GB2542192A - Chewable medicament - Google Patents

Abstract

Chewing gum compositions comprising at least one biologically active ingredient, a chewing gum base and at least one sweetening or flavouring agent are described, in which the gum compositions have a compression modulus of less than 7 kPa. The gum compositions exhibit improved patient compliance when compared with prior art gums, as well as offering improved release characteristics of the active ingredient contained therein.

Description

CHEWABLE MEDICAMENT

INTRODUCTION

[0001] The present invention relates to a chewing gum composition comprising at least one biologically active ingredient, as well as to a process for the preparation of the chewing gum composition.

BACKGROUND OF THE INVENTION

[0002] Chewing gums provide a convenient and discrete way of administering actives to the oral cavity for localised or systemic delivery. Use of chewing gum as a delivery vehicle has the advantages of rapid therapeutic action, avoidance of first-pass metabolism, comparatively long residence time in the buccal cavity, useful for localised treatment and a safe delivery system as the gum can be removed from the mouth to cease treatment, also any active will remain in the chewing gum should it be accidentally swallowed and will not be released into the body. The challenges of chewing gum as a delivery system include taste-masking of often bitter actives, the very firm chew of medicated gums, also most medicated gums only release 75% of the active in 30 minutes [see R. C. Rowe. "By gum - A buccal delivery system." Drug Discovery Today 2003:8(14): 617-618, the contents of which are incorporated by way of example]; which is a profligate use of the most expensive component of the formulation. The problem of taste-masking bitter actives released from medicated chewing gum is compounded by the often incomplete release of the flavour from the chewing gum.

[0003] The hard chew profile of medicated chewing gums can reduce patient compliance and may also damage teeth and gums; prevent use of a treatment by denture wearers and may cause jaw ache in users.

[0004] Although there are a number of medicated chewing gums commercially available there are still areas for improvement in medicated chewing gum formulation to improve the sensory aspects, which in turn may well improve patient compliance. Another area that may benefit from formulation improvements is the release of expensive components from the chewing gum that are traditionally only partially released from the gum base i.e. actives and flavours. Novel formulations could improve the consumer experience with more flavour, reduce raw material costs and potentially extend acceptance of medicated gum to people who have previously rejected use due to the hard texture such as temporomandibular joint (TMJ) disorder sufferers.

[0005] Nicotine chewing gum for smoking cessation is one of the most common forms of medicated chewing gum and there is significant prior art describing gums with modified nicotine release profiles; from mimicking the nicotine blood plasma levels achieved when smoking a cigarette (US 8,529,875 & US 8,828361), formulations that will provide rapid nicotine craving relief (US 8,524,196, US 8,858,919), formulations having a sustained release of nicotine (US 8,623,332 & US 9,028,803) and formulations that will provide an initial burst of nicotine followed by a more steady nicotine delivery (EP1107730 & CA 2346330). However, in spite of the advances made by these disclosures, the incomplete release of nicotine from chewing gums remains an unresolved problem in that a sizable amount of nicotine remains in the chewing gum after it has been chewed.

[0006] The present invention was devised with the foregoing in mind.

SUMMARY OF THE INVENTION

[0007] According to a first aspect of the present invention there is provided a chewing gum composition comprising a chewing gum base, at least one biologically active ingredient and at least one sweetening or flavouring agent, wherein the chewing gum composition has a compression modulus of less than 7 kPa.

[0008] According to a further aspect of the present invention there is provided a process for the preparation of the chewing gum composition as defined herein, the process comprising the step of: a) mixing, until homogenous, the gum base, at least one biologically active ingredient and at least one sweetening or flavouring agent.

[0009] According to a further aspect of the present invention there is provided a chewing gum composition obtainable, obtained or directly obtained by a process defined herein. DETAILED DESCRIPTION OF THE INVENTION Chewing gum compositions [0010] As discussed hereinbefore, the present invention provides a chewing gum composition comprising a chewing gum base, at least one biologically active ingredient and at least one sweetening or flavouring agent, wherein the chewing gum composition has a compression modulus of less than 7 kPa.

[0011] The present invention addresses a number of shortcomings of prior art compositions Perhaps most notably, the compositions of the present invention release substantially all of a biologically active ingredient contained therein over a 30 minute chew period. It will be understood that in the context of the present invention, the term “substantially all” means an amount greater than or equal to 85 wt% of the total quantity of biologically active ingredient contained within the composition. For example, conventionally, a 4 mg nicotine gum only releases about 3 mg or less of the contained nicotine, whereas using a chewing gum composition of the present invention would allow loading of 3 mg of nicotine into the chewing gum to achieve an equivalent delivery. Alternatively, a 4 mg nicotine gum could be formulated into a composition as described herein to deliver an increased dose of the active, comparative to 4 mg compositions of the prior art, to the user and provide more effective craving relief.

[0012] The improved release characteristics of the present compositions are conferred, at least in part, by the novel chew profile of the gum, as measured by the gum’s compression modulus. The chewing gum compositions of the present invention have a compression modulus of less than 7 kPa at all stages of the chewing profile. By chewing these compositions, the active is released from the chewing gum. Saliva coats the oral tissues under the tongue (sublingual) and the sides of the mouth where the active may partition from the saliva into the oral mucosa. It is thought that chewing creates pressure in the buccal cavity which forces the active ingredient directly into the systemic system of the individual through the oral mucosa contained in the buccal cavity. This greatly accelerates absorption of the active into the systemic system, compared to the typical gastro-intestinal routes.

[0013] The chew profile of a chewing gum measured by compression can be defined as firm (or hard), medium or soft. A hard or firm chew profile can be defined as a chewing gum with a compression modulus above or about 12 kPa. A medium chew profile can be characterised by a compression modulus with values between about 7 kPa and about 12 kPa. A soft chewing gum is defined by a compression modulus of about or less than 7 kPa. It can be envisioned that a chewing gum may not fall within a defined hardness range for the duration of a chew but be first described as a hard or firm chew at the outset and then soften with chewing to become a medium chew gum. Obviously gums may move between all grades of chew (hard to soft) during a 30 minute chew period. It is a desirable property for a chewing gum to have a consistent chew throughout the chewing period.

[0014] The chew profile of a chewing gum can be described as the firmness of the gum during chewing. The initial chewing phase consists of the first 10 to 20 seconds, it includes the first bite into the gum and the first few chews where the gum mass should stay in one piece and not crumble. The intermediate period of chewing a gum is the period where most of the flavours and sweeteners are extracted from the gum matrix, this phase starts after the initial 10 to 20 seconds and usually lasts one to three minutes for a confectionery gum, for a medicated gum that may have specific chewing instructions such as ‘park and chew’ the intermediate period may last longer than three minutes. The end of the intermediate chewing stage is reached when most of the bulk sweeteners have been extracted. During the intermediate chewing phase the gum will soften as the gum mass temperature is raised in the oral cavity, the sweeteners dissolve and the gum cud is hydrated with saliva, the ideal is to have as little change in the size and texture of the gum as possible during the entire chewing experience. The final chewing phase starts once the majority of the bulk sweeteners have been chewed out until the gum is removed from the mouth. The chewing gum may well undergo a degree of hardening compared to the intermediate phase.

[0015] In addition to the improved release properties, the gum compositions of the present invention markedly improve user compliance due to their comparatively softer chew profile. The compositions of the invention therefore carry with them a notably reduced risk of jaw ache, or damaged teeth, gum and dentures.

[0016] A further advantage conferred by the present invention is a potential reduction in pollution. A chewing gum containing a pharmaceutically active ingredient that is disposed of improperly has the potential to release the remaining active ingredients into its surroundings over time which may damage the environment or cause harm to humans and animals.

[0017] In an embodiment, the chewing gum composition has a compression modulus of less than 7 kPa at all stages during a 30 minute chewing cycle. It will be understood that most active-containing chewing gums prescribe a 30 minute chew cycle for delivery of the active. Suitably, the chewing gum composition has a compression modulus of 0.5 to 7 kPa at all stages during a 30 minute chewing cycle. More suitably, the chewing gum composition has a compression modulus of 1.5 to 6 kPa at all stages during a 30 minute chewing cycle. Most suitably, the chewing gum composition has a compression modulus of 3 to 6 kPa at all stages during a 30 minute chewing cycle.

[0018] The compression modulus (hardness) values stated herein are calculated according to the following protocol: a chewed gum cud (chewed for a predetermined amount of time) is immediately transferred to a level, non-compressible surface, covered with a wet, nylon disc and compressed using a known mass, for example by a person standing on the nylon disc covering the gum cud for 10 s. The nylon disc is removed from the gum cud and the diameter of the gum cud is measured using a calibrated vernier caliper gauge or a ruler. Ideally at least two readings of the diameter, perpendicular to each other, are recorded and averaged to give a representative indication of the compressed gum cud size. The compression modulus is calculated using the following equations: 1) radius of sphere (rs)

where: rs = radius of spherical gum cud (m)

V = volume (g) and assume density of gum cud = 1; d=m/V 2) surface area of compressed gum cud (SA) SA = nr2 where: SA = surface area of compressed gum (m2) r = radius of compressed gum cud disc (m) 3) compression ratio (c)

where: c = compression ratio rs = radius of spherical gum cud (m), equation 1 r = average radius of gum cud after compression (m) 4) compression modulus (G)

where: G = compression modulus (kPa) m = mass of compression force (Kg) g = weight force acceleration due to gravity (9.8 m/s2) SA = surface area of compressed gum cud (m2), equation 2 c = compression ratio, equation 3 [0019] In another embodiment, the chewing gum composition releases greater than or equal to 90% of the total weight of biologically active ingredient into the oral cavity during a 30 minute chewing cycle. Suitably, the chewing gum composition releases greater than or equal to 95% of the total weight of biologically active ingredient into the oral cavity during a 30 minute chewing cycle. In another embodiment, the chewing gum composition releases greater than or equal to 99% of the total weight of biologically active ingredient into the oral cavity during a 30 minute chewing cycle. Nicotine release values quoted herein were determined using EP 7th Ed dissolution apparatus b, using 1.6 mm jaw gap, 40“ rotation, 40 chews min, 37 “C temperature, 40 ml. mastication medium (pH6 phosphate buffer).

[0020] The chewing gum compositions are composed of a water-insoluble chewable gum base portion, a water-soluble bulk portion comprising actives and/or flavours. During chewing the water soluble bulk portion is dissolved in saliva and dissipates out of the gum, into the oral cavity taking with it a portion of the active and/ or flavour. The water-insoluble gum base portion remains in the oral cavity for the duration of the chew.

[0021] The term ‘chewing gum’ is used in its broadest sense and encompasses both chewing gum and bubble gum.

[0022] The gum base (or gumbase) is the water-insoluble masticatory substance of the composition and is generally composed of elastomers, resins, plasticisers and water insoluble adjuvant other optional components including antioxidants and colourants. Some gum bases may include amphiphilic or degradable polymers to minimise chewing gum littler pollution in the environment.

[0023] The amount of gum base used in the composition will vary depending on a number of factors such as the type of gum base used, the weight of the final chewing gum, the desired gum cud (bolus) size and other components of the chewing gum. In an embodiment, the gum base is present in amounts from 5 to 90% by weight of the total gum composition. Suitably, the gum base is present in amounts from 15 to 80% by weight of the total gum composition. More suitably, the gum base is present in amounts from 40 to 75% by weight of the total gum composition. Even more suitably, the gum base is present in amounts from 50 to 60% by weight of the total gum composition. Most suitably, the gum base is present in amounts from 52 to 58% by weight of the total gum composition.

[0024] The gum base may comprise 1 to 70% by weight of an elastomeric material, based on the total weight of the gum base. The elastomeric material provides desirable elasticity and textural properties as well as bulk. The elastomer may be any water-insoluble polymer known in the art, including gum polymers for chewing gum and bubble gum listed in Food and Drug Administration, CFR, Title 21, Section 172.615 as “Masticatory Substances of Natural Vegetable Origin” and “Masticatory Substances, Synthetic”. Details of typical synthetic elastomeric polymers used in gum base are given in Chapter 4, ‘Formulation and Production of Chewing Gum and Bubble Gum’ Ed Douglas Fritz (2006) pp. 93-118 and is included herein for reference.

[0025] In an embodiment, the elastomeric material selected from one or more of arabic gum, smoked or liquid latex (Hevea brasiliensis), chicle, crown gum, balata, gutta kay, gutta hang kang, gutta-percha, jelutong, lechi-capsi, massaranduba, massaranduba chocolate, niger gutta, nispero, perillo, rosadinha, sorva, tunu and the like, polyisobutylene, butadiene-styrene copolymer and isobutylene-isoprene copolymer.

[0026] Butadiene styrene rubber (SBR) is a non-linear, random copolymer composed of styrene and butadiene monomer units. Typically the ratio of styrene to butadiene is in the range of 20:80 through to 60:40 styrene: butadiene with a molecular weight less than 600,000 g/mol. Butyl rubber (isobutylene-isoprene copolymer) is a branched polymer composed of isoprene (2-methyl-1,3-butadiene) monomer units copolymerised with isobutylene (2-methylpropene) monomer. Typically the molecular weight of butyl rubber in chewing gum base is in the range 150.000 g/mol to 1,000,000 g/mol. Polyisobuytylene rubber (PIB) is a branched polymeric elastomer obtained by polymerisation of isobutylene (2-methylpropene). It is available in a wide range of molecular weights; medium molecular weight grades range between 36,000 g/mol to 75.000 g/mol. The high molecular weight grades are available in a range between 200,000 g/mol to 4,100,000 g/mol.

[0027] Suitably, the elastomeric material is selected from: a. A mixture of isobutylene-isoprene copolymer and polyisobutylene, wherein the polyisobutylene has a molecular weight of 36,000 to 75,000 g/mol; or b. A mixture of a first polyisobutylene having a molecular weight of 36,000 to 75.000 g/mol and a second polyisobutylene having a molecular weight of 200.000 to 4,100,000 g/mol.

[0028] In an embodiment, the elastomeric material is present in an amount from 5 to 20% of the total weight of the gum base. Suitably, the elastomeric material is present in an amount from 7 to 15% of the total weight of the gum base.

[0029] The gum base may comprise 5 to 70% by weight of an elastomer plasticiser, based on the total weight of the gum base. Elastomer plasticisers (also known as elastomer solvents) aid in softening the elastomeric material. Examples of elastomer plasticisers suitable for use in the chewing gum base of the present invention include the pentaerythritol ester of partially hydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerol ester of partially dimerized rosin, glycerol ester of polymerised rosin, glycerol ester of tall oil rosin, glycerol ester of wood rosin and partially hydrogenated wood rosin and partially hydrogenated methyl ester of rosin; terpene resins derived from d-limonene, α-pinene or β-pinene and mixtures thereof. In an embodiment, the gum base comprises an elastomer plasticiser selected from one or more of methyl glycerol, a pentaerythritol ester of a rosin or a modified rosin, and a terpene resin derived from d-limonene, α-pinene or β-pinene. Suitably, the elastomer plasticiser is a terpene resin derived from d-limonene.

[0030] In an embodiment, the elastomer plasticiser is present in an amount from 15 to 30% of the total weight of the gum base.

[0031] The gum base may comprise 15 to 45% by weight of a non-toxic vinyl polymer, based on the total weight of the gum base. Such polymers may have some affinity for water. In an embodiment, the gum base comprises a non-toxic vinyl polymer selected from one or more of poly(vinyl acetate), ethylene acetate, vinyl acetate and a copolymer of vinyl laurate and vinyl acetate. Suitably, the non-toxic vinyl polymer is poly(vinyl acetate).

[0032] The non-toxic vinyl polymer should have a molecular weight of at least 2000. Suitably, the non-toxic vinyl polymer should have a molecular weight between 10,000 and 55,000. Unless otherwise specified, the unit of molecular weight used in this specification is g/mol.

[0033] In an embodiment, the non-toxic vinyl polymer is present in an amount from 20 to 30% of the total weight of the gum base.

[0034] The gum base may comprise 0 to 40% by weight of a filler, based on the total weight of the gum base. The filler (also known as a water-insoluble adjuvant) is preferably a particulate filler. Fillers are used to modify the texture of the gum base and aid in its processing. In an embodiment, the gum base comprises a filler selected from one or more of calcium carbonate, talc, amorphous silica, tricalcium phosphate, magnesium carbonate, alumina, aluminium hydroxide and aluminium silicate. Suitably, the filler is talc, or calcium carbonate.

[0035] The size of the filler particle has an effect on cohesiveness, density and processing characteristics of the gum base on compounding. The mean particle size for talc and calcium carbonate fillers are suitably in the range from about 0.1 micron to about 15 microns.

[0036] In an embodiment, the filler is present in an amount from 5 to 25% of the total weight of the gum base. Suitably, the filler is present in an amount from 12 to 22% of the total weight of the gum base. More suitably, the filler is present in an amount from 16 to 20% of the total weight of the gum base.

[0037] The gum base may comprise 15 to 40% by weight of a softener or emulsifier, based on the total weight of the gum base. Softeners are used to regulate cohesiveness, to modify the texture and to introduce sharp melting transitions during chewing of a product. Softeners ensure thorough blending of the gum base and may further plasticize the elastomers of the gum base. Emulsifiers aid in dispersing the immiscible components of the chewing gum composition into a single stable system. In an embodiment, the gum base comprises at least one softener or emulsifier selected from one or more of hydrogenated vegetable oils, lanolin, stearic acid, sodium stearate, potassium stearate, glycerine, lecithin, glycerol, glycerol monooleate, lactylic esters of fatty acids, lactylated fatty acid esters of glycerol and propylene glycol, mono-, di-, and tri-stearyl acetates, monoglyceride citrate, stearic acid, stearyl monoglyceridyl citrate, stearyl-2-lactylic acid, triacyetyl glycerin, triethyl citrate and polyethylene glycol. Suitably, the softener or emulsifier is selected from one or more of hydrogenated vegetable oils, acetic acid esters of monoglycerides, lecithin and glycerol monostearate.

[0038] In an embodiment, the softener or emulsifier is present in an amount from 18 to 25% of the total weight of the gum base.

[0039] The gum base may comprise 0.04 to 0.09% by weight of an antioxidant, based on the total weight of the gum base. Antioxidants prolong the shelf life of gum base and the resulting gums including fats and flavourings. In an embodiment, the gum base comprises an antioxidant selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, betacarotenes, propyl gallate and an acidulants (e.g. vitamin C). Suitably, the antioxidant is butylated hydroxytoluene.

[0040] The water-soluble portion of the chewing gum may be composed of ingredients such as bulk sweeteners, softeners, high-intensity sweeteners, flavouring agents, acidulents, sensates to provide cooling, warming or tingling sensations, pharmaceutical actives, nutraceutical actives, herbal extracts, stimulants, fragrances, microencapsulates, abrasives, whitening agents, buffers, colouring agents, fillers, antioxidants, actives and any other components required to give the desired sensory attributes.

[0041] In an embodiment, the biologically active ingredient can be a breath freshener, a dental care component, a biologically active material, an effervescing system, an appetite suppressant, a vitamin, a mineral, a nutritional supplement, a micronutrient, a nutraceutical, a mouth moistening component, a throat care active, an energy or concentration boosting component or any combination thereof.

[0042] In another embodiment, the biologically active ingredient is any substance which modifies a chemical or physical process in the human or animal body. Suitably, the biologically active ingredient is a pharmaceutically active ingredient and is, for instance, selected from antiplatelet aggregation drugs, erectile dysfunction drugs, decongestants, anaesthetics, oral contraceptives, cancer chemotherapeutics, psychotherapeutic agents, cardiovascular agents, NSAID's, NO Donors for angina, non-opioid analgesics, antibacterial drugs, antacids, diuretics, anti-emetics, antihistamines, anti-inflammatories, antitussives, anti-diabetic agents (for instance, insulin), opioids, hormones and combinations thereof. More suitably, the active ingredient is a stimulant such as caffeine or nicotine. Alternatively, the active ingredient is an analgesic. A further example of an active ingredient is insulin.

[0043] In another embodiment of the invention, the biologically active ingredient is a nonsteroidal anti-inflammatory drug (NSAID), such as diclofenac, ketoprofen, ibuprofen or aspirin. Alternatively the active ingredient is paracetamol (which is generally not classed as an NSAID).

[0044] The biologically active ingredient may be an anti-emetic, for instance Dolasetron. Alternatively the biologically active ingredient is an erectile dysfunction drug, such as sildenafil citrate.

[0045] The biologically active ingredient may be any alkaloid chemical compound having a wide range of pharmacological activity such as antimalaria, antiasthma, anticancer, cholinomimetic, vasodilatory, antiarrhythmic, analgesic, antibacterial or antihyperglycemic properties.

[0046] In a particular embodiment, the biologically active ingredient is a ‘tobacco alkaloid’, including nicotine and nicotine-like alkaloids that may be in a free-base form or any pharmaceutically acceptable salt form. Suitably, the biologically active ingredient is nicotine. Nicotine may be bound as a salt to a suitable complex or compound. The nicotine may be bound to a cation exchange resin containing suitable acidic groups. Suitable acidic groups may be carboxylic, sulfonic, phosphoric, and phenolic acid. The ion exchange resin may be composed of cross-linked polymers of styrene and divinylbenzene, divinylbenzene and methacrylic acid or acrylic acid and the like. Applicable ion exchange resins are described in US Patent No.3,845,217 & US Patent No. 3,901,248 and are included herein for reference. The nicotine may also be stabilised by reversible adsorption onto an inorganic mineral filler such as calcium carbonate as described in US patent applications US 2012/ 0039981 and US 2012/ 0321751 and included here for reference. The preferred ion exchange resin for nicotine is a weakly acidic cation exchange resin of methacrylic acid and divinylbenzene sold as Amberlite IRP-64.

[0047] The quantity of biologically active ingredient will depend on the desired therapeutic effect. In an embodiment, the chewing gum composition comprises 0.1 to 5% by weight of nicotine, based on the total weight of the chewing gum composition. Suitably, the chewing gum composition comprises 0.1 to 1% by weight of nicotine, based on the total weight of the chewing gum composition. More suitably, the chewing gum composition comprises 0.2 to 0.6% by weight of nicotine, based on the total weight of the chewing gum composition.

[0048] The chewing gum composition may also comprise one or more buffers (pH adjusting agent) present in a quantity of 0.1 to 10% by weight of the total chewing gum composition. Suitably, the one or more buffers is present in a quantity of 0.5 to 5% by weight of the total chewing gum composition. More suitably, the one or more buffers is present in a quantity of 2 to 4% by weight of the total chewing gum composition. The buffers should elevate the pH of saliva in the mouth to the range of about 7.5 to about 10, preferably in the range of about 8 to about 9.5. The buffers should be delivered to the oral cavity at a rate appropriate for optimal maintenance of the salivary pH whilst the active ingredient (e.g. nicotine) is released from the chewing gum to the mouth. Nicotine chewing gum often contain pH adjusting agents to optimise the absorption of nicotine across the buccal cavity. This is done by raising the pH of the buccal cavity above normal mouth pH to convert ionised nicotine into the unionised form which will readily cross the buccal membrane allowing direct delivery of the nicotine into the bloodstream (avoiding hepatic first pass effect).

[0049] In an embodiment, the buffer is selected from one or more of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium hydroxide, magnesium oxide, potassium citrate and sodium glycinate. Suitably, the buffer is selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate.

[0050] Depending on the desired release of the buffers from the gum the buffers may be encapsulated to delay or prolong the delivery time from the gum mass to the oral cavity. Encapsulation techniques such as wax granulation, wet granulation, spray drying, spray chilling, fluid bed coating, coascervation and fibre extrusion may all be employed. US patent application US 2012/0087875 describes a method of incorporating the buffers into the gum base to modify the release and is included herein for reference.

[0051] The at least one sweetening or flavouring agent of the chewing gum composition may comprise one or more bulk sweeteners. Bulk sweeteners include both sugar and sugar-free components. Bulk sweeteners often act as bulking agents whilst improving the juiciness and aiding the flavour profile of the chewing gum. In an embodiment, the bulk sweetener is present in an amount from 5 to 90% of the total weight of the chewing gum composition. Suitably, the bulk sweetener is present in an amount from 20 to 80% of the total weight of the chewing gum composition. More suitably, the bulk sweetener is present in an amount from 30 to 60% of the total weight of the chewing gum composition. Even more suitably, the bulk sweetener is present in an amount from 30 to 45% of the total weight of the uncoated chewing gum composition. Most suitably, the bulk sweetener is present in an amount from 32 to 42% of the total weight of the uncoated chewing gum composition.

[0052] In an embodiment, the bulk sweetener is selected from one or more of sucrose, dextrose, glucose syrup, hydrogenated glucose syrup, fructose, corn syrup solids, maltose, levulose, saccharose, lactose, galactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, sorbitol, mannitol, xylitol, maltitol, isomalt and erythritol.

[0053] The at least one sweetening or flavouring agent of the chewing gum composition may comprise one or more high intensity sweeteners. Depending on the sweetness and flavour profile desired for the chewing gum product, bulk sweeteners may be used in combination with high intensity sweeteners. Suitable high intensity sweeteners include but are not limited to aspartame, acesulfame K, alitame, cyclamic acid and its salts, dihydrochalacones, glycyrrhizin, monellin, saccharin and its salts, sucralose, thaumatin and similar. The high intensity sweeteners may be encapsulated to prolong the sweetness delivery and flavour perception. Techniques such as spray drying, fluid bed coating, spray chilling, wet granulation, coascervation, wax granulation, and fibre extrusion may all be employed to tune the release rate.

[0054] Suitably, the high intensity sweetener is one or more of aspartame, acesulfame K and sucralose.

[0055] In an embodiment, the high intensity sweetener is present in an amount from 0.01 to 10% of the total weight of the chewing gum composition. Suitably, the high intensity sweetener is present in an amount from 0.5 to 1.5% of the total weight of the chewing gum composition.

[0056] The at least one sweetening or flavouring agent of the chewing gum composition may be a flavouring agent. Chewing gums will typically contain flavours, these may be of synthetic or natural origin may be in liquid or solid form, they may be essential oils, natural components, whole cells, essences, extracts, powders etc. Patent US 2015/0201644 Al include a wide range of possible flavour oils, aldehydes and esters, sensates, warming agents, tingling agents, effervescence agents and colouring agents that may be incorporated into chewy confectionery and gum and is included herein for reference. In an embodiment, the chewing gum composition comprises a flavouring agent in a quantity of 0.1 to 10% by weight of the chewing gum composition. Suitably, the chewing gum composition comprises a flavouring agent in a quantity of 3 to 7% by weight of the chewing gum composition. More suitably, the chewing gum composition comprises a flavouring agent in a quantity of 4 to 6% by weight of the chewing gum composition.

[0057] The chewing gum composition of the present invention may have a coating (e.g. a crunchy chewing gum coating). Any suitably coating composition may be used. In an embodiment, the coating is present in a quantity of 20-25% by weight, based on the total weight of the coated chewing gum composition.

[0058] In an embodiment, the coating comprises a crystallisable sweetener, gum arabic, high intensity sweetener and inorganics. Suitably, the coating comprises 90 to 95 wt% of crystallisable sweetener, 0.5 to 4 wt% gum arabic, 0.1 to 2 wt% high intensity sweetener, and 0.5 to 3 wt% inorganic materials [0059] In a particular embodiment, the coating contains 90 to 95 wt% of crystallisable sweetener, 1 to 3 wt% gum arabic, 0.4 to 1 wt% high intensity sweetener, 0.5 to 1.5 wt% Ti02, and 0.4 to 1 wt% CaCC>3.

[0060] In another embodiment, the chewing gum composition may comprise a biodegradable polymer.

[0061] The following numbered paragraphs describe particular embodiments of the chewing gum compositions of the present invention: 1) 40-75wt% of a gum base, 0.1-2wt% of a biologically active ingredient 0.001-0.1 wt% of a colourant 20-80wt% of a bulk sweetener 0.01-5wt% of a high intensity sweetener 1 -10wt% of a flavouring 0.5-5wt% of a buffer 2) 50-65wt% of a gum base, 0.1-1wt% of a biologically active ingredient 0.001 -0.5wt% of a colourant 30-60wt% of a bulk sweetener 0.1-5wt% of a high intensity sweetener 1 -10wt% of a flavouring 1 -5wt% of a buffer 3) 50-60wt% of a gum base, 0.1-1wt% of a ‘tobacco alkaloid’, including nicotine and nicotine-like alkaloids 0.001 -0.5wt% of a colourant 30-60wt% of a bulk sweetener 0.1-5wt% of a high intensity sweetener 1 -10wt% of a flavouring 1 -5wt% of a buffer 4) 50-60wt% of a gum base, of which 7-15wt% is an elastomeric material 10-50wt% is a mixture of a non-toxic vinyl polymer, a softener and an emulsifier 15-30wt% is an elastomer plasticiser 15-25wt% is a filler 0.04-0.09wt% is an antioxidant 0.1-1wt% of a ‘tobacco alkaloid’, including nicotine and nicotine-like alkaloids 0.001 -0.5wt% of a colourant 30-60wt% of a bulk sweetener 0.1-5wt% of a high intensity sweetener 1 -10wt% of a flavouring 1 -5wt% of a buffer 5) 50-60wt% of a gum base, of which 7-15wt% is an elastomeric material 30-50wt% is a mixture of a non-toxic vinyl polymer, a softener and an emulsifier 20-30wt% is an elastomer plasticiser 15-25wt% is a filler 0.04-0.09wt% is an antioxidant 0.1-0.8wt% of a ‘tobacco alkaloid’, including nicotine and nicotine-like alkaloids 0.001-0.1 wt% of a colourant 30-45wt% of a bulk sweetener 0.1-3wt% of a high intensity sweetener 3-7wt% of a flavouring 1 -5wt% of a buffer 6) 50-60wt% of a gum base, of which 7-15wt% is an elastomeric material selected from i) A mixture of isobutylene-isoprene copolymer and polyisobutylene, wherein the polyisobutylene has a molecular weight of 36,000 to 75,000 g/mol; or ii) A mixture of a first polyisobutylene having a molecular weight of 36,000 to 75,000 g/mol and a second polyisobutylene having a molecular weight of 200,000 to 4,100,000 g/mol 30-50wt% is a mixture of a non-toxic vinyl polymer, a softener and an emulsifier 20-30wt% is an elastomer plasticiser that is a terpene resin derived from d-limonene 15-25wt% is a filler selected from is talc or calcium carbonate 0.04-0.09wt% is a butylated hydroxytoluene antioxidant 0.1-0.8wt% of a ‘tobacco alkaloid’, including nicotine and nicotine-like alkaloids 0.001-0.1 wt% of a colourant 30-45wt% of a bulk sweetener selected from one or more of sucrose, dextrose, glucose syrup, hydrogenated glucose syrup, fructose, corn syrup solids, maltose, levulose, saccharose, lactose, galactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, sorbitol, mannitol, xylitol, maltitol, isomalt and erythritol. 0.1-3wt% of a high intensity sweetener selected from one or more of aspartame, acesulfame K and sucralose 3-7wt% of a flavouring 1-5wt% of a buffer selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate 7) 52-58wt% of a gum base, of which 7-15wt% is an elastomeric material selected from i) A mixture of isobutylene-isoprene copolymer and polyisobutylene, wherein the polyisobutylene has a molecular weight of 36,000 to 75,000 g/mol; or ii) A mixture of a first polyisobutylene having a molecular weight of 36,000 to 75,000 g/mol and a second polyisobutylene having a molecular weight of 200,000 to 4,100,000 g/mol 40-50wt% is a mixture of a non-toxic vinyl polymer, a softener and an emulsifier 20-30wt% is an elastomer plasticiser that is a terpene resin derived from d-limonene 15-22wt% is a filler selected from is talc or calcium carbonate 0.04-0.09wt% is a butylated hydroxytoluene antioxidant 0.1-0.6wt% of a ‘tobacco alkaloid’, including nicotine and nicotine-like alkaloids 0.005-0.1wt% of a colourant 32-42wt% of a bulk sweetener selected from one or more of sucrose, dextrose, glucose syrup, hydrogenated glucose syrup, fructose, corn syrup solids, maltose, levulose, saccharose, lactose, galactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, sorbitol, mannitol, xylitol, maltitol, isomalt and erythritol. 0.5-2wt% of a high intensity sweetener selected from one or more of aspartame, acesulfame K and sucralose 3-7wt% of a flavouring 1-5wt% of a buffer selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate

Preparation of chewing gum compositions [0062] As discussed hereinbefore, the present invention also provides a process for the preparation of the chewing gum composition of any preceding claim, the process comprising the step of: a) mixing, until homogenous, the gum base, at least one biologically active ingredient and at least one sweetening or flavouring agent.

[0063] In an embodiment, step a) is conducted at a temperature of 20 to 80°C. Suitably, step a) is conducted at a temperature of 40 to 60^ [0064] In another embodiment, step a) comprises for following sequential steps: a1) adding the at least one active ingredient, a2) adding the gum base, and a3) adding the at least one sweetening or flavouring agent, wherein steps a1, a2 and a3 are performed with mixing.

[0065] Chewing gum may be manufactured by adding the ingredients step-wise into a sigma or z-blade mixer or other suitable mixer such as a twin-screw extruder. One the chewing gum mixture is homogenous the gum mass is discharged from the mixer and formed into the desired size and shape, this may be by rolling into sheets and cutting into sticks or by extruding into chunks or casting into pellets.

[0066] In general the chewing gum base is warmed to a pliable consistency either before or after addition to the mixer - colours and actives may be added at this stage. Addition of bulk and high intensity sweetener, syrup and softener may be added early in the mix process, further portions of the bulk sweetener(s) may be added to the mixture once the first addition was incorporated. Flavouring agents may be added with the final portion of the bulk sweetener. Buffers may be added with the bulk sweetener at any stage.

[0067] A chewing gum mixing process typically takes about 5 to 15 minutes but can take longer. Variations to the above procedure maybe used, a one step process is described in US patent application 2004/0115305 and included herein for reference.

[0068] In accordance with the present invention the chewing gum may take any form or structure, such as pellet, a stick, a ball, a chunk, a tablet, a pill, a pastille or a sphere. The chewing gum may be center filled with liquid or solid.

[0069] In an embodiment, the process may comprise an additional step b) of coating the chewing gum composition. The chewing gum core may constitute 0.1 to 75% of the coated chewing gum weight. Suitable coatings include hard coatings, soft coatings and film coatings. The coating may be sugar or sugar-free. The preferred coating is a hard coating. A hard coating gives a sweet, crunchy layer that improves the consumer experience and protects the cores from environment stresses such as ingress of moisture. It will be understood that any of the coating compositions defined herein may be used.

[0070] A sugar crunchy coating may be prepared with any suitable crystallisable sugar such as sucrose or dextrose. Alternatively the coating may be prepared with non-cariogenic, crystallisable sweeteners such as sorbitol, xylitol, maltitol, mannitol, erythritol, isomalt, lactitol or tagatose.

[0071] The coating may also contain functional ingredients such as colours, flavours, pharmaceutical actives and teeth whitening components.

[0072] A hard coating is prepared by the application of a syrup containing crystallisable sweetener (sugar or polyol) to the cores in a rotating drum. The water from the syrup is driven off by cool air and low humidity and the sweetener crystallises onto the surface of the cores, this addition of the syrup is repeated numerous times, typically 3 to 80, to build up the coating size or weight to that desired.

[0073] A film coating may be applied to the chewing gum cores, the film is generally one or more film forming polymers, the film coating may also contain plasticizers, pigments, opacifiers, colours, waxes and saccharide compounds. Typically a film coating is 20-1 OOprn thick and applied by spraying the cores with atomised droplets of the coating solution. The film is built up in layers with the film forming spray being allowed to dry on the cores before the next application of the coating solution. This process is repeated until the desired coating thickness is achieved.

[0074] Suitable polymers for the film coating include edible cellulose derivatives such as methyl cellulose (MC), hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). Acrylic polymers and copolymers and mixtures of acrylate polymers and cellulose derivatives may be used.

[0075] In another embodiment, prior to step a), the gum base is prepared by a process comprising the step of: i) mixing, until homogenous, one or more elastomeric materials, one or more non-toxic vinyl polymers, one or more elastomer plasticisers, one or more fillers, one or more antioxidants, and one or more emulsifiers or softening agents.

[0076] Suitably, step (i) is conducted at a temperature of 100 to 150 °C. More suitably, step (i) is conducted at a temperature of 110 to 130 °C.

[0077] In another embodiment, step (i) comprises the following sequential steps: ia) adding the one or more elastomeric materials, ib) adding the one or more elastomer plasticisers and one or more fillers, ic) adding the one or more non-toxic vinyl polymers id) adding the one or more antioxidants and one or more emulsifiers or softening agents, wherein steps ia, ib, ic and id are performed with mixing.

[0078] Preparation of a gum base may be performed in a z-blade or sigma-blade mixer operating at a temperature in the region of 105 to 120 “C. The initial part of the gum base manufacture sequence is compounding; formation of a homogenous mass of the elastomer, elastomer plasticizer and filler. Once the compounding of the elastomers has been completed the remainder of the gum base manufacture is homogenisation of the vinyl polymers, softeners, emulsifiers and antioxidant.

[0079] In an initial compounding stage, all of the elastomer and a portion of the elastomer plasticizer and filler, such as about one third of the elastomer plasticiser and filler, may be added to the mixer. The exact amount of elastomer plasticizer and filler added to the mixer at this stage is determined by the batch size, the mixer size and dimensions. The ingredients are mixed for anywhere between about 15 and 90 minutes depending on the exact nature of the ingredients; such as the molecular weight of the elastomers, the mixer efficiency and the desired final consistency of the gum base. After the initial ingredients are homogenised and compounded the remaining portions of the elastomer plasticizer and filler are added and mixed until homogenous. Typically this initial homogenisation of the elastomer with elastomer plasticizer and filler will take up to one hour. The second stage of gum base manufacture is incorporation and homogenisation of the remaining gum base ingredients such as vinyl polymer, softener, emulsifier and antioxidant. Each of these ingredients is incorporated in portions and the contents of the mixer homogenised prior to subsequent additions. This second stage of ingredient addition typically takes about 60 minutes, with the gum base mass being allowed to become homogenous before discharge from the mixer.

[0080] In an embodiment, the finished gum base is filtered through a mesh (200 microns minimum) to ensure the absence of undesirable particles either raw materials or contamination during manufacture. The molten gum base mass is discharged into coated or lined pans, extruded or cast into any desirable shape and allowed to cool and solidify. Those skilled in the art will recognise that there are variations to the above procedure that would be suitable for the production of a suitable gum base.

[0081] Gum base can be produced using continuous mixing for example in a twin-screw extruder (US 6,010,723) or as an automated continuous production (US 6,017,565); as compressible gum base granules (US 8,734,763)and as part of a one-step process (US 2004/ 0,115,305), these patents are hereby incorporated for reference.

[0082] The preparation of the chewing gum base, chewing gum core and coated gum may use any of the equipment commonly reported in the art for said purpose. A useful guide to methods for manufacturing chewing gum and ingredients suitable for incorporation therein may be found in ‘Formulation and Production of Chewing Gum and Bubble Gum’ Ed Douglas Fritz (2006), the contents of which is incorporated by way of example.

[0083] A common measurement used for characterising the properties of the gum base is softening point. The softening point of the gum base as measured by the ring and ball method; well known to those skilled in the art. In a particular embodiment of the invention, the softening point of the gum base is 45“C to 65“C. Suitably, the softening point of the gum base is 50“C to 60“C.

EXAMPLES

[0084] Examples of the invention will now be described, for the purpose of illustration only, with reference to the accompanying figure, in which:

Fig. 1 shows the hardness, at set time points during a 30 minute chew cycle, of Commercial gum 1 and Inventive Gum 3 (described in Example 4) chewed gum cuds. Values are reported in Example 7.

Methods and materials

Ingredients [0085] All ingredients were obtained from standard suppliers of ingredients for use in chewing gum and used without further purification.

Reference Chewing Gum (Commercial 1) [0086] A standard commercial nicotine gum, Nicorette Original Flavor uncoated 4 mg gum obtained from retail stores in the USA, was used as the control in the experiments. This product is the Reference Listed Drug for nicotine gum in the U.S. Food and Drug Administration’s reference guide (FDA Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations) and thus an appropriate standard for the experiments. It will be referred to as Commercial 1 in the Examples below.

Reference method A: Drug release tests on medicated chewing gums [0087] Nicotine release is measured using a method based on that described in the European Pharmacopoeia. The gum sample is masticated using mechanical chewing apparatus (EP approved dissolution apparatus B) and the samples analysed using reverse phase HPLC based on the method described in the European Pharmacopoeia.

Preparation of phosphate buffer [0088] Weigh 34 g ±0.1 g potassium dihydrogen orthophosphate into a beaker. Add approximately 2 L purified water and sonicate using an ultrasonic bath until the potassium dihydrogen orthophosphate has completely dissolved. Fill the beaker to approx 4.0 L. Using a calibrated pH meter measure the pH of the phosphate buffer. Adjust the pH of the phosphate buffer slowly to 6.0 using 1.0M potassium hydroxide. Transfer to 5 L volumetric flask, dilute to volume with purified water and mix thoroughly.

Preparation of Ammonium Dihydrogen Orthophosphate Buffer Solution [0089] Weigh 11.5 g ± 0.1 g ammonium dihydrogen orthophosphate and transfer to a 2 L beaker. Add approximately 300 mL purified water and sonicate using an ultrasonic bath until the ammonium dihydrogen orthophosphate has completely dissolved. Adjust pH to 8.5 using ammonium hydroxide. Transfer contents of the 2 L beaker into a 2L volumetric flask, dilute to volume with purified water and mix thoroughly.

Procedure for Analysing the Release Profiles of Active Ingredients from Gum [0090] Each piece of gum was weighed before chewing, and the weight recorded to allow estimation of the total quantity of drug in each piece.

[0091] A ERWEKA DRT-1 chewing apparatus (European Pharmacopoeia 7th Edition approved dissolution apparatus B) from AB FIA was used, which operates by alternately compressing and twisting the gum in between two mesh grids. A water jacket, with the water temperature set to 37 °C was used to regulate the temperature in the mastication cell to match that expected when chewed in vivo, and the chew rate was set to 40 ‘chews’ per minute. The parameters used in mastication are summarised below in Table 1.

Table 1: Chewing Parameters

[0092] 40 ml. phosphate buffer was added to the mastication cell, then a plastic mesh placed at its bottom. A piece of gum of known weight was placed on the centre of the mesh, and a second piece of mesh put on top. At the start of each run, the cell containing the artificial saliva and gum was left for 5 minutes so that the system could equilibrate to 37 °C. The gum was then masticated. A sample volume of 0.5 ml. was then withdrawn from the test cell after mastication for analysis.

[0093] All the samples were then analysed by HPLC using a Agilent 1100 Series High Performance Liquid Chromatography system, equipped with an autosampler, pump, and diode array detector. Data handling and instrument control was provided via ChemStation software. Gemini NX, 3pm, C18 (2), 100A, 50mm x 4.6mm columns were used. The mobile phase was a mixture of 75% (v/v) ammonium dihydrogen orthophosphate buffer solution (5.4) and 25% (v/v) acetonitrile. The flow rate was 1 mL/min and column temperature was 40 °C. A UV detector set to monitor a wavelength of 260 nm was used for analysis.

Reference method B: Comparison of the chew profiles of gum [0094] To determine the chew profile of a gum, it is chewed by volunteers for a set period of time, removed from the mouth and the mass of the gum cud recorded. The gum cud is then immediately transferred to a non-compressible surface and subjected to a known force. The diameter of the compressed gum cud is measured and recorded. The mass, diameter and compression force are used to calculate the compression modulus which is a measure of the hardness of the chewing gum at that chew time.

[0095] A gum piece is given to a volunteer with instructions to chew the gum for a set period of time. Once the gum has been chewed for the predetermined time the gum cud is removed from the mouth, excess saliva removed and the mass of the gum cud recorded. The gum cud is immediately transferred to a level, non-compressible surface, covered with a wet, nylon disc and compressed using a known mass, for example by a person standing on the nylon disc covering the gum cud for 10 s. The nylon disc is removed from the gum cud and the diameter of the gum cud is measured using a calibrated vernier caliper gauge or a ruler. Ideally at least two readings of the diameter, perpendicular to each other, are recorded and averaged to give a representative indication of the compressed gum cud size. Ideally replicate samples of each gum are chewed for each time point of the chew profile. Standard time points for the chew profile are 1, 2, 3, 5, 10, 20 and 30 minutes. The region of greatest change of gum hardness are early in the chew, so more time points are collected in this region. Nicotine gum patient information leaflets advise chewing the gum until most of the tingle is gone (about 30 minutes).. As such the experiment concluded after 30 minutes chewing. 1) radius of sphere (rs)

where: rs = radius of spherical gum cud (m)

V = volume (g) and assume density of gum cud = 1; d=m/V 2) surface area of compressed gum cud (SA) SA = nr2 where: SA = surface area of compressed gum (m2) r = radius of compressed gum cud disc (m) 3) compression ratio (c)

where: c = compression ratio rs = radius of spherical gum cud (m), equation 1 r = average radius of gum cud after compression (m) 4) compression modulus (G)

where: G = compression modulus (kPa) m = mass of compression force (Kg) g = weight force acceleration due to gravity (9.8 m/s2) SA = surface area of compressed gum cud (m2), equation 2 c = compression ratio, equation 3

The average results of these calculations for each gum cud at each time point may be plotted on an appropriate graph to give a visual representation of the chew profile of a chewing gum.

Example 1 - Preparation of gum base [0096] A gum base is prepared composed of the ingredients listed in Table 2 below:

Table 2: Gum base Ingredients

[0097] Exemplary elastomers are i) A mixture of isobutylene-isoprene copolymer and polyisobutylene, wherein the polyisobutylene has a molecular weight of 36,000 to 75,000 g/mol; and ii) A mixture of a first polyisobutylene having a molecular weight of 36,000 to 75,000 g/mol and a second polyisobutylene having a molecular weight of 200,000 to 4,100,000 g/mol.

[0098] The resin is composed of non-toxic vinyl polymer, softener and emulsifier. Exemplary resin components are poly(vinyl acetate) (molecular weight between 10,000 and 55,000 g/mol), hydrogenated vegetable oils, acetic acid esters of monoglycerides, lecithin and glycerol monostearate.

[0099] Exemplary plasticisers are polyterpene resins derived from d-limonene.

[00100] Exemplary fillers (water insoluble adjuvant) are talc and calcium carbonate.

[00101] An exemplary antioxidant is BHT.

[00102] Any suitable heated mixing vessel may be used for the preparation of gum base, in this instance a z-blade mixer which has been heated to 120 “C. The elastomer is cut into small pieces before adding to the mixer where it is softened by the heat and mechanical action of the z-blades. The elastomer plasticizer and water insoluble adjuvant is added in approximate one-third portions and homogenised over a period of approximately 30 to 50 minutes. The resin is added to the mixer in portions over about 10 to 20 minutes and mixed until homogenised. The softening ingredients are then added portion-wise over the next 20 to 40 minutes and mixed until homogenous. The full gum base mixing process will take approximately 60 to 120 minutes. The molten gum base mixer is removed from the mixer and allowed to cool to room temperature.

Example 2 - Preparation of uncoated gum core (Gum 1) [00103] Nicotine chewing gum is prepared using the gum base of Example 1, the chewing gum is prepared in a conventional mechanical mixer with moderate heat applied. The composition of the chewing gum core is described in Table 3 below.

Table 3: Chewing Gum Ingredients Used to Make Gum 1

[00104] Exemplary bulk sweeteners are sucrose, dextrose, glucose syrup, hydrogenated glucose syrup, fructose, corn syrup solids, maltose, levulose, saccharose, lactose, galactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, sorbitol, mannitol, xylitol, maltitol, isomalt and erythritol.

[00105] Exemplary high intensity sweeteners are aspartame, acesulfame K and sucralose.

[00106] Exemplary buffers are sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate.

[00107] Nicotine chewing gum is typically prepared in a z-blade mixer, heated to approximately 50“C. The gum base may be warmed to soften it prior to addition to the mixer.

Components of the chewing gum added to the mixer in portions to ensure a homogenous mixture. The active component is added to the gum base at the start and a premix of defined duration is performed to ensure thorough mixing. Flavour components are added towards the end of the mixing process to minimise the time that volatile components are exposed to heat. Mixing procedures may last from 5 to 15 minutes but may take longer.

[00108] After discharge from the mixer the chewing gum is formed into approximately 1 g pieces containing 4 mg of nicotine.

Example 3 - Preparation of uncoated gum core (Gum 2) [00109] Nicotine chewing gum is prepared using the gum base of Example 1, the chewing gum is prepared in a conventional mechanical mixer with moderate heat applied. The composition of the chewing gum core is described in Table 4 below.

Table 4: Chewing Gum Ingredients Used to Make Gum 2

[00110] Exemplary bulk sweeteners are sucrose, dextrose, glucose syrup, hydrogenated glucose syrup, fructose, corn syrup solids, maltose, levulose, saccharose, lactose, galactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, sorbitol, mannitol, xylitol, maltitol, isomalt and erythritol.

[00111] Exemplary high intensity sweeteners are aspartame, acesulfame K and sucralose.

[00112] Exemplary buffers are sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate.

[00113] Nicotine chewing gum is typically prepared in a z-blade mixer, heated to approximately 50“C. The gum base may be warmed to soften it prior to addition to the mixer. Components of the chewing gum added to the mixer in portions to ensure a homogenous mixture. The active component is added to the gum base at the start and a premix of defined duration is performed to ensure thorough mixing. Flavour components are added towards the end of the mixing process to minimise the time that volatile components are exposed to heat. Mixing procedures may last from 5 to 15 minutes but may take longer.

[00114] After discharge from the mixer the chewing gum is formed into approximately 1 g pieces containing 2 mg of nicotine.

Example 4 - Preparation of uncoated gum core (Gum 3) [00115] Chewing gum is prepared using the gum base of Example 1; the chewing gum is prepared in a conventional mechanical mixer with moderate heat applied. The composition of the chewing gum core is described in Table 5 below. The preparation procedure is the same as described for Example 2.

Table 5: Chewing Gum Ingredients Used to Make Gum 3

[00116] Exemplary bulk sweeteners are sucrose, dextrose, glucose syrup, hydrogenated glucose syrup, fructose, corn syrup solids, maltose, levulose, saccharose, lactose, galactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, sorbitol, mannitol, xylitol, maltitol, isomalt and erythritol.

[00117] Exemplary high intensity sweeteners are aspartame, acesulfame K and sucralose.

[00118] Exemplary buffers are sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate.

[00119] After discharge from the mixer the chewing gum is formed into approximately 1 g pieces. These gums were essentially identical to those made in Example 2 (Gum 1), with the exception that they didn’t contain nicotine and were found to have very similar physical properties. The absence of nicotine allowed them to be chewed by non-smokers as described in Example 7.

Example 5 - Preparation of coated nicotine gum (Gum 4) [00120] Coated chewing gums are prepared using the uncoated chewing gum in Example 2 as the gum cores using a conventional coating technique in a rotating coating pan. The coating composition is described in Table 6 below.

Table 6: Chewing Gum Ingredients Used to Make the Coating on Gum 4

[00121] A syrup containing a crystallisable sweetener, gum arabic solution, high intensity sweetener and inorganics is prepared and added to the cores step-wise to create a number of layers, the coating will typically be built up over approximately 3 to 80 layers. Crunchy chewing gum coatings are applied using a coating pan or drum familiar to those skilled in the art. The coating layers are built up around the chewing gum core to compose approximately 20-25% of the final coated chewing gum mass.

Example 6 - Preparation of coated nicotine gum (Gum 5) [00122] Coated chewing gums are prepared using the uncoated chewing gum in Example 3 as the gum cores using a conventional coating technique in a rotating coating pan. The coating composition is described in Table 7 below.

Table 7: Chewing Gum Ingredients Used to Make the Coating on Gum 5

[00123] A syrup containing a crystallisable sweetener, gum arabic solution, high intensity sweetener and inorganics is prepared and added to the cores step-wise to create a number of layers, the coating will typically be built up over approximately 3 to 80 layers. Crunchy chewing gum coatings are applied using a coating pan or drum familiar to those skilled in the art. The coating layers are built up around the chewing gum core to compose approximately 20-25% of the final coated chewing gum mass.

Example 7 - Comparison of the chew profiles [00124] The chew profile of samples of a commercial nicotine chewing gum and Inventive Gum 3 (Example 4) were evaluated using the procedure described in Reference Method B (Table 8).

Table 8: Chew Profile of Inventive and Non-lnventive Gum

[00125] As will be observed from Fig. 1, the inventive gum sample was found to be significantly softer than the commercial standard, and showed a compression modulus of approximately <5 kPa for the duration of the 30 minute chew regime, thus giving rise to a more pleasant chew.

Example 8 - Comparison of release [00126] Samples of the commercial nicotine chewing gum, Inventive Gum 4 containing 4 mg nicotine (Example 5) and inventive gum 5 containing 2 mg nicotine (Example 6) were masticated for 30 minutes and the amount of nicotine released after 30 minutes analysed using the method described in Reference Method A (Table 9).

Table 9: Nicotine Release Profile of Inventive and Non-lnventive Gum

[00127] Whilst only 62% of the nicotine active had been released after 30 minutes from the commercial gum, a total of 96% had been released from inventive Gum 4 after this period of time and 93% had been released from inventive Gum 5.

[00128] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.

Claims (44)

1. A chewing gum composition comprising a chewing gum base, at least one biologically active ingredient and at least one sweetening or flavouring agent, wherein the chewing gum composition has a compression modulus of less than 7 kPa.

2. The chewing gum composition of claim 1, wherein the chewing gum composition has a compression modulus of 1.5 to 6 kPa.

3. The chewing gum composition of claim 1 or 2, wherein the chewing gum composition has a compression modulus of 3 to 6 kPa.

4. The chewing gum composition of any of claims 1,2 or 3, wherein the gum base is present in an amount from 40 to 75% of the total weight of the chewing gum composition.

5. The chewing gum composition of any preceding claim, wherein the gum base is present in an amount from 50 to 60% of the total weight of the chewing gum composition.

6. The chewing gum composition of any preceding claim, wherein the gum base is present in an amount from 52 to 58% of the total weight of the chewing gum composition.

7. The chewing gum composition of any preceding claim, wherein the at least one sweetening or flavouring agent comprises a bulk sweetener present in an amount from 30 to 60% of the total weight of the chewing gum composition.

8. The chewing gum composition of claim 7, wherein the bulk sweetener is selected from one or more of sucrose, dextrose, glucose syrup, hydrogenated glucose syrup, fructose, corn syrup solids, maltose, levulose, saccharose, lactose, galactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, sorbitol, mannitol, xylitol, maltitol, isomalt and erythritol.

9. The chewing gum composition of any preceding claim, wherein the at least one sweetening or flavouring agent comprises a high intensity sweetener present in an amount from 0.01 to 10% of the total weight of the chewing gum composition.

10. The chewing gum composition of claim 9, wherein the high intensity sweetener is selected from one or more of aspartame, acesulfame K, alitame, cyclamic acid and its salts, dihydrochalacones, glycyrrhizin, monellin, saccharin and its salts, sucralose and thaumatin.

11. The chewing gum composition of claim 10, wherein the high intensity sweetener is selected from one or more of aspartame, acesulfame K and sucralose.

12. The chewing gum composition of any preceding claim, wherein the gum base comprises an elastomeric material selected from one or more of arabic gum, smoked or liquid latex (Hevea brasiliensis), chicle, crown gum, balata, gutta kay, gutta hang kang, gutta-percha, jelutong, lechi-capsi, massaranduba, massaranduba chocolate, niger gutta, nispero, perillo, rosadinha, sorva, tunu and the like, polyisobutylene, butadiene-styrene copolymer and isobutylene-isoprene copolymer.

13. The chewing gum composition of claim 12, wherein the elastomeric material is selected from: a. A mixture of isobutylene-isoprene copolymer and polyisobutylene, wherein the polyisobutylene has a molecular weight of 36,000 to 75,000 g/mol; or b. A mixture of a first polyisobutylene having a molecular weight of 36,000 to 75.000 g/mol and a second polyisobutylene having a molecular weight of 200.000 to 4,100,000 g/mol.

14. The chewing gum composition of claim 12 or 13, wherein the elastomeric material is present in an amount from 7 to 15% of the total weight of the gum base.

15. The chewing gum composition of any preceding claim, wherein the gum base comprises an elastomer plasticiser selected from one or more of methyl glycerol, a pentaerythritol ester of a rosin or a modified rosin, and a terpene resin derived from d-limonene, α-pinene or β-pinene.

16. The chewing gum composition of claim 15, wherein the elastomer plasticiser is a terpene resin derived from d-limonene.

17. The chewing gum composition of claim 15 or 16, wherein the elastomer plasticiser is present in an amount from 15 to 30% of the total weight of the gum base.

18. The chewing gum composition of any preceding claim, wherein the gum base comprises a non-toxic vinyl polymer selected from one or more of poly(vinyl acetate), ethylene acetate, vinyl acetate and a copolymer of vinyl laurate and vinyl acetate.

19. The chewing gum composition of claim 18, wherein the non-toxic vinyl polymer is poly(vinyl acetate).

20. The chewing gum composition of claim 18 or 19, wherein the non-toxic vinyl polymer is present in an amount from 20 to 30% of the total weight of the gum base.

21. The chewing gum composition of any preceding claim, wherein the gum base comprises a filler selected from one or more of calcium carbonate, talc, amorphous silica, tricalcium phosphate, magnesium carbonate, alumina, aluminium hydroxide and aluminium silicate.

22. The chewing gum composition of claim 21, wherein the filler is a particulate filler having an average particle size of 0.1 to 15 pm.

23. The chewing gum composition of claim 21 or 22, wherein the filler is talc or calcium carbonate.

24. The chewing gum composition of claim 21,22 or 23, wherein the filler is present in an amount from 12 to 22% of the total weight of the gum base.

25. The chewing gum composition of any preceding claim, wherein the gum base comprises at least one softener or emulsifier selected from one or more of hydrogenated vegetable oils, lanolin, stearic acid, sodium stearate, potassium stearate, glycerine, lecithin, glycerol, glycerol monooleate, lactylic esters of fatty acids, lactylated fatty acid esters of glycerol and propylene glycol, mono-, di-, and tri-stearyl acetates, monoglyceride citrate, stearic acid, stearyl monoglyceridyl citrate, stearyl-2-lactylic acid, triacyetyl glycerin, triethyl citrate and polyethylene glycol.

26. The chewing gum composition of claim 25, wherein the softener or emulsifier is selected from one or more of hydrogenated vegetable oils, acetic acid esters of monoglycerides, lecithin and glycerol monostearate.

27. The chewing gum composition of claim 25 or 26, wherein the softener or emulsifier is present in an amount from 18 to 25% of the total weight of the gum base.

28. The chewing gum composition of any preceding claim, wherein the gum base comprises an antioxidant selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, betacarotenes, propyl gallate and an acidulants (e.g. vitamin C).

29. The chewing gum composition of claim 28, wherein the antioxidant is butylated hydroxytoluene.

30. The chewing gum composition of claim 28 or 29, wherein the antioxidant is present in an amount from 0.06 to 0.09% of the total weight of the gum base.

31. The chewing gum composition of any preceding claim, wherein the chewing gum composition further comprises a buffer selected from one or more of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium hydroxide, magnesium oxide, potassium citrate and sodium glycinate.

32. The chewing gum composition of claim 31, wherein the buffer is selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate.

33. The chewing gum composition of claim 31 or 32, wherein the buffer is present in an amount from 2 to 4% of the total weight of the chewing gum composition.

34. The chewing gum composition of any preceding claim, wherein the biologically active ingredient is a tobacco alkaloid (e.g. nicotine).

35. The chewing gum composition of any preceding claim, wherein, over the course of a 30 minute chewing cycle, the chewing gum releases greater than or equal to 85% by weight of the total quantity of active ingredient contained therein prior to chewing.

36. The chewing gum composition of any preceding claim, wherein, over the course of a 30 minute chewing cycle, the chewing gum releases greater than or equal to 90% by weight of the total quantity of active ingredient contained therein prior to chewing..

37. The chewing gum composition of any preceding claim, wherein, over the course of a 30 minute chewing cycle, the chewing gum releases greater than or equal to 95% by weight of the total quantity of active ingredient contained therein prior to chewing..

38. The chewing gum composition of claims 35 to 37, wherein the release of the biologically active ingredient is measured using a European Pharmacopoeia 7th Edition dissolution apparatus b, and using the following parameters: jaw gap of 1.6 mm 40“ rotation 40 chews per minute 37 “C temperature 40 ml. mastication medium (pH6 phosphate buffer).

39. A process for the preparation of the chewing gum composition of any preceding claim, the process comprising the step of: a. mixing, until homogenous, the gum base, at least one biologically active ingredient and at least one sweetening or flavouring agent.

40. The process of claim 39, wherein step a) is conducted at a temperature of 20 to 80^.

41. The process of claim 39 or 40, wherein step a) comprises for following sequential steps: a1) adding the at least one active ingredient, a2) adding the gum base, and a3) adding the at least one sweetening or flavouring agent, wherein steps a1, a2 and a3 are performed with mixing.

42. The process of any of claims 39, 40 or 41, wherein prior to step a), the gum base is prepared by a process comprising the step of: i) mixing, until homogenous, one or more elastomeric materials, one or more non-toxic vinyl polymers, one or more elastomer plasticisers, one or more fillers, one or more antioxidants, and one or more emulsifiers or softening agents.

43. The process of claim 42, wherein step (i) is conducted at a temperature of 100 to 150 °C.

44. The process of claim 42 or 43, wherein step (i) comprises the following sequential steps: ia) adding the one or more elastomeric materials, ib) adding the one or more elastomer plasticisers and one or more fillers, ic) adding the one or more non-toxic vinyl polymers id) adding the one or more antioxidants and one or more emulsifiers or softening agents, wherein steps ia, ib, ic and id are performed with mixing.