IE980990A1 - Composition and Method for Medicated Chewing Gum Delivery System - Google Patents

Abstract

A medicated chewing gum delivery system has gum base matrix material and at least one active substance for an immediate or a sustained release profile, or both.

Description

COMPOSITION AND METHOD FOR MEDICATED CHEWING GUM pELIVERY^ SYSTEM By: Subraman R. Cherukuri ILOLOGE® ««SB*»’' Field of the Invention The present invention relates to medicated chewing gum delivery systems, as well as to a method for making same. In particular, the invention relates to various chewing gum delivery systems containing one or more active substances.

Background of the Invention Medicated chewing gums that contain active ingredients are known in the art. Active ingredients include those substances which elicit some type of physiological or pharmacological response in the body. As an example, chewing gums containing vapor action nasal decongestants, analgesics or nicotine have been used to deliver medication to the body as the gum is masticated. Formulations are known which attempt to provide an immediate release or sustained release of the active substance, or both. Many times, the active substance is contained within the gum base material to be released upon chewing. Alternately, the active substance is mixed with an edible confectionery shell or coating which surrounds the entire gum base. There are certain disadvantages associated with these and other formulations, however. Addition to the gum base matrix of the active substance often results in a formulation in which the active is bound too tightly within the matrix itself. This can result in an uneven release, a reduced release profile, or no release at all. Many times the gum base materials are simply incompatible with the active substance, and thus provide ineffective release profiles. Including the active within a candy shell may help to ensure a more thorough release, but the release is immediate and short-lived. The consumer often gets an overwhelming burst of active which is followed by a rapid decrease or dissipation of the effect. Other chewing gum systems utilize granulates made up of gum base material which are compressed together to provide a final formulation. These formulations, however, have not been optimally utilized to date to provide a truly effective delivery system for active substances.

What is therefore needed in the art are new medicated chewing gum delivery system formulations which provide a more effective and relipbierimmediate'and/orwstained'releaseprofile thands presently obtainable in the art.

OPEN TO PUBLIC ^'ERECTION JNL. NOJ.hL.ft r-FriWcU Ό.9 Summary of the Invention The invention provides a medicated chewing gum delivery system for active ingredients which can provide immediate and/or sustained release of one or more active ingredients.

In a further embodiment of the invention, there is provided a chewing gum delivery system having a gum base matrix which facilitates release of the active substance in either an immediate release or a sustained release profile, or both.

Also provided as part of the invention is a medicated chewing gum delivery system comprising compressed granulates of gum base material having interspersed therebetween one or more active substances for delivery in an immediate and/or sustained release fashion. The gum base matrix may be composed of one or more hydrophilic or hydrophobic materials, depending upon the active substance to be utilized and the release profile desired.

In yet another embodiment, a chewing gum delivery system has a gum base matrix which at least partially surrounds a centerfill containing one or more active substances.

Another embodiment of the present invention includes a medicated gum delivery system in which a coating material at least partially surrounds a gum base matrix. The coating material can contain one or more active substances for immediate and/or sustained release.

It is within the scope of the invention that any of the foregoing embodiments be utilized separately or together, as hereinafter set forth.

Further provided as part of the invention Is a method of forming the chewing gum delivery systems described herein.

Brief Description of the Drawings Figure 1 is a cross section of the chewing gum composition of a preferred embodiment of the invention.

Figure 2 is a cross section of another chewing gum composition according to another preferred embodiment of the invention.

Figures 3 - 9 are graphs of examples comparing the invention according to various embodiments with one or more other formulations and/or a commercially available formulation.

Detailed Description of the Preferred Embodiments The invention provides a medicated chewing gum delivery system for one or more active ingredients. The active ingredient may be dispersed into or onto a gum base matrix to facilitate its release according to an immediate or a sustained release profile. In certain preferred embodiments, the chewing gum delivery system will provide for both immediate and sustained release of the active.

In one embodiment, there is provided a chewing gum delivery system comprised of a gum base matrix material which facilitates release of the active substance. Both the type and the amount of gum base matrix material can vary somewhat, depending on various factors such as the consistency desired and other components used to make the final gum product, as well the release profile sought for the active ingredient(s). In general, the gum base matrix will comprise about 5 to 85% by weight of the final chewing gum composition. The gum base is comprised of water-insoluble, natural and synthetic polymer material available in the industry. Illustrative examples of suitable polymers include elastomers and rubbers. For example, those polymers which include, without limitation, natural substances such as chicle, jelutong, gutta percha and crown gum. Synthetic elastomers such as butadiene-styrene copolymers, isobutylene-isoprene copolymers (e.g, “butyl rubber” in the art), polyethylene, polyisobutylene, polyvinylaceatate (PVA) and mixtures thereof may also be particularly useful. It is highly preferred that the gum base matrix material be selected so as to provide a final chewing gum composition which has a relatively “soft” chew both at the onset of mastication, as well towards the end of the chewing process (after about 30 to 60 minutes or so). Since at least one desirable characteristic of the chosen gum base material should be its ability to facilitate the release of the active ingredient(s), hereinafter described, as well as their subsequent absorption by the body, it is highly preferred that one or more gum base materials that have at least partially hydrophilic characteristics be utilized. It is even more prefered that the gum base material have significant hydrophilic moieties. Of these types of material, polyvinylacetate is particularly preferred, and low to medium weight polyvinylacetate is particularly preferred. Polyvinylacetate with a molecular weight (MW) of from about 12,000 to 45,000 is often especially desirable. In at least one preferred embodiment of the invention, the amount of polyvinylacetate (PVA) in the gum base is maximized with substantially no butyl rubber present, and the quantity of other non-PVA polymers such as butadiene-styrene, butylene-based polymers and copolymers is preferably minimized. It has now been discovered that polyvinylacetate provides a gum base which often yields a softer, less brittle and less sticky chewing gum composition, thereby contributing to a more organoleptically pleasing chewing sensation. Polyvinylacetate also tends to be more hydrophilic in nature then certain other polymers, and thereby allows a better release profile which can be highly suitable to both immediate and sustained release profiles.

In another embodiment of the invention, the type of gum base matrix material used to facilitate release of the active substance includes at least some butyl rubber, with additional amounts of polyisobutylene, and with polyvinylacetate (preferably PVA having a MW of approximately 12,000) also being present. This butyl rubber- based material appears to have certain advantages when used together with certain types of actives, such as for example, nicotine salts.

The foregoing gum base material (from whatever source) will preferably comprise from about 40 to 85% of the chewing gum composition delivery system of the invention (unless otherwise stated, all percentages provided herein are weight percentages, based on either the total weight of the gum base matrix or of the final chewing gum composition, where noted). It is many times preferred to utilize less than about 70% by weight of chewing gum base. In certain embodiments too much gum base may interfere with the release of the active substances, and additionally, may contribute to tackiness and poor mouth-feel of the final product. In an especially preferred embodiment of the invention, the chewing gum composition will contain about 50 to 60% of gum base, and desirably about 55%. Of the foregoing amounts, about 25 - 65% thereof, more preferably about 35 - 55% thereof, will be the polymer material(s) heretofore described.

Also included as part of the chewing gum base is one or more elastomer solvent materials to aid in softening the polymer component. Such elastomer solvents may include methyl, glycerol, or pentaerythritol esters of rosins or modified rosins, such as hydrogenated, dimerized or polymerized rosins or mixtures thereof. Examples of elastomer solvents suitable for use herein include the pentaeryrhritol ester of partially hydrogenated wood rosin. glycerol ester of wood rosin, glycerol ester of tall oil rosin, glycerol ester of wood rosin and partially hydrogenated wood rosin and partially hydrogenated methyl ester of rosin, such as polymer of alpha pinene or beta-pinene; terpene resins including polyterpene and mixtures thereof. The solvent may typically be employed in an amount ranging from about 10 to 75% and preferably about 45 to 70% by weight of the gum base. It may be preferable, however, to minimize or even eliminate the quantity of rosin/resin in the gum base. In certain embodiments, depending upon the active, it may be especially desirable not to exceed about 10% by weight of the gum base with rosin/resin compound(s).

A variety of traditional ingredients such as plasticizers or softeners such as lanolin, stearic acid, sodium stearate, potassium stearate, glycerol triacetate, glycerin and the like, including for example, natural waxes, such as paraffin waxes and microcrystalline waxes may also be incorporated into the gum base to obtain a variety of desirable textures and consistency properties. In accordance with the invention, however, these ingredients may be reduced in amount or in some cases, may be eliminated entirely. When present, these materials are generally employed in amounts of up to about 15% by weight, and preferably in amounts of from about 3 to 10% by weight of the gum base matrix material.

The chewing gum may additionally include conventional additives of coloring agents such as titanium oxide; emulsifiers such as lecithin and glycerol monostearate; additional fillers or bulking agents such as aluminum hydroxide, alumina, aluminum silicates; calcium carbonate, and talc and combinations thereof; and additional flavoring agents. These fillers may also be used in the gum base in various amounts. Preferably, the amount of fillers when used will vary from about 4 to 35% by weight of the final chewing gum composition.

Further provided as part of the medicated chewing gum composition of the invention are one or more sweeteners. These are included to impart a palatable sweetness or savoriness to the final formulation. Sweeteners can be chosen from the known saccharide material available in the industry. Sweeteners can include mono-, di- and tri- and polysaccharide materials, either alone or in combination, and their related oligomers. Invert sugar, sucrose, fructose, maltose, dextrose, polydextrose, polydextrin, glucose (com syrup), maltodextrin (com syrup solids) etc. are just some examples of suitable sweeteners. Other highly suitable sweeteners include saccharin, aspartame, acesulfame, sucralose, and sugar alcohols such as sorbitol, mannitol, maltitol, isomalt, xylitol as well as other commercially available sweeteners such as the dihydrochalcone compounds, glycyahizin, glycerine, Stevia Rebaudiana (Stevioside), and the hydrogenated starch hydrolysates. Of the foregoing, those sweeteners considered in the industry to be “sugarless” or “non-sucrose” are perhaps more preferred. Particularly preferred in some formulations are those sweeteners known to be noncariogenic or anti-cavity, such as xylitol, sorbitol, maltitol, isomalt, lactitol and polydextrose, either alone or in combination. Other sweeteners contemplated by the skilled artisan which are typically utilized in the food or confectionery industry may also be used. The sweeteners are added in amounts equal to about 0 - 40% of the composition, and preferably within the range of about 0.01 - 20%. More preferably, the sweeteners will comprise about 0.1 - 10% of the final medicated chewing gum formulation according to its various embodiments.

Flavor oils traditionally utilized in chewing gum preparations are also a component of the medicated chewing gum of the invention. These may be selected from a wide variety of natural and synthetic oils and essences known in the industry. Peppermint oil, spearmint oil, cinnamon oil, oil of Wintergreen, menthol, menthone, citrus oils and other fruit oils and essences are the most commonly used flavor oils which are employed in the present invention. Additional flavorings may be chosen from extracts of plant material, as well as aldehyde and ester flavorings, both natural and man-made. These flavors will typically comprise from about 0.1 to 10% of the chewing gum composition.

Flash-flow processing of one or more of the various edible, water-soluble components heretofore described (non-gum base) as comprising the chewing gum composition is contemplated. Thus, for example, the flavor oil(s) and saccharide materials may be processed together in a flash-flow apparatus for intimate mixing and dispersion upon addition to the gum base material. “Flash-flow” processing involves subjecting a feedstock to conditions of temperature and force which induce the feedstock to rapidly undergo physical and/or chemical transformation. The time during which the feedstock material is subjected to temperatures is extremely short. The term “flash-flow” has become recognized as referring to the conditions of temperature and force required to transform a solid feedstock having a certain morphological and/or chemical structure into a different morphological and/or chemical form without subjecting the materials to the excess heat or other requirements inherent in other forms of processing. Flash-flow processing can be accomplished either by either the flash heat method or via a flash shear method.

In the flash heat process, a spinning machine developed by Fuisz Technologies Ltd. of , Chantilly, VA and patented under U.S. Patent No.s 5,427,811, 5,458,823 and 5,834,033 may be preferred. This patent describes a spinning machine which has a series of elongated heating elements arranged in between a base and a cover. The heating elements, base and cover together define a chamber into which a non-solubilized feedstock material is inserted which is capable of intraparficle flow upon application of heat and force. Means are provided for individually heating each of the elongated heating elements, and restriction means in the form of a cylindrical shell or annular plate which circumscribes the heating elements permits restrictive flow of the processed feedstock which is expelled from the chamber. Other apparatus and methods useful in the flash-heat process include those set forth in U.S. Patent No.s 5,445,769, 5,447,423 and 5,458,823. The apparatus is operated at the temperature and speed which permits flash heat of the feedstock without deterioration of any of its ingredients, and these parameters can easily be optimized by those skilled in the art. In flash-flow processing, the time during which the feedstock material is subjected to elevated temperature is very short. In the flash-heat method, the feedstock is subjected to elevated temperature usually for only tenths of a second, and in the flash-shear method the feedstock is subjected to elevated temperatures for a time on the order of seconds. This has specific benefits in situations when materials might be degraded or otherwise detrimentally affected by excessive exposure to heat.

In the flash shear process, a shearform matrix is formed by thermally controlling the feedstock material, which includes a non-solubilized carrier, to a point where the carrier undergoes intra-particle flow. The carrier component is preferably a saccharide-based material. The feedstock is advanced and ejected from the machinery while the carrier is undergoing intra-particle flow and is then subjected to disruptive fluid shear forces to form multiple parts or masses, also known as microparticulate dispersions. The feedstock may be delivered to the ejector via one or more extruding devices or other mixing apparatus known in the art such as high and low shear mixers, as for example, Littleford type mixers. The flash shear process also contemplates the use of vertical and horizontal type mixers to deliver the feedstock to the actual flash shear apparatus.

An apparatus for flash shear processing of the feedstock is described in U. S. Patent 5,380,473. The means for shearing is arranged proximally to the ejector and is disposed to effect the shear of the feedstock while it is in the internal flow condition. Preferably, the means for shearing is the means for delivering fluid such as air at sufficient velocity against the feedstock stream as it exists a nozzle. Such a device can be an external atomizing nozzle. The stream of air is directed against the feedstock exterior by the nozzle to provide discontinuities in the feedstock and basically transform the morphology of the original feedstock into a new morphology achieved by free-flow solidification as discontinuous masses. In Figure 3 of the *473 patent, an air stream is in fluid communication with an annular channel which surrounds the internal nozzle device. Feedstock is fed to the nozzle and is subjected to high velocity air which is created by the combination of tortuous path exits provided by an air cap and a retaining ring. In another embodiment, the means for shearing can also be a chamber in which the environment can be maintained to induce shear upon the collision of a high velocity of a stream of feedstock directed against a preselected and maintained environment.

The individual components of the novel composition herein described may thus be subjected to flash shear processing as well. Those skilled in the art may find that flash-shear methodology and parameters can be further adjusted to their particular needs. Whether processed by flash-heat or flash-shear methods, the flash-flow processed material is combined with the chewing gum base materials to provide intimate mixing and dispersion within the gum base matrix.

Further included as part of the novel medicated chewing gum composition are one or more active substances, either alone or in combination with one another. Active substances include any materials, which when ingested produce some type of effect within the body, whether physiological, pharmacological, biological, or chemical etc. Actives can include solid, semi-solid and liquid substances, but are more desirably solid or semi-solid. A listing of suitable actives may be found in U.S. Patent No. 5,582,855, and these include antitussives (e.g., dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate and chlorphedianol hydrochloride), antihistamines (e.g., chlorpheniramine maleate, phenindamine tartrate, phyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate), decongestants (e.g., phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, hydrochloride ephedrine), alkaloids (e.g., codeine phosphate, codeine sulfate and morphine), mineral and nutraceutical supplements (e.g., potassium chloride and calcium carbonate, other calcium salts, magnesium oxide, and other alkali and alkaline metal salts), nutaceuticals in the form of herbals (ginkoba, St. Johns wort, ginseng, etc.) laxatives, vitamins, e.g. vitamin D3, antacids, ion exchange resins (e.g., nicotine ion exchange resins), anti-cholesterolemics, anti-lipid agents, antiarrhythmics, antipyretics, analgesics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infectives, psycho-tropics, antimanics, stimulants, gastrointestinal agents, sedatives, antidiarrheal preparations, anti-anginal drugs, vasodialators, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and antithyroid preparation, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics, cough suppressants, mucolytics, anti-uricemic drugs, and mixtures thereof.

Especially preferred actives include pharmaceutical substances, and of these, over-thecounter preparations are desirable. For example, cough and cold actives, especially those with “vapor action” characteristics may be useful. Menthol, for example, is contemplated. Other antitussive and antihistamine actives are also useful. Certain chemical stimulants may also be utilized. Among these, caffeine is desirable, as is nicotine, e.g. nicotine polacrilix or nicotine salts such as nicotine hydrogen tartrate. Other active substances may include analgesics as well, as for example aspirin and non-aspirin pain relievers like acetaminophen and ibuprofen. Nutraceuticals are also desirable. Actives will typically comprise from about 0.01 to 50% of the chewing gum delivery system of the invention.

One or more of the active substances and/or flavorants or sweeteners may be provided as part of an encapsulation matrix. In this way, the active is preserved and enrobed within the chewing gum until it is consumed by the customer. Encapsulations may be prepared using methods known in the art. In order to effectively encapsulate the active ingredients, one or more other food-grade materials are employed as processing aids. These food grade materials can include oleaginous material, as well as saccharides, proteins and other non-toxic polymeric material, especially those materials with emulsifying properties. Highly suitable encapsulation processing aids are preferably oleaginous material, e.g. fats and oils. It is believed that the oleaginous material surrounds and enrobes individual particles of the active ingredients, thereby creating a matrix of several thousand or even more individually enrobed particles once combined into the final chewing gum composition. Suitable oleaginous material includes various food-grade oils and fats available in the industry. Of these, those with emulsifying properties are often particularly desirable. Vegetable and animal oils and fats may be utilized for this purpose. Stearine may be utilized as an encapsulating agent, while certain mono- and diglyceride-based fat products are also efficacious. Canola oil, soybean oil and cottonseed oils may be prefened as well in certain embodiments. Also useful are one or more while medium chain triglyceride (MCT) oils, as well as other mono-, di- and triglyceride based fatty acid oils. Oleaginous material as encapsulating/processing aids will typically comprise about 0.1 to 40% of the chewing gum composition of the invention, and more desirably will make up from about 0.1 to 15% thereof. The skilled artisan may utilize more or less of the foregoing amounts, depending upon such factors as the type and quantity of active substance(s) to be utilized, the particular oleaginous material(s), the degree of encapsulation desired, as well as the overall mouthfeel contemplated in the final medicated chewing gum composition. In addition to the active ingredient(s), it is also within the scope of the invention that one or more of the heretofore described flavorants may also be encapsulated according to the methods herein described.

Various encapsulation techniques may be utilized to provide the encapsulated active substance matrix as part of the chewing gum composition of the invention. In one embodiment, the flash-shear processing techniques set forth in U.S. Patent No. 5,380,473 can be utilized. The techniques of the ‘473 patent may be further utilized in conjunction with a unique tower device in which material to be encapsulated is provided in free fall by a sprayer at the top of the tower, and an encapsulant material such as oleaginous substances is extruded in the form of droplets to coat and encapsulate the dry, particulate material exiting the tower. This is described, for example, in Irish Patent Application No. 980395. Other methods available in the art such as, e.g. spray-drying, atomizing and simple and complex extrusion .processes are also within the scope herein set forth. Simple mixing methods with industrial scale mixing equipment (Hobart and Sigma type mixers) may also be utilized to prepare encapsulations, either alone or in combination with any of the foregoing other encapsulation methods as well.

In addition to the foregoing components, the medicated chewing gum delivery system according to at least one embodiment may optionally contain a buffer material or system. Buffering agents are those compounds which adjust the pH inside the mouth and thereby assist the mucous membranes in the absorption of the active substance once it is released from the formulation upon chewing. In certain instances, it maybe preferable to utilize those compounds which help to create a basic or alkaline pH environment inside the mouth and saliva, either alone or in combination with one another. Of these, certain salts such as for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium citrate and dipostassium phosphate, including one or more mixtures thereof, are particularly preferred. Potassium carbonate may often be especially desirable. Other known buffering agents or buffering systems known in the art may also be utilized.

The buffering agent will comprise about 0.1 to 10% of the delivery system chewing gum formulation, and when used in conjunction with an active such as nicotine, may desirably be within the range of about 0.5 to 5% thereof. In particular, an about 1 to 5% quantity of buffer may be especially desirable in the final formulation. In one preferred embodiment of the invention, it is preferable that the buffer system be adapted so as to yield a pH in excess of at least about 7.5 inside the mouth, and even more desirably in excess of about 8.0, or even greater than about 8.5. As heretofore stated, the presence of the buffering system not only seems to facilitate absorption of certain actives such as nicotine inside the mouth, but also seems to facilitate the release of nicotine from certain nicotine ion exchange resins, in particular nicotine polacrilix, as well as from nicotine salts. At the same time, the buffer system is preferably optimized so that it does not result in a “dumping” of nicotine inside the mouth which would overwhelm the user. The quantity and type of buffer materials furthermore should not cause unpleasant organoleptic side effects, such as irritation, burning, coughing or choking, etc. The buffer system to be utilized in this embodiment of the invention can provide a predictable, yet sustained and manageable release of actives such as nicotine, as well as aid in the absorption thereof by the mucosal membranes.

In still a further embodiment of the invention, there is provided one or more of noncariogenic, anti-cavity and tooth whitening ingredients to be incorporated into one or more of the medicated chewing gum delivery systems herein described. These are preferably utilized with the non-cariogenic sweeteners heretofore described. U.S. Patent No. 5,762,911 describes anti-cariogenic agents such as calcium salts, arginine and a cariostatic anion such as a organic phosphate compound. Tooth-whitening compounds include, for example, kaolin, calcium carbonate, silicon dioxide and certain cellulosic materials.

The foregoing ingredients making up the chewing gum delivery system, e.g. gum base matrix, sweetener(s), active(s) optional buffers and filler(s) etc., of the invention may be admixed together to produce the final formulation using mixing methods known in the art.

For example, the gum base may be heated and softened using the heretofore described solvent material, and then blended with sweeteners, flavors and actives, etc. The result is a medicated chewing gum delivery system in which the active is reliably released both upon initial mastication and upon sustained chewing thereafter. An internal delivery system is thereby achieved, in which the active substance is an “internal” or integral part of the gum base.

Since the gum base matrix is desirably chosen to facilitate release of the active substance, then the amount of actual mastication may be preferably be minimized. In other words, the end user may in many instances simply “park” the composition inside the mouth and still attain reliable release. The invention according to at least one embodiment thereby achieves a goal of an excellent immediate release and/or sustained release profile.

In a particularly preferred embodiment, the active material(s) together with the nonactives, heretofore described, are provided in a substantially non-liquid format. That is, the formulation of the invention is substantially 0% liquid. Typically, chewing gum formulations comprise three major components. These are gum base, solids and liquids. By excluding substantially all liquid from the formulation, incompatibility problems between the various components are avoided, as are the concomitant problems of instability (especially of the active materials), migration and interaction among the actives, flavors, sweeteners and buffers, etc.

In a further embodiment of the invention, there is provided a chewing gum delivery system in which a gum base matrix material in the form of granulates has one or more active substances interspersed among the granulates. The gum base granulates together with the active(s) are compressed to yield the final formulation. The gum base matrix may be material as heretofore described, i.e. that which facilitates release of the active (as for example that having a hydrophilic moiety), or may be other gum matrix material known in the art. For example, a low moisture, non-aqueous gum base matrix having a high degree of hydrophobicity may be utilized in certain formulations. In certain situations, the gum base matrix material and the active(s) can have different, somewhat incompatible moieties so that the active is not strongly retained by the gum base matrix, and can be released more easily.

In this embodiment of the invention wherein gum base granulates are used, it is especially desirable that the active substance(s) be thoroughly dispersed among the gum base granulate matrix, but preferably not be contained within the granulates themselves. It may also be desirable that the active substance substantially enrobe or surround each of the individual granulates as well.

To therefore prepare this embodiment of the medicated chewing gum composition of the invention, the procedures set forth in U.S. Patent No. 4,405,647 may be especially helpful to the skilled artisan. Briefly stated, the gum base material may be melted or softened using one or more of the softening agents, plasticizers and/or solvent and filler materials heretofore described. The sweeteners and flavors, whether processed via flash-flow processing or other traditional mixing methods, are then admixed into the gum base. This is accomplished by comminuting the gum base material together with the water-soluble ingredients in a bed or blender within a gaseous medium at room temperature, as described in the ‘647 reference. This material is continuously pulverized and thereby chopped into much smaller particles. To prevent adherence of the resultant particles to one another, additional filler or bulking material may be added like lubricants, glidants and other tableting and compression aids well known in the pharmaceutical industry, such as for example, silica gel or calcium carbonate. Granules of any desired size and shape may be obtained upon the introduction of a standard mess screen to separate the particulates once formed.

The next step in forming the final chewing gum composition involves adding the active substance to the formed particulates. This is done by admixing the actives, whether encapsulated or in free form, with the pulverized materials so as to substantially disperse the particulates. In a preferred mode, the active is added along with the tableting, lubrication or other compression aids. The active material thus becomes substantially entrapped in the multitude of spaces between the individual gum particles. Upon thorough mixing by any suitable device, the materials are then compressed and compacted in a tablet press or other suitable device. In this way the active materials are sandwiched in the voids in between the compressed particulate gum granulate material. The active substance is thoroughly dispersed between and throughout the resulting matrix. The active is thus “external” to the gum base material itself. The result is an extemai delivery system for the active material. In a particularly preferred embodiment, the active material(s) together with the non-actives, heretofore described, are provided in a substantially non-liquid format. That is, the formulation of the invention is substantially 0% liquid.

Referring now to Figure 1, the composition of the invention thus achieves intimate mixing and dispersion of one or more active ingredients without embedding the actives within the gum base material itself. Figure 1 shows the gum base particulates 10, and interspersed therebetween is the active 20. Subsequent release of the active thereby becomes less dependent on the mastication effort of the consumer. The active ingredient has merely to be released from between the gum base material, rather than from within the actual granulates. This embodiment may therefore be particularly desirable in an immediate-release chewing gum delivery system. In addition, the formulation of the invention can easily be adapted to a sustained release formulation as well by inclusion of many particulates (with actives therebetween or coated thereon) within the final composition. The more particulates there are, the more spaces between which active may be interspersed.

A preferred example of the foregoing embodiment provides for an active substance such as nicotine to be encapsulated in an oleaginous matrix which is then utilized to coat and/or surround the gum base particulates. In this way, the nicotine can be subsequently released upon chewing, and is not bound up by the gum matrix itself. Any of the gum base materials heretofore described may be utilized to make up the granulate matrix, which can then be utilized with the nicotine.

Referring now to Figure 2, in still a further embodiment of the invention, there is set forth a medicated chewing gum delivery system having a gum base matrix 10 which at least partially surrounds a centerfill 20. The centerfill will contain one or more active substances. The centerfill may be a liquid or semi-liquid material and preferably is low fat or is fat free.

In addition to the active(s), the centerfill may contain one or more sweeteners and/or flavorants as heretofore described. A combination of saccharide material, flavoring, polyol and edible gel material is one example. One or more of the active ingredient(s) and/or the sweeteners and flavorants, etc. may be encapsulated as previously set forth, and then incorporated into the centerfill.

The centerfill embodiments set forth in Figure 2 may be prepared using methods known in the confectionery and chewing gum industries. For example, U.S.. Patent No. 3,806,620 describes a method for forming centerfill chewing gum by extruding a hollowcentered rope of chewing gum through an orifice having a pair of concentric conduits extending therethrough. A centerfill material is fed through the inner conduit to the hollow center upstream through a space between the inner and outer conduits. The centerfill rope of chewing gum is passed to a sizing unit having a plurality of pairs of rollers for progressively decreasing a cross-sectional dimension of the gurn rope. The plurality of pairs of rollers includes at least one vertical pair of rollers having vertically aligned axes or rotation and overlapping lower flange portions. Ramp means are provided for guiding the gum rope above the roller flange portions upon entry of the gum rope between the vertical pair of rollers.

Other methods of forming centerfill chewing gum known in the art may also be utilized.

The centerfill embodiment may be particularly desirable wherein immediate release of the active is desired. Encapsulating the active ingredient(s) in this embodiment may help to taste-mask those actives which provide an undesirable organoleptic sensation. Other than the centerfill, it is preferred that the formulation ingredients of this embodiment also be substantially liquid-free, or about 0% liquid.

Any of the foregoing medicated chewing gum delivery systems herein described may be further formulated with a coating material to yield yet another embodiment of the invention. The coating material will at least partially surround the entire chewing gum composition according to the latter’s various embodiments. The coating material may be a water-soluble confectionery shell which dissolves upon contact with saliva. Alternatively, the coating material may be a water-insoluble material, such as a polymeric gum base material which is the same or different from the gum base matrix itself. The coating material can contain one or more active substances, or be substantially devoid of actives. In addition, the coating material and the gum base matrix may contain the same or different active substances. In this way, the skilled artisan can have an immediate release of one active from the coating material, followed by a more sustained release of the same or another active from the gum base matrix.

EXAMPLES 15 In the following examples, “chew outs” were conducted utilizing the medicated delivery system of the invention according to various embodiments containing nicotine as the active substance, as compared to certain control formulations, as well as the commercial formulation available under the trademark NICORETTE®. For each chew out, the following protocol was observed: A serving size of nicotine gum (approximately 1.0 gram each) was masticated for a total period of 30 minutes at a rate of either 10 or 20 chews per minute, as noted. Each serving of gum contained 2.2 mg. of nicotine. At the intervals noted on the graphs corresponding to the Examples, the amount of nicotine remaining in the gum was measured to determine the percentage released after that time period. Nicotine measurements were made using standard nicotine extraction solutions, and compared with High Performance Liquid Chromatography (HPLC) standards. pH measurements were made utilizing standard laboratory scale pH equipment. The results are indicated below. Standard artificial saliva solutions and mastication simulators available in the art may be used to assist the skilled artisan in conducting the chew outs.

Example 1 - In this example a chew out was conducted using Formula A according to one embodiment of the invention, as compared to NICORETTE gum. Formula A contained 55% gum base, of which approximately 35 - 40% was PVA polymer material (with no butyl rubber), along with 100% nicotine polacrilix as the nicotine active. The delivery system of Formula A was buffered using a combination of sodium carbonate and sodium bicarbonate. The same participant chewed each gum separately over time at a rate of 10 chews/minute.

The percentage of nicotine released is shown in Figure 3. As can be seen from Figure 3, the NICORETTE formulation released its nicotine quite slowly over the entire 30 minute period. Formula A, on the other hand, provided an excellent release of nicotine within the first 3-5 minutes, and a steady release thereafter. The participant reported obtaining a better nicotine buzz” from Formula A.

Example 2 - For this example another chew out was conducted using a different participant. Formula A was again utilized, as was NICORETTE. Formula B was also tested, which was identical to Formula A, except that 100% nicotine salt (nicotine tartrate) served as the nicotine active. The chew rate was 20 chews/minute over the course of 30 minutes total. The results are shown in Figure 4. Again, Formula A of the invention had an excellent release rate of nicotine. Formula B’s release rate, while better than that of NICORETTE, was not quite as fast as that of Formula A.

Example 3 - In this example the pH generated as a result of chewing was measured during the chew out period (20 chews/minute) for three formulations: Formula A, NICORETTE and Formula C. Formula C was identical to Formula A, except that the buffering system was a combination of potassium carbonate and potassium bicarbonate. The results are set forth in Figure 5. As can be seen, the pH obtained with Formulas A and C were considerably higher than was the pH obtained with the NICORETTE formulation. This demonstrates that a buffering system as part of a nicotine delivery system greatly facilitates a higher pH environment inside the mouth. This, in turn, further facilitates the absorption of a pH dependent compound such as nicotine.

Example 4 - For this example, Formulas D and E were compared with NICORETTE gum. Formula D was identical to Formula A, except that potassium carbonate provided the buffer. Formula E contained about 55% of butyl rubber-based (approximately 5% thereof as butyl rubber) gum base, together with 100% nicotine polacrilix as the active, and potassium carbonate as the buffer. The only difference between Formulas D and E, therefore, was the type of gum base in the formulation. As shown in Figure 6, Formula D gave a higher initial release rate of nicotine after about 3 minutes that did Formula E or NICORETTE gum.

Example 5 - In this example, Formulas E and F were compared with NICORETTE gum. Formula G was the same as Formula E, but with 100% nicotine salt (nicotine hydrogen tartrate) utilized as the active. The only difference between Formulas E and F, therefore, was that Formula E contained 100% nicotine polacrilix, while Formula F contained 100% nicotine salt as the active. In Figure 7, the results clearly indicate that the butyl rubber gum base/nicotine salt combination had a significantly higher release rate than did either NICORETTE or the butyl rubber gum base/nicotine polacrilix combination.

Example 6 - In this example, Formulas D and G were compared with NICORETTE gum.

Formula G was the same as Formula D, but with 100% nicotine salt (nicotine hydrogen tartrate) utilized as the active. The only difference between Formulas D and G, therefore, was that Formula D contained 100% nicotine polacrilix, while Formula G contained 100% nicotine salt as the active. In Figure 8, the results show that the butyl rubber gum base/nicotine salt combination had a slightly higher release rate than did either NICORETTE or the butyl rubber gum base/nicotine polacrilix combination.

Example 7 - Here Formula G was contrasted with Formula F and NICORETTE. Each of Formulas G and F contained nicotine hydrogen tartrate as the active, while the gum base for each was different as set forth above. Figure 9 graphs the results, and shows that with . nicotine salt, the butyl rubber gum base of Formula F clearly provides a better release of nicotine up front, i.e. early on within about 3 minutes, than did Formula G’s PVA-based gum 'base.

The invention also provides that the buffering system heretofore described may be utilized with any type of active delivery system in which a controlled release under proper pH, and preferably alkaline pH conditions, is warranted.

It is expected that certain changes or modifications to the invention herein described may be effected by those skilled in the art without departing from the true spirit and scope thereof as set forth in the claims and the accompanying specification.

Claims (19)

CLAIMS: What is claimed is;

1. A medicated chewing gum delivery system comprising one or more active substances, and a gum base matrix which facilitates release of said active substance according to at least one profile selected from the group consisting of imrriediate release and sustained release, said chewing gum delivery system being substantially liquid-free.

2. The medicated chewing gum delivery system of Claim 1, wherein said gum base matrix comprises a polymer which is substantially hydrophilic, said polymer being selected from the group consisting of low to medium molecular weight polyvinylacetate.

3. The medicated chewing gum delivery system of Claim 2, said gum base matrix having substantially no butyl rubber.

4. The medicated chewing gum delivery system of Claim 1, wherein said polymer comprises butyl rubber, polyisobutylene and polyvinylacetate having a molecular weight of about 12,000.

5. A medicated chewing gum delivery system comprising compressed granulates of gum base material having interspersed therebetween one or more active substances, said delivery system providing at least one profile selected from the group consisting of immediate release and sustained release.

6. The medicated chewing gum delivery system of Claim 5, wherein said chewing gum is substantially liquid free.

7. The medicated chewing gum delivery system of Claim 6, wherein said gum base material is selected from the group consisting of non-aqueous polymers having hydrophobic moieties.

8. The medicated chewing gum delivery system of Claim 7, wherein said active substance is nicotine.

9. The medicated chewing gum delivery system of Claim 8, further comprising a coating material which surrounds said delivery system.

10. A medicated chewing gum delivery system comprising a gum base matrix, said gum base matrix containing a centerfill comprising one or more active substances in liquid or semiliquid medium.

11. The medicated chewing gum delivery system of Claim 10, wherein said active substance is encapsulated in an oleaginous material.

12. A method of forming a medicated chewing gum composition delivery system which comprises the steps of: a) forming gum base granulates; b) dispersing at least one active substance between said granulates; and c) compressing said granulates and said active substance into a chewing gum composition.

13. The method according to Claim 12, wherein said step a) further comprises admixing at least one gum base material with at least one member selected from the group consisting of sweeteners and flavorants.

14. The method according to Claim 13, wherein said gum base material is at one least one polymer having at least partial hydrophobic moieties.

15. The method according to Claim 13, wherein said active substance is provided as part of an encapsulation.

16. The method according to Claim 15, wherein said active substance is encapsulated using a flash-shear process.

17. The method according to Claim 12, wherein said active substance is at least one member selected from the group consisting of antitussives, antihistamines, analgesics, and chemical stimulants.

18. The medicated chewing gum composition of Claim 17, wherein said active substance is at least one stimulant selected from the group consisting of caffeine and nicotine.

19. The medicated chewing gum composition of Claim 18, wherein said active substance is nicotine.