contain compressed chewing gum particles containing gum base.

In a further, and still more preferred embodiment of the invention, 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.

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. Thus, according to this embodiment, the present invention concerns a compressed chewing gum tablet comprising a first, second and third compressed module, wherein said tablet comprises at least one metformin and compressed chewing gum particles containing gum base.

In one embodiment, the first and the third compressed module (i.e. modules 21 and 23) have the properties, and contains the features, discussed above in connection with the first compressed module, whereas the second compressed module (i.e. module 22) has the properties, and contains the features, discussed above in connection with the second compressed module. Thus, according to this particular embodiment, the present invention concerns a compressed chewing gum composition comprising a first, a second and a third compressed module, wherein the first and third compressed module comprise chewing gum particles containing gum base, and wherein the second compressed module contains the at least one metformin. Preferably, the first and/or the third compressed module do not contain any metformin and the second compressed module does not contain any chewing gum particles containing gum base. Moreover, the second compressed module preferably comprises tablet material. Referring to Figure 2, it will be understood that this particular embodiment corresponds to the situation where the first compressed module 21 does not contain any metformin, but contains compressed chewing gum particles containing gum base; the second compressed module 22 contains the at least one metformin, but does not contain compressed chewing gum particles containing gum base; and the third compressed module 23 does not contain any metformin, but contains compressed chewing gum particles containing gum base.

In another embodiment, the first and the third compressed module (i.e. modules 21 and 23) have the properties, and contains the features, discussed above in connection with the second compressed module, whereas the second compressed module (i.e. module 22) has the properties, and contains the features, discussed above in connection with the first compressed module. Thus, according to this particular embodiment, the present invention concerns 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 metformin, and wherein the second compressed module comprises chewing gum particles containing gum base. Preferably, the second compressed module does not contain any metformin and the first and/or third compressed modules do not contain any chewing gum particles containing gum base. Moreover, the first and/or the third compressed module preferably contain tablet material. Referring to Figure 2, it will be understood that this particular embodiment corresponds to the situation where the first compressed module 21 contains the at least one metformin, but does not contain compressed chewing gum particles containing gum base; the second compressed module 22 does not contain any metformin, but contains compressed chewing gum particles containing gum base; and the third compressed module 23 contains the at least one metformin, but does not contain compressed chewing gum particles containing gum base.

It will be understood that independent of the actual design of the compressed chewing gum tablet, 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. In a preferred embodiment of the invention, 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 metformin in order to obtain a co-release of such components.

In further embodiments, metformin, 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.

In general, and independent of the specific design of the chewing gum tablet, the present inventors have found that a surprisingly high absorption of metformin through the buccal mucosal membrane is achieved with the compressed chewing gum tablets of the present invention compared to conventional chewing gum designs. Taste masking agent

The compressed chewing gum tablet may, as discussed above, comprise one or more taste masking agents. As will be understood, the necessity of incorporating a taste masking agent in the chewing gum tablet is due to the unpleasant taste of metformin when released from the chewing gum.

Since metformin 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 unpleasant taste of metformin. In general, the taste masking agent and metformin is preferably located within the same compressed module(s). Moreover, it is generally preferred that 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 metformin and the taste masking agent are co-released from the compressed chewing gum tablet upon chewing. In this context, the term "co-release" means that when metformin is released from the chewing gum during chewing, at least some taste masking agent is also released. Evidently, it is preferred that when metformin is released from the chewing gum tablet during chewing, an amount of taste masking agent, which is sufficient to mask the unpleasant taste of metformin, 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 metformin, but which simultaneously provides the chewing gum with a good palatability. In the context of the present invention, the term "taste-masking agent" may refer to inter alia flavouring agents and food acids.

In a preferred embodiment, the taste masking agent is a polyol sweetener.

A specific example of one category of polyol sweeteners include sugars, in particular a sugar selected from the group consisting of dextrose, sucrose, maltose, fructose, lactose, and combinations thereof.

Another specific example of another category of 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. The amount of polyol sweetener is in the amount of 0 - 75% by weight of the tablet, such as 1 - 50%, 2 - 40%, 3 - 30%, 4 - 20%, or 5 - 10% by weight of the tablet. Alternatively, polyol sweetener is present in an amount of 5-50%, such as 5-40%, 5-30%, 7-25%, 7-20%, or 10-20%.

In another embodiment of the invention, 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.

In one embodiment, the taste-masking agent is one or more flavouring agents, optionally in combination with one or more food acids. Flavours which can be used in the tablet according to the present invention include, but are not limited to, coconut, coffee, cola, chocolate, vanilla, grape fruit, menthol, licorice, anise, apricot, caramel, honey, pineapple, strawberry, raspberry, tropical fruits, cherries, cinnamon, peppermint, wintergreen, spearmint, eucalyptus and mint flavors. In one embodiment, the flavours are chosen from menthol, caramel, coffee, cola, and combinations thereof, in particular the combination of menthol and caramel.

In an interesting embodiment, the tablet of the invention comprises two or more taste masking agent, such as a polyol sweetener and a high intensity sweetener. In this case, 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. Preferably, 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. More preferably, 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.

Still other examples of suitable taste masking agents include salts of gluconate, such as sodium gluconate.

In some embodiments of the invention at least 2% (wt/wt) of the amount of metformin formulated in a chewing gum tablet is absorbed through the oral mucosal membrane. It is even more preferred that at least 5% (wt/wt), such as at least 10% (wt/wt) or at least 15% (wt/wt) of the amount of metformin formulated in a chewing gum tablet is absorbed through the oral mucosal membrane.

In some embodiments of the invention at least 20% (wt/wt) of the amount of metformin formulated in a chewing gum tablet, preferably at least 40% (wt/wt), and even more preferably at least 60% (wt/wt) of the amount of metformin formulated in a chewing gum tablet is absorbed through the oral mucosal membrane.

In other embodiments of the invention absorption of 5% (wt/wt) of the amount of metformin formulated in a chewing gum through the oral mucosal membrane is considered to be satisfactory. Even better is absorption of 6, 7, 8, 9, or 10% (wt/wt) through the oral mucosal membrane.

Absorption enhancer

In order to increase the absorption of metformin through the buccal mucosa, the compressed chewing gum tablet of the invention may advantageously contain an absorption enhancer.

Absorption enhancers according to the present invention may be selected from one or more of the following groups and sub-groups:

• solubilization agents;

• charge modifying agents; • pH control agents; • degradative enzyme inhibitors;

• mucolytic or mucus clearing agents;

• membrane penetration-enhancing agents (e.g., o (i) a surfactant, o (ii) a bile salt, o (iii) a phospholipid or fatty acid additive, mixed micelle, liposome, or carrier, o (iv) an alcohol, o (v) an enamine, o (vi) 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-acetylamino acid or salt thereof, o (xvi) an enzyme degradative to a selected membrane component, o (xvii) an inhibitor of fatty acid synthesis, o (xviii) an inhibitor of cholesterol synthesis; or o (xiv) any combination of the membrane penetration enhancing agents of (i)-(xviii)); • modulatory agents of epithelial junction physiology, such as o nitric oxide (NO) stimulators, o chitosan, and chitosan derivatives;

• vasodilator agents;

• selective transport-enhancing agents; and • stabilizing delivery vehicles, carriers, supports or complex- forming species with which the metformin is/are effectively combined, associated, contained, encapsulated or bound to stabilize the active agent for enhanced mucosal delivery.

• small hydrophilic penetration enhancers, • Emulsifiers In an embodiment of the invention, the absorption enhancer contains, or even consists of, one or more degradatϊve enzyme inhibitors.

In another embodiment of the invention, the absorption enhancer contains, or even consists of, one or more mucolytic or mucus clearing agents.

In yet an embodiment of the invention, the absorption enhancer contains, or even consists of, one or more membrane penetration-enhancing agents. Examples of useful membrane penetration-enhancing agents are e.g. a surfactant; a bile salt; a phospholipid or fatty acid additive, mixed micelle, liposome, or carrier; an alcohol; an enamine; an NO donor compound; a long-chain amphipathic molecule; a small hydrophobic penetration enhancer; sodium or a salicylic acid derivative; a glycerol ester of acetoacetic acid; a cyclodextrin or beta-cyclodextrin derivative; a medium-chain fatty acid; a chelating agent; an amino acid or salt thereof; an N- acetylamino acid or salt thereof; an enzyme degradative to a selected membrane component; an inhibitor of fatty acid synthesis; an inhibitor of cholesterol synthesis; or any combination thereof. In a preferred embodiment of the invention the absorption enhancer contains one or more penetration-enhancing surfactants. Examples useful penetration-enhancing surfactants are CPC (Cetylpyridinium Chloride), Benzalkonium chloride, Sodium lauryl sulfate, Polysorbate 80, Cetyltrimethylammonium bromide, Laureth 9, and combinations thereof.

In a further embodiment of the invention, the absorption enhancer contains, or even consists of, one or more modulatory agents of epithelial junction physiology, e.g. such as a nitric oxide (NO) stimulator, chitosan, chitosan derivatives, or combinations thereof.

In an embodiment of the invention, the absorption enhancer contains, or even consists of, one or more vasodilator agents.

In yet an embodiment of the invention, the absorption enhancer contains, or even consists of, one or more selective transport-enhancing agents. In another embodiment of the invention, the absorption enhancer contains, or even consists of, one or more stabilizing delivery vehicles, carriers, supports or complex-forming species with which the metformin is effectively combined, associated, contained, encapsulated or bound to stabilize the active agent for enhanced mucosal delivery.

In still an embodiment of the invention, the absorption enhancer contains, or even consists of, one or more small hydrophilic penetration enhancers.

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,

Transcutol, Urea, Azone, Nonionic surfactants, Sulfoxides, Laurie acid/PG, POE 23 lauryl ether, Methoxysalicylate, Dextran sukfate, Methanol, Ethanol, Sodium cholate, Sodium taurocholate, Lysophosphatidyl choline, Cyclodextrin, Alkylglycosides, Polysorbates, Sorbitan esters, Poloxamer block copolymers, PEG- 35 castor oil, PEG-40 hydrogenated castor oil, Caprocaproyl macrogol-8 glycerides, PEG-8 caprylic/capric glycerides, Dioctyl sulfosuccinate, Polyethylene lauryl ether, Ethoxydiglycol, Propylene glycol mono-di-caprylate, Glycerol monocaprylate, Glyceryl fatty acids (Csub.8-C.sub.18) ethoxylated, Oleic acid, Linoleic acid, Glyceryl caprylate/caprate, Glyceryl monooleate, Glyceryl monolaurate, Capryliccapric triglycerides, Ethoxylated nonylphenols, PEG-(8-50) stearates, Olive oil PEG-6 esters, Triolein PEG-6 esters, Lecithin, d-alpha tocopherol polyethylene glycol 1,000 succinate, Citric acid, Sodium citrate, BRIJ, Sodium laurate, 5-methoxysalicylic acid, Bile salts, Acetyl salicylate, ZOT, Docosahexaenoic acid, Alkylglycosides, Sodium glycocholate (GC-Na), Sodium taurocholate (TC-Na), EDTA, Choline salicylate, Sodium caprate (Cap-Na), N- lauryl-beta-D-maltopyranoside (LM), Diethyl maleate, Labrasol, Sodium salicylate, Mentol, Alkali metal alkyl sulphate, Sodium lauryl sulphate, Glycerin, Bile acid, Lecithin, phosphatidylcholine, phosphatidylserine, sphingomyelin, phophatidylethanolamine, cephalin, lysolecithin, Hyaluronic acid: alkalimetal salts, sodium, alkaline earth and aluminium, Octylphenoxypolyethoxyethanol, Glycolic acid, Lactic acid, Chamomile extract, Cucumber extract, Borage oil (Danish: "Hjulkrone olie"), Evening primrose oil, Polyglycerin, Lysine, Polylysine, Triolein, Monoolein, Monooleates, Monolaurates, Polydocanol alkyl ethers, Chenodeoxycholate, Deoxycholate, Glycocholic acid, Taurocholic acid, Glycodeoxycholic acid, Taurodeoxycholic acid, Sodium glycocholate, Phosphatidylcholine, Phosphatidylserine, Sphingomyelin, Phosphatidylethanolamine, Cephalin, Lysolecithin, Alkali metal hyaluronates, Chitosan, Poly-L-arginine, Alkyl glucoside, Saccharide alkyl ester, Fusidic acid derivatives, Sodium taurdihydrofusidate (STDHF), L-α-phosphatidylcholine Didecanoyl (DDPC), Polysorbate 20, Nitroglycerine, nitropruside, NOC5 [3-(2- hydroxy-l-(methyl-ethyl)-2-nitrosohydrazino)-l- propanamine], NOC12 [iV-ethyl- 2-(l-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine, SNAP [S-nitroso-N-acetyl-DL- penicillamine, NORI, NOR4, deacylmethyl sulfoxide, azone, salicylamide, glyceryl- 1,3-diacetoacetate or l,2-isopropylideneglycerine-3-acetoacetate), Amino acids, Amino acid salts, monoaminocarboxlic acids, Glycine, alanine, phenylalanine, praline, hydroxyproline, hydroxyamino acids, serine, acidic amino acids,, aspartic acid, Glutamic acid, Basic amino acids, Lysine, N-acetylamino acids, N- acetylalanine, N-acetylphenylalanine, TM-acetylserine, N-acetylglycine, N- acetyllysine, N-acetylglutamic acid, N-acetylproline, N-acetylhydroxyproline, lactic acid, malic acid and citric acid and alkali metal salts thereof, pyrrolidonecarboxylic acids, alkylpyrrolidonecarboxylic acid esters, N-alkylpyrrolidones, proline acyl esters, sodium lauryl phosphate, sodium lauryl sulphate, sodium oleyl phosphate, sodium myristyl sulphate, polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, caproϊc acid, alkylsaccharide, Fusidic acid, Polyethylene glycol, Cetyl alcohol, Polyvinylpyrolidone, Polyvinyl alcohol, Lanolin alcohol, Sorbitan monooleate, Ethylene glycol tetraacetic acid, Bile acid conjugate with taurine, Cholanic acid and salts, Cyclodextran, Cyclodextrin (beta), Hydroxypropyl-β- cyclodetran, Sulfobutylether-β-cyclodextran, Methyl-β-cyclodextrin, Chitosan glutamate, Chitosan acetate, Chitosan hydrochloride, Chitosan hydrolactate, 1-0- alkyl-2-hydroxy-sn-glycero-3-phosphocholine, 3-O-alkyl-2~acetoyl-sn-glycero-l- phosphocholine, l-0-alkyl-2-0-acetyl-sn-glycero-3-phospho(N,N,N- trimethyl)hexanolamine, Propylene glycol, Tetradecylmaltoside (TDM), and Sucrose dedecanoate. Further possible absorption enhancers include alkali metal alkyl sulfate, glycerin, a bile acid or bile salt, lecithin, hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening primrose oil, polyglycerin, lysine, polylysine, triolein, monoolein, monooleates, monolaurates, menthol, polidocanol alkyl ethers, chenodeoxycholate, deoxycholate and pharmaceutically acceptable salts thereof.

Furthermore, 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-δ-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.

Finally, 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, Carbomer 940, Carbomer 971, Polyethylene Oxide, Dextrin, Poly(Methyl Vinyl Ether/Maleic Anhydride), Polycarbophil (Polymers of acrylic acid crosslinked with divinyl glycol), Poly vinyl pyrrilidone (PVP), Agar, Tragacanth, Sodium Alginate, Karaya gum, MEC, HPC Hydroxy propyl cellulose, Lectins, AB Block copolymer of oligo (methyl methacrylate) and PAA, Polymers with thiol groups, Spheromers, Thiomers, Alginic acid sodium salt, Carbopol 974P (Carbomer), Etylcellulose EC), Carboxymethyl cellulose (CMC), Dextran, Guar Gum, Pectins, Starch, Gelatin, Casein, Acrylic acid polymers, Polymers of acrylic acid esters, Acrylic acid copolymers, Vinyl polymers, Vinyl copolymers, Polymers of Vinyl alcohols, Alcoxy polymers, Polyethylene oxide polymers, and Polyethers.

It thus appears that 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.

Furthermore, other examples of suitable 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.

Particularly preferred enhancers include: Sodium lauryl sulfate, sodium glycocholate, Polysorbate 80, Polysorbate 20, L-α- phosphatidylcholine Didecanoyl (DDPC), Polyethylene glycol, Cetyl alcohol, Polyvinylpyrolidone, Polyvinyl alcohol, Lanolin alcohol, Sorbitan monooleate, Methyl-β-cylodextrin isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate, sodium dodecyl sulfate, sorbitan esters, C_≥ or C₃ alcohols, C₃ or C₄ diol, DMSO, DMA, DMF, l-n-dodecyl-cyclazacyclo-heptan-2-one, N-methyl pyrrolidone, N-(2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate, dimethyl isosorbide, Tetradecylmaltoside (TDM), Sucrose dedecanoate, 1-O-alkyl- 2-hydroxy-sn-glycero-3-phosphocholine, 3-O-alkyl-2-acetoyl-sn-glycero-l- phosphocholine, l-O-alkyl-2-O-acetyl-sn-glycero-3-phospho(N,N,N- trimethyl)hexanolamine, l-O-hexadecyl-2-hydroxy-sn-glycero-3-phosphocholine, l-0-octadecyl-2-hydroxy-sn-glycero-3-phosphocholine, 3-O-hexadecyl-2-acetoyl- sn-glycero-1-phosphocholine, l-O-hexadecyl-2-O-acetyl-sn-glycero-3- phospho(N,N,N-trimethyl)hexanolamine, a bile salt comprising a steroidal detergent consisting of a member of the group consisting of natural and synthetic salts of cholanic acid, and mixtures thereof. Sodium glycocholate and sodium lauryl sulfate are especially preferred absorption enhancers.

Each absorption enhancer can be present in a concentration of up to about 30, 20, 15, 10, 5, 2, 1, 0.5, or 0.01 w/w % based on the total weight of the compressed chewing gum tablet. The total amount of absorption enhancers is less than about 30, preferably less than about 20, and more preferably less than about 10 or 7 w/w % based on the total weight of the compressed chewing gum tablet.

In general, the absorption enhancer and the metformin 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.

Mucoadhesive agent

In order to facilitate mucoadhesion, and hence buccal absorption, of metformin, 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.

One particular class of hydrophilic polymers includes the cellulose derivatives. Thus, in one embodiment of the invention 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.

Other examples of suitable 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. 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.

In general, the mucoadhesive agent and metformin are 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.

Tablet material

As discussed supra, the chewing gum tablet preferably contains tablet material. It will be understood that it is in general preferred that the module(s) containing the at least one metformin also contain(s) tablet material.

It is well known to the man skilled in the art that 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.

Generally, 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.

Examples of useful glidants and lubricants are stearic acid, metallic stearates, talc, colloidal silica, sodium stearyl fumarate and alkyl sulphates. Likewise, 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. Examples of wet binders are PVP (polyvinylpyrrolidone), HPMC (hydroxymethylpropylcellulose) or gelatine.

A filler substance may be any pharmaceutically acceptable substance that does not interact with metformin or with other excipients. Useful filler substances include sorbitol, mannitol, dextrins, maltodextrins, inositol, erythritol, isomalt, lactitol, maltitol, mannitol, xylitol, low-substituted hydroxypropylcellulose, starches or modified starches (e.g. potato starch, maize starch, rice starch, pre- gelatinised starch), polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, agar (e.g. sodium alginate), carboxyalkylcellulose, dextrates, gelatine, gummi arabicum, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysaccharides e.g. dextran, soy polysaccharide, sodium carbonate, and sodium chloride.

In addition, ingredients such as metformin, absorption enhancers, mucoadhesive agents, pH controlling agents, taste masking agents etc. usually also form part of the "water soluble ingredients".

Chewing gum particles containing gum base

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, all of which are hereby incorporated by reference.

The chewing gum particles may be in any suitable form such as pellets, granules, agglomerates or powder. Thus, in some embodiments, the particles have been particulated prior to application. Particulation may be in any form of "building up" particles from smaller primary particles into macro particles or in any form of "building down" from larger substances into macro particles. Any form of particulation may be applied, such as granulation, pelletizing, agglomeration, or any other suitable means for particulation. Thus, the particles may also to be understood as macroparticles.

In a preferred embodiment of the invention, the compressed chewing gum tablet comprises chewing gum particles which have been prepared by grinding, e.g. of larger pellets or of conventional gum base.

In another preferred embodiment, the compressed chewing gum tablet comprises compressed chewing gum particles which have been prepared by grinding and chewing gum particles which have been prepared by pelletizing.

It has surprisingly been found that compressed chewing gum tablets according to the invention, which comprise chewing gum particles prepared by grinding, tend to delay the release of metformin, which again appears to improve the organoleptic properties of the resulting compressed chewing gum tablet.

As indicated above, the chewing gum particles contain gum base. The content of gum base in the particles may vary. In some embodiments, 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. In some embodiments, 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.

In some other embodiments, 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. In some embodiments, the particles are made entirely of gum base, substantially without conventional chewing gum ingredients. In this case, 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.

In some other embodiments, the particles are made of chewing gum, substantially without further needs for chewing gum ingredients in the compression process. Of course, 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.

In preferred embodiments, the average particle size of the particles is in the range of 50-2000 μm measured as the longest dimension of the particle, preferably in the range of 100-1500 μm, and even more preferred in the range of 200-1300 μm.

In even more preferred embodiments, 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 μm measured as the longest dimension of the particle, preferably in the range of 100-1500 μm, and even more preferred in the range of 200-1300 μm.

Gum base

The chewing gum tablet of the invention comprises a gum base. 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. In addition to the above definition of the expression "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. In preferred embodiments, 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.

In some embodiments of the invention, the compressed chewing gum tablet furthermore comprises particles of grinded gum base.

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.

However, 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.

In a preferred embodiment, 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. e.g. having an average molecular weight in the range of about 10,000 to 1,000,000 including the range of 50,000 to 80,000, isobutylene-isoprene copolymer (butyl elastomer), styrene- butadiene copolymers e.g. having styrene-butadiene ratios of about 1 :3 to 3: 1, polyvinyl acetate (PVA), e.g. 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.

It is possible to combine a synthetic elastomer having a high molecular weight and a synthetic elastomer having a low molecular weight elastomer in a gum base. Presently preferred combinations of 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.

Typically, 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. In preferred embodiments, 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. In the present context, 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, pentaerythrito! esters of partially hydrogenated rosins, methyl esters of rosins, partially hydrogenated methyl esters of rosins and pentaerythritol esters of rosins. Other useful 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. The choice of resins will vary depending on the specific application, and on the type of elastomer(s) being used.

The resins disclosed as useful components in the gum base may also, individually or in combination, be useful as encapsulation material as disclosed infra.

Usually, 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. In preferred embodiments, 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. In the present context, the term "softener" may be used interchangeably with terms 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.

In a preferred embodiment, 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.

Further examples of useful emulsifier 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. the product sold under the trade name

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.

Some emulsifiers 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.

In preferred embodiments, 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. In useful embodiments, 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. 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 60⁰C, and preferably between about 45⁰C 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. In addition to the low melting point waxes, 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. Such high melting waxes include beeswax, vegetable wax, candelilla wax, canauba wax, most petroleum waxes, and the like, and mixtures thereof.

Further useful 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.

Anhydrous glycerin may also be employed as a softening agent, such as the commercially available United States Pharmacopeia (USP) 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.

In an embodiment of the invention, 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. Preferably, 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.

In a preferred embodiment, the gum base of the chewing gum according to the invention comprises a filler. The fillers/texturizers may include magnesium and calcium carbonate, sodium sulphate, ground limestone, silicate types such as magnesium and aluminium silicate, kaolin, clay, aluminium oxide, silicium oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, and combinations thereof. The fillers/texturizers may also include natural organic fibres such as fruit vegetable fibres, grain, rice, cellulose and combinations thereof.

Chewing gum ingredients The chewing gum tablet typically comprises further chewing gum ingredients. Examples of such chewing gum ingredients include, but are not limited to, bulk sweeteners, high intensity sweeteners, flavouring agents, cooling agents, warming agents, and combinations thereof.

In a useful embodiment of the present invention, 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 Sϋddeutsche Zucker), maltodextrins; hydrogenated starch hydrolysates; hydrogenated hexoses; and hydrogenated disaccharides.

Furthermore, 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.

In a preferred embodiment of the invention, the bulk sweetener is present in an amount ranging from 0-80% by weight of the chewing gum tablet, such as in an amount ranging from 10-70%. Preferably, 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. For example, 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.

In a preferred embodiment of the invention, the compressed chewing gum tablet comprises bulk sweetener, which bulk sweetener comprises at least 75% (w/w) low-hygroscopic polyol sweetener relative to the total amount of bulk sweetener, and preferably at least 80% (w/w), such as at least 90% (w/w) of low- hygroscopic polyol sweetener.

The low-hygroscopic polyol sweetener may comprise one or more polyol sweetener selected from the group consisting of isomalt, isomaltol, mannitol, maltitol, erythritol, lactitol and combinations thereof

In an interesting embodiment, the chewing gum tablet further comprises a high intensity sweetener. Useful 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. neohesperidϊn dihydrochalcone (NHDC), thaumatin, monellin, stevioside, Twinsweet (aspartame-acesulfame salt) and combinations thereof.

In order to provide longer lasting sweetness and flavour perception, it may be desirable to encapsulate or otherwise control the release of at least a portion of the high intensity sweetener. Likewise, 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.

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. Thus, the level of high intensity sweetener will typically vary from about 0.02% to 8% by weight of the chewing gum tablet. When carriers used for encapsulation are included, 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. If a low calorie chewing gum tablet is desired, a low calorie bulking agent can be used. Examples of 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^®). However, 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.

Other useful 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. Generally 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.

Further examples of 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 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), 2-ethyl butyraldehyde (berry fruits), hexenal, i.e., trans-2 (berry fruits), tolyl aldehyde (cherry, almond), veratraldehyde (vanilla), 2,6-dimethyl-5-heptenal, i.e., melonal (melon), 2,6-dimethyloctanal (green fruit), and 2-dodecenal (citrus, mandarin), cherry, grape, strawberry shortcake, and mixtures thereof.

In some embodiments, the flavouring agent may be employed in either liquid form and/or dried form. When employed in the latter form, suitable drying means such as spray drying the oil may be used. Alternatively, 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.

In some embodiments, 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.

The present inventors have discovered that metformin-containing compressed chewing gum tablets have an unpleasant taste, which is particularly difficult. Surprisingly, they have found that the unpleasant taste is reduced by designing the chewing gum to provide an initial burst of flavour upon chewing.

Thus, in a preferred embodiment of the invention, the compressed chewing gum tablet provides an initial flavour burst, i.e. at least 10% (w/w) of the flavouring agent(s) of the tablet is(are) released during the first 10 seconds of chewing relative to the total amount of flavouring agent(s) which is(are) released during the first 5 minutes of chewing. Preferably, at least 20% (w/w) of the flavouring agent(s) of the tablet is(are) released during the first 10 seconds of chewing relative to the total amount of flavouring agent(s) which is(are) released during the first 5 minutes of chewing. Even more preferably at least 30% (w/w), such as at least 40% (w/w), of the flavouring agent(s) of the tablet is(are) released during the first 10 seconds of chewing relative to the total amount of flavouring agent(s) which is(are) released during the first 5 minutes of chewing.

In preferred embodiments of the invention, the compressed chewing gum tablet comprises an initial burst flavouring agent.

The term "initial burst flavouring agent" relates to flavouring agents which are completely or nearly completely release from the compressed chewing gum tablet during the first 10 seconds of chewing. Preferably at least 50% (w/w) of the initial burst flavouring agent, relative to the total amount of the initial burst flavouring agent, is released during the first 10 seconds, and even more preferably at least 75% (w/w) of the initial burst flavouring agent, relative to the total amount of the initial burst flavouring agent, is released during the first 10 seconds of chewing, such as at least 90% (w/w).

Useful examples of an initial burst flavouring agent are a beaded flavouring agent, a powdered flavouring agent, a spray dried flavouring agent, or any combination thereof. Useful examples of initial burst flavouring agent are e.g. Duraroma, Flexaroma.

Another useful initial burst flavouring agent is particles of a bulk sweetener, which particles comprise dispersed flavour agent. Such particles may be prepared by drying a conventional coating syrup comprising the flavouring agent and the bulk sweetener, and grinding the dried syrup into particles.

A preferred flavouring agent is a caramel flavouring agent, e.g. in combination with a butter or butterscotch flavouring agent. The compressed chewing gum tablet may e.g. comprise caramel/butter flavouring agent in an amount of 0.05- 8% (w/w) relative to the total weight of the compressed chewing gum tablet.

Another preferred flavouring agent is a cinnamon flavouring agent. The compressed chewing gum tablet may e.g. comprise cinnamon flavouring agent in an amount of 0.05-8% (w/w) relative to the total weight of the compressed chewing gum tablet.

Yet another preferred flavouring agent is a menthol flavouring agent, e.g. in combination with a lemongrass flavouring agent. The compressed chewing gum tablet may e.g. comprise menthol/lemongrass flavouring agent in an amount of 0.05-8% (w/w) relative to the total weight of the compressed chewing gum tablet.

Yet another preferred flavouring agent is a coca cola flavouring agent. The compressed chewing gum tablet may e.g. comprise coca cola flavouring agent in an amount of 0.05-8% (w/w) relative to the total weight of the compressed chewing gum tablet.

Other preferred flavouring agents include wintergreen, spearmint, chili, peanut, coffee, liquorice, anis, or a combination thereof.

The amount of flavouring agent employed herein may be a matter of preference subject to such factors as the type of final chewing gum, the individual flavour, the gum base employed, and the strength of flavour desired. Thus, the amount of flavouring may be varied in order to obtain the result desired in the final product and such variations are within the capabilities of those skilled in the art without the need for undue experimentation. In chewing gum compositions, the flavouring agent is generally present in amounts from about 0% to about 10% by weight, preferably 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. 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. This method for encapsulating flavours may also be applied as an alternative way of encapsulating metformin, absorption enhancers, and/or mucoadhesive agents. Useful 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-cyclo-decanone (from International Flavors and Fragrances); 2- isopropanyl-5-methylcyclohexanol (from Hisamitsu Pharmaceuticals, hereinafter "isopregol"); hydroxycarboxylic acids with 2-6 carbon atoms; menthone glycerol ketals (FEMA 3807, tradename FRESCOLAT(TM) type MGA); 3-1- menthoxypropane-l,2-diol (from Takasago, FEMA 3784, (hereinafter "TCA")); menthyl lactate; (from Haarman & Reimer, FEMA 3748, tradename FRESCOLAT(TM) type ML). These and other suitable 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. Among the useful warming compounds included are 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, homodihydrocapsaicin, ethanol, isopropol alcohol, iso-amylalcohol, benzyl alcohol, glycerine, and combinations thereof. Furthermore, useful warming agents include capsicum and nicotinate esters, such as benzyl nicotinate.

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. For example, 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. Similarly, the dye known as F.D.& C. Green No. 1 comprises a triphenylmethane dye and is the monosodium salt of 4-[4-(N-ethyl-p-sulfoniumbenzylamino) diphenylmethylene]-[l-(N-ethyl-N-p~ sulfoniumbenzyl)~delta-2,5- cyclohexadieneimine]. 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. In an embodiment of the invention, the chewing gum comprises a center filling. Furthermore, 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.

Coating

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 and increases the flavour and/or sweetener bust of the compressed chewing gum products as defined above, relative to a chewing gum of the same composition that is not coated. Thus, 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. Preferably, 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. In 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 and/or polyols such as sucrose or dextrose, which, depending on the stage of coating reached, may contain other functional ingredients, e.g. fillers, colours, etc. In the present context, the sugar coating may contain further functional or active compounds including flavour compounds, metformin and/or other therapeutically active compounds. In the production of chewing gums it may, however, be preferred to replace the cariogenic sugar compounds in the coating by other, preferably crystallizable, sweetening compounds that do not have a cariogenic effect. In the art such coating is generally referred to as sugarless or sugar-free coatings. Preferred non- cariogenic hard coating substances include polyols, e.g. 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. One advantage of using polyols in the coating is that they may act simultaneously as a sweetener and as a taste masking agent.

The coating, in general, typically comprises one or more layers. For example 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.

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.

Method of preparing a compressed chewing gum tablet

Initially, chewing gum particles containing gum base are provided. Useful particles may be manufactured according to conventional methods e.g. as described in EP 1 474 993, EP 1 474 994 and EP 1 474 995, all of which are hereby incorporated by reference. Compressed chewing gum tablets may be prepared by the methods disclosed in WO 04/004479, WO 04/004480, WO 04/068964, WO 04/068965, and WO 05/063038, all of which are incorporated herein 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. In some embodiments of the invention, 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.

Thus, in a specific embodiment 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 -40⁰C and, preferably, between -10 and -40⁰C; 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. In some embodiments, 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. In some other embodiments, the pellets are pelletized in a strand pelletizing process with cool air.

Thus, in a specific embodiment, 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.

In useful embodiments, the provided chewing gum particles are made entirely of a gum base, substantially without conventional chewing gum ingredients. In this case, 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.

However, under some circumstances it may be useful to provide chewing gum particles made entirely of a chewing gum composition, substantially without further needs for chewing gum ingredients in the compression process.

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.

Of course, 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.

By adding the chewing gum ingredients to the chewing gum particles, 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.

In accordance with the present invention, 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.

In one aspect of the present invention, there is provided a method of preparing a compressed chewing gum tablet, comprising one compressed module, the method comprising the steps of: a) providing a portion comprising metformin, 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 metformin, 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.

Thus, the compressed chewing gum tablet is prepared by providing a portion comprising the metformin, 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. In accordance with the present invention, one or more chewing gum ingredients may, as described above, may be provided and compressed together in step d) with the portion comprising the metformin, the portion comprising taste-masking agent and the chewing gum particles containing gum base. However, the one and more chewing gum ingredients may also be added to the gum base in the extruder as described above.

In a further aspect of the present invention, the method comprising the steps of a) providing a portion comprising metformin, 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 metformin, 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. Thus, the portions of the chewing gum components are mixed before the loading of the tablet machine.

In a useful embodiment, the methods according to the invention furthermore comprise a step of coating the first compressed module with the above mentioned coatings.

In an embodiment, 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).

Useful tablet materials are mentioned above. Furthermore, 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 metformin 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. It will be understood, that the portion comprising metformin 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).

In a useful embodiment, 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.

In an interesting embodiment, a tablet material is further provided in step b).

In a still further aspect, there is provided 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 metformin, 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. It will be understood, that the portion comprising metformin 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 according comprises a step of coating the coherent compressed chewing gum tablet of step e). In a useful embodiment, 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.

In an interesting embodiment, a tablet material is further provided in step b).

In a further aspect of the present invention, there is provided 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 metformin; c) providing a portion comprising tablet material and a portion comprising metformin; 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. It will be understood, that 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.

In a useful embodiment, 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 metformin, 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.

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 metformin and a portion comprising a taste-masking agent; c) providing a portion comprising tablet material and a portion comprising metformin 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. It will be understood, that the a portion comprising metformin and the portion comprising a taste-masking agent may be dosed individually or mixed together before dosed in the tablet machine.

The examples are included to demonstrate particular embodiments of the inven- tion. However, those of skill in the art should, in view of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. The following examples are offered by way of illustration and are not intended to limit the invention in any way.

Encapsulation of taste masking agents, metformin and absorption enhancers 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. However, in relation to various chewable confectionary products, the release of taste masking agents such as e.g. food acids and flavouring agents do not always follow the same release profile upon chewing. Usually food acids tend to release rather quickly from the confectionary product upon chewing, while e.g. flavouring agents tend to remain in the confectionary product for a longer period. Consequently, if food acids are released from the confectionary product 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.

For some food acids and flavouring agents it 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. Alternatively, 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.

Another interesting option is to encapsulate metformin together with the one or more food acids. The metformin 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 metformin may be encapsulated together with one or more flavouring agents as well as one or more food acids. Alternatively, metformin, 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 metformin and/or absorption enhancers together or separately may also be advantageous for obtaining desired release characteristics. Encapsulation of metformin may in particular achieve slow or controlled release of metformin in order to avoid excessive ingestion of metformin via the gastrointestinal route. Encapsulation of metformin 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, metformin 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.

Another interesting option is to encapsulate one or more mucoadhesive agents together with the one or more absorption enhancers. 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. It is also envisioned that metformin may be encapsulated together with one or more absorption enhancers as well as one or more mucoadhesive agents. Alternatively, metformin, 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.

It may also be envisioned encapsulating metformin, 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 metformin and the one or more absorption enhancers together, while the one or more flavouring agents are encapsulated separately from metformin and the one or more absorption enhancers. The encapsulation material of metformin 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.

It may further be envisioned encapsulating metformin, 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 metformin, 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 metformin 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 metformin and the one or more absorption enhancers. The encapsulation material of metformin 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.

It may even be desirable to include one or more components in the compressed chewing gum tablet in both an encapsulated form as well as in a non- encapsulated form in order to ensure that a fraction of the compound is released relatively fast, whereas the remaining (encapsulated) part is released relatively slowly.

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.

Also, the at least one polyterpene resin may comprise styrenated polyterpene resin.

The encapsulation material may comprise a combination of two or more polyterpene resins. For example 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.

In an embodiment of the invention, 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.

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.

In one embodiment, the encapsulation material may comprise at least one polyvinyl acetate. For example, 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.

Also, 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.

Alternatively, 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. Useful encapsulation materials comprising polyvinyl acetate are disclosed in the U.S. patent application with the publication No. 2005/0 260 266, the contents of which are incorporated herein by reference in its entirety.

The encapsulation component, e.g. food acids, 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.

In other words, 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.

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.

Further details on encapsulating food acids and other components for chewing gums etc. may be found inter alia in WO 2007/095939, U.S. patent application with the publication No. 2005/0 260 266, and U.S. patent No. 5,789,002, all of which are incorporated herein by reference in their entirety.

Metformin

As stated above, "metformin" covers metformin base, i.e. N, N- dimethylimidodicarbonimidic diamide, as well as pharmaceutically acceptable salts thereof, such as the p-chlorophenoxyacetate, embonate, and hydrochloride salts thereof, in particular the hydrochloride salt thereof. Other pharmaceutically acceptable salts of metformin base are salts formed with food acids, such as citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, adipic acid and lactic acid, and mixtures thereof. In a preferred embodiment of the invention, the compressed chewing gum tablet contains metformin hydrochloride. In another preferred embodiment, the compressed chewing gum tablet contains metformin base.

Metformin is typically present in the compressed chewing gum tablet in the form of metformin particles, and preferably in the form of a metformin granulate. During the production of the compressed chewing gum tablet, the metformin particles or metformin granulate are typically compacted and compressed together with the other ingredients to form a coherent chewing gum tablet.

The metformin granulate may furthermore comprise one or more granulate excipients.

Binders are an important type of granulate excipient, and useful binders may e.g. include bulk sweetener such as sorbitol, isomalt, PVP (polyvinylpyrrolidone), HPMC (hydroxypropylmethylcellulose), gelatine, Gum Arabic, dextrin, dextrates, starch, starch derivatives, pregelatinϊzed starch, HPC (hydroxypropyl cellulose), EC (etyl cellulose), alginates, hydroxypropylmethylcdellulose Phthalate (HPMCP), Hydroxyethylcellulose (HEC), or mixtures thereof.

One or more taste masking agents as described herein, and particularly polyols and/or flavouring agents, may also be used as granulate excipients.

In a preferred embodiment, the compressed chewing gum tablet comprises metformin in the form of a metformin granulate, which metformin granulate comprises metformin, one or more binders and one or more flavouring agents.

In a preferred embodiment, the metformin particles or the metformin granulate allows for direct compression. The metformin granulate can be prepared via various granulation techniques such as dry granulation, wet granulation, or other granulation methods available to the person skilled in the art.

A dry granulation process may e.g. involve the steps of: i) Milling of metformin and granulate excipients (if needed) ii) Mixing of milled powders iii) Compression into large, hard tablets to make slugs iv) Screening of slugs v) Milling the slugs and screening the resulting powder through a suitable sieve to obtain a metformin granulate with an acceptable particle size

A wet granulation process may e.g. involve the steps of: i) Mixing metformin and granulate excipients (if needed) ii) Preparing of binder solution iii) Mixing of binder solution with powder mixture to form wet mass. iv) Coarse screening of wet mass using a suitable sieve v) Drying of moist granules. vi) Screening of dry granules through a suitable sieve to obtain a metformin granulate with an acceptable particle size.

In embodiments of the present invention, the average particle size of the metformin particles or the metformin granulate is in the range of 20-1000 μm measured as the longest dimension of the particle, preferably in the range of 100- 500 μm, and even more preferred in the range of 150-350 μm, such as about

250 μm. The inventors have found that this embodiment surprisingly may improve the uniformity of the dosage of metformin throughout a batch of compressed chewing gum tablets.

In another embodiment of the invention, the metformin particles or the metformin granulate has the following particle size profile measured by sieving:

about 0% (w/w) > 850 μm, at most 10% (w/w)> 425 μm, at most 60% (w/w)> 250 μm, and at most 80% (w/w)> 150 μm.

In yet another embodiment of the invention, the metformin particles or the metformin granulate has the following particle size profile measured by sieving:

about 0% (w/w) > 850 μm, about 0% (w/w)> 425 μm, at most 50% (w/w)> 250 μm, and at most 70% (w/w)> 150 μm.

Measurement of the particle size profile by sieving may be conducted according to the international standard ISO 2591-1, preferably using dry particles or dry granulate.

Relatively small metformin particles or the metformin granulates are preferred for embodiments where metformin is located in a layer of the tablet which contains tablet material and substantially no chewing gum particles comprising gum base.

Larger metformin particles or the metformin granulates are preferred for embodiments where metformin is located in a layer of the tablet which also contains chewing gum particles comprising gum base.

Additional therapeutically active compounds

In one embodiment of the invention, the compressed chewing gum tablet comprises, in addition to the at least one metformin, at least one additional therapeutically active compound. Preferably, the additional therapeutically active compound is an anti-diabetic compound.

Examples of anti-diabetic compounds include therapeutically active compounds selected from the group consisting of sulfonylureas, biguanides different from metformin, meglitinides, thiazolidinediones, α-glucosidase inhibitors and DPP-4 inhibitors.

Specific examples of 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^®).

Specific examples of biguanides different from metformin are phenformin and buformin.

Specific examples of meglitinides include repaglinide (Prandin^®) and nateglinide (Starlix^®).

Specific examples of thiazolidinediones include rosiglitazone (Avandia^®), pioglitazone (Actos^®) and troglitazone (Rezulin^®).

Examples of α-glucosidase inhibitors include miglitol (Glyset^®) and acarbose (precose^®).

Specific examples of DPP-4 inhibitors include vildagliptin (Galvus^®) and sitagliptin.

In general, the additional therapeutically active compound and metformin are 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.

Therapy

As discussed previously, the tablet of the invention is useful for the treatment of, or ameliorating the symptoms of, diabetes mellitus, in particular diabetes mellitus type II.

An effective amount of metformin should be included in the present compressed chewing gum tablet. As used herein, the term "effective amount" refers to that amount of metformin needed to bring about the desired result, such as obtaining the intended therapeutic treatment or prevention of a disorder in a patient, or regulating a physiological condition in a patient. Such an amount will therefore be understood as having a therapeutic and/or prophylactic effect in a patient. It will be appreciated that the effective amount will vary depending on the parameters determined for metformin, the nature and severity of the disorder being treated, the patient being treated, and the characteristics of the carrier used.

The amount of the pharmaceutical agent, i.e. metformin, can be from about 50 to 850 milligrams.

Typically, the present compressed chewing gum tablets will contain about 50 to 500 milligrams metformin per dose, such as 80 to 400 milligrams metformin per dose, 100 to 350 milligrams metformin per dose, or 200 to 300 metformin milligrams per dose. Depending on the dosing regimen, each dose can contain 50, 112.5, 250 milligrams or 500 milligrams. It will be appreciated that the amount will vary depending on, amongst other things, the release characteristics of the carrier employed. The amount of metformin will be adjusted so that the amount of metformin released will have the intended therapeutic and/or prophylactic effect.

Each dose can contain from about 5 to 90 w/w %, more preferably from about 10 to 80 w/w %, and even more preferably from about 20 to 80 or 20 to 50 w/w % of metformin based on the total weight of the compressed chewing gum tablet, depending upon the amount of the carrier present.

Yet an aspect of the invention relates to a pharmaceutical package containing a sealed compartment comprising a compressed chewing gum tablet as disclosed herein and a desiccant. The present inventors have found it advantageous to use a desiccant in combination with the compressed chewing gum tablet during storage to improve the stability of the tablet and thus prolonging its shelf-life. The pharmaceutical package may e.g. be a blister package, an aluminium bag, a metal cylinder (e.g. of aluminium), or a Duma bottle EXAMPLES

Example 1

A compressed chewing gum tablet according to the present invention having two different modules was produced using the mixtures for each module as disclosed below.

Mixture I (Module 1) % g/1200 g *)

Gum base 40.00 480

Sweetener - Xylitoi 52.30 627.6

High intensity sweetener acesulfame

(encapsulate - as commercially available) 2.40 28.8

High intensity sweetener acesulfame 0.20 2.4

Flavour 5.00 60

Colour 0.10 1.2

Magnesium stearate q.s.

Total 100 1200

Mixture II (Module 2) % g/500g *)

Metformin HCI DC 95% **) 52.63 263

Sorbitol 38.99 195

Sodium saccharin 1.00 5

Sodium laurylsulfate 0.24 1.2

Sodium glycocholate 0.24 1.2

Flavour 6.90 34.5

Magnesium stearate q.s.

Total 100 500

1000 tablets of 1700 mg.

*) Lab production

**) Metformin HCI dose: 250 mg/piece ~

263 mg Metformin HCI DC 95%

The ingredients for each layer are 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 a first and second compressed module.

The mixtures gave a total of 1000 tablets where each tablet is made op of layer 1 = 1200 mg and layer 2 = 500 mg. The content of Metformin HCI is 250 mg per piece.

Example 2

In vitro release of Metformin of the chewing gum tablets obtained in Example 1 The in vitro release of Metformin from the tablet was performed with a standard chewing apparatus as described in the European Pharmacopeia. 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 ⁰C is added. During the chewing cycle the two horizontal pistons move towards each other and press the chewing gum between them before returning to the starting point. Before the next cycle the vertical piston moves down and presses the chewing gum down, resulting in a better and reproducible chewing of the gum. The cycle rate is set to 60 per minute.

At 2, 5 and 10 minutes a sample is removed from the reservoir and the content of metformin is determined.

In vivo release of Metformin of the chewing gum tablets obtained in Example 1 The in vivo release of Metformin from the tablet was performed with minimum 3 persons from a highly trained test panel. A chewing gum tablet was placed in a clean mouth, the saliva working in a manner similar to the buffer very close to 37 ⁰C. The chewing rate is 60 chews per minute and the person chews to a metronome.

The chewing gum pieces were each chewed for 2, 5 and 10 minutes, the chewing gum residue was removed from the mouth and the content of metformin was determined. Results for conventional chewing gums and a compressed chewing gum tablet according to the present invention are presented below.

* The composition of the conventional chewing gum is similar to the composition of the formulation described in example 1, i.e. containing the same ingredients. The conventional chewing, however does not have any separation of the different components, but contains a mix of all the components, including gum base.

In addition, the persons in test panel felt dizziness already after a few minutes of chewing the compressed chewing gum tablets according to the present invention. This indicates that absorption through the oral mucosal membrane of metformin occurs when chewing compressed chewing gum tablets according to the present invention.

Example 3

Stability of metformin in chewing gum tablets.

The chewing gum tablets obtained in example 1 were packed in commercial packages (blister packs, Duma bottles and aluminium bags) and stored for up to 3 months at conditions 40°C/75% RH, 30°C/65% RH and 25°C/60% RH.

The amount of metformin was measured at the beginning of the storage (initial amount) and after 1, 2 and 3 months.

The results indicate that the compressed chewing gum tablets of the present invention have an acceptable shelf-life according to the standards in the art. Example 4

Further formulations of compressed chewing gum tablets

A number of different chewing gum tablet formulations have been prepared and some of these have subsequently been tested with respect to stability (see Example 5).

Formulation 5475-145:

This formulation pertained to a caramel flavoured two-layer medicated chewing gum containing 250 mg Metformin HCI, added as granulated Metformin HCI. The particle size of the metformin granulate was 90-300μm.

Label Declaration: Metcontrol, 250 mg/piece, Caramel * Incl. 3% process overage. The calculation is based on a granulated Metformin HCI concentration of 95%. This corresponds to 250 mg of pure Metformin HCI.

** The sorbitol content is calculated and used for adjustment to 500.0 mg layer two on the basis of the Metformin HCI DC 95% concentration. *** Magnesium Stearate was added during the tabletting process as a processing aid to prevent the product from sticking to the punches and dies.

Formulation 5475-167:

Same formulation as 5475-145, except for the bulk sweetener, which was isomalt. The particle size on metformin was approx. 150-850μm.

Formulation 5475-169:

Same formulation as 5475-167, except for the particle size of metformin, which was 31.8% > 425 μm, 76.1% > 250 μm, 97.1% > 150 μm.

Formulation 5475-179:

Same formulation as 5475-169, except for the particle size of metformin, which was 100-300 μm.

Formulation 5475-189: One layer tablet:

Formulation 5475-154A:

5475-154 was the same formulation as 5475-154A except without the caramel and butterscotch in layer two. 5475-157 was the same formulation as 5475-154 just without metformin, the metformin was replaced with sorbitol. 5475-157A was the same formulation as 5475-154A just without metformin, the metformin was replaced with sorbitol.

Formulation 5475-155A:

5475-155 was the same formulation as 5475-155A except without the caramel and butterscotch in layer two. 5475-158 was the same formulation as 5475-155 just without metformin, the metformin was replaced with isomalt. 5475-158A was the same formulation as 5475-155A just without metformin, the metformin was replaced with isomalt.

Example 5

Stability tests evaluated visually The stability of a number of the formulations of Example 4 has been tested. The compressed chewing gum tablets were exposed to room temperature, to 30°C/65% relative humidity and to 40°C/75% relative humidity for 6 months and were subsequently inspected visually.

It was found that tablets which contained sorbitol and xylitol were more prone to discolouration and instability than tablets which contained isomalt. This indicates that the use of less hygroscopic polyols increase the stability of the compressed chewing gum tablets.

Claims

1. A compressed chewing gum tablet comprising a first compressed module, wherein said tablet comprises metformin and compressed chewing gum particles containing gum base.

2. The tablet according to claim 1, wherein substantially all of said metformin is contained outside said compressed chewing gum particles containing gum base.

3. The tablet according to any one of claims 1 and 2, wherein said first compressed module contains compressed tablet material, at least part of said tablet material not being contained in said compressed chewing gum particles containing gum base.

4. The tablet according to any of the preceding claims, wherein said tablet comprises a second compressed module containing metformin and/or compressed chewing gum particles containing gum base.

5. The tablet according to claim 4, wherein substantially all of said metformin is contained outside said compressed chewing gum particles containing gum base of said second compressed module.

6. The tablet according to claim 4 or 5, wherein substantially all of said metformin is contained in said second compressed module.

7. The tablet according to any one of claims 4 to 6, wherein substantially all gum base is contained in said second compressed module.

8. The tablet according to any one of claims 4 to 7, wherein the second compressed module comprises compressed tablet material.

9. The tablet according to claim 8, wherein substantially all tablet material is contained in said second compressed module.

10. The tablet according to any one of the preceding claims, wherein said tablet comprises a taste masking agent.

11. The tablet according to any one of the preceding claims, wherein said tablet comprises an absorption enhancer.

12. The tablet according to any one of the preceding claims, wherein said tablet comprises a mucoadhesive agent.

13. The tablet according to any one of claims 10 to 12, wherein said taste masking agent, said absorption enhancer, and/or said mucoadhesive agent are contained in the same part of said tablet as metformin.

14. The tablet according to any one of the preceding claims for use as a medicament.

15. A method of making a chewing gum tablet according to any one of claims 1- 13, wherein said method comprises compression of chewing gum particles and metformin into a tablet.

16. A chewing gum tablet obtained by or obtainable by a method according to claim 15.

17. Use of a tablet according to any one of claims 1 to 13 or 16 for the manufacture of a medicament for the treatment of, or ameliorating the symptoms of, diabetes mellitus and/or obesity.

18. The tablet according to any one of claims 1 to 13 or 16 for the treatment of, or ameliorating the symptoms of, diabetes mellitus and/or obesity.

19. A method for the treatment of, or ameliorating the symptoms of, diabetes mellitus and/or obesity, said method comprising administering a tablet according to any of claims 1 to 13 or 16 to a patient in need thereof.