WO2006063189A2

WO2006063189A2 - Multi-layered chewing gum tablet with quick disintegration layer

Info

Publication number: WO2006063189A2
Application number: PCT/US2005/044523
Authority: WO
Inventors: Christopher Edward Fankhauser; Alexander Mark Schobel
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2004-12-10
Filing date: 2005-12-08
Publication date: 2006-06-15
Also published as: WO2006063189A3

Abstract

A multi-layered drug delivery system contains at least one gum layer and at least one rapidly dissolving tablet layer. The tablet layer contains a therapeutically effective amount of a medicament which is susceptible to rupture upon chewing, thereby causing the release of the drug. The invention is especially useful as a delivery system for oral hygienic agents, pharmaceuticals, and nutritive and dietary supplements. Useful delivery systems include those for nicotine, and cough, cold, allergy and/or sinus medicaments.

Description

Quick disintegrating drug delivery system

Field of the Invention

The present invention relates to a drug delivery system composed of a distinct gum layer and a tablet layer. The tablet layer quickly disintegrates upon contact with saliva or upon chewing.

Background of the Invention

Many people are either unwilling or unable to swallow tablets, capsules or other traditional solid dosage delivery forms containing a medicament. One approach suitable for such persons is the use of a tablet which contains a chewing gum and a drug.

WO 02/078459 A1 discloses a tablet of a gum base powder and a tablet base powder containing a medicament wherein the tablet base and the gum base are homogeneously distributed into a compacted tablet. Upon ingestion, the tablet exhibits a first crumbly stage which changes to a chewing gum stage upon disinteg ration of the medicament. The resulting product is often organoleptically unacceptable to the end user. In addition, the medicament may be released at an unacceptable rate; the gum base powder not forming as a chewing gum until the medicament is disintegrated. Further, the medicament within the tablet often becomes absorbed within the gum base which prevents rapid release of the medicament.

Alternatively, tablets are desired which more quickly release the medicament and more expeditiously transform the tablet to chewing gum.

Summary of the Invention

The present invention comprises a drug delivery system containing at least one tablet layer having at least one medicament and at least one gum layer. The tablet layer containing the medicament disintegrates quickly upon contact with saliva or upon chewing. One or more additional medicaments may be contained within the tablet layer or the gum layer. The medicament is ultimately absorbed by various routes, including buccal, gastrointestinal and sublingual. Either the tablet layer or gum layer may further contain other desirable additives such as stabilizers, disintegration agents, processing aids, colorants, lubricants or flavorants, organoleptic agents or effervescent aids.

Once the drug delivery system is placed in the mouth, the tablet layer disintegrates rapidly and completely without any or with minimal voluntary action by the patient. The tablet layer contains a therapeutically acceptable amount of medicament. Chewing of the tablet layer need not be required for disintegration of the medicament to occur since the medicament is quickly released from the tablet layer.

The tablet layer may be the outer or inner layer of the drug delivery system. Where the tablet layer is the outer layer of the drug delivery system, the tablet layer may contain a protective layer which shields the medicament from contact with the outside environment.

The drug delivery system is of a size and shape adapted for direct oral administration to the end user. The drug delivery system, as a multi-layered chewing gum, provides an alternative to conventional tablets and is especially useful to those individuals who cannot or refuse to chew conventional tablets, such as debilitated patients, elderly patients, patients who have difficulty swallowing solids, as well as patients who seek to defeat the administration by not swallowing the tablet.

Detailed Description of the Preferred Embodiments

The drug delivery system according to the invention is a multi-layered tablet prepared from at least two distinct layers - at least one gum layer and at least one quick disintegrating tablet layer containing at least one medicament, typically in particulate form. The multilayer drug delivery system is preferably prepared by compressing one of the layers onto the other layer; the other layer having been previously compacted. The resulting drug delivery system product typically contains an upper and a bottom layer and is organoleptically pleasant.

The multilayer drug delivery system is an excellent delivery system for the medicament since the tablet layer quickly disintegrates and the medicament may be quickly absorbed into the patient's system. Instead of being reduced into a particulated form, ingestion of the multilayer drug delivery system of the invention renders quick disintegration of the tablet layer which may be readily swallowed with saliva, leaving solely a chewing gum. The quick disinteg rating tablet layer is capable of releasing the medicament more rapidly than the formation of a chewable gum from the gum layer. Generally prior to the gum layer forming as a chewable bolus, the bulk of the medicament, if not all of the medicament, within the tablet layer is absorbed within the patient.

The particle sizes of the gum base and the tablet base may range from 10 microns to 2mm, preferably between from 20 to 160 microns, more preferably from 40 to 120 microns and most preferably from 50 to 100 microns.

Preferably, the gum base is present in an amount of from 5% to 99%, preferably from 10% to 80% and more preferably from 30% to 70%, by weight and the tablet base is present in an amount from 1% to 95%, preferably from 20% to 90% and more preferably from 30% to 70%, by weight based on the weight of the tablet.

The gum base is to be chewed rather than eaten and is preferably ground powder which may be directly compressible. The gum base is a neutral and essentially tasteless insoluble masticatory gum base, such as plasticized rubber or polymer which is softened.

The gum may be available from a commercial source such as those ground, directly compressible gums available from SPI Pharma or Roquette America. Such gums may include additives that are easily flowable and processable. Such additives include plasticizers, fillers (such as texturizers), softeners, waxes and/or emulsifiers.

The gum base may be of any conventional nature known in the art, such as an elastomer selected from the group consisting of natural and synthetic elastomers. For example, those elastomers which are suitable in gum bases, include, without limitation, substances of vegetable origin such as chicle, jelutong, lechi de caspi gum, soh gum, siak gum, kahau gum, sorwa gum, balata gum, pendase gum, Malaya gum, peach gum, natural cauchouc and natural resins such as dammac and mastlix, gutta percha, guayle and crown gum, butadiene -sty rene copolymers, isobutylene-isoprene copolymers, polyethylene, polyisobutylene and mixtures thereof. The amount of gum base in the gum layer is typically between from about 80 to about 95 weight percent. The gum layer may further contain processing additives such as fillers, plasticizers, softeners, waxes and emulsifiers, as well as additives which provide an organoleptically acceptable taste. Further, sweeteners are often added to the gum layer to render to it a confectionery quality. Such processing additives may be added to the gum base or be a part of a commercially available gum.

Such additives include elastomeric solvents to aid in softening the elastomer. Such elastomeric solvents can 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 pentaerythritol ester of partially hydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerol ester of partially dimerized rosin, glycerol ester of polymerized rosin, glycerol ester of tall oil rosin, glycerol ester of wood rosin, and partially hydrogenated wood rosin, and partially hydrogenated methyl ester of rosin and mixtures thereof. The solvent may be employed in an amount ranging from about 10% to about 75% and preferably about 45% to about 70% by weight of the gum base.

Suitable softeners and texturizers are lanolin, stearic acid, sodium state, potassium stearate, glyceryl triacetate, triacetin, glycerine and the like. Such materials provide a variety of desirable textures and consistency properties. These additional materials are generally employed in amounts of up to about 30% by weight and preferably in amounts of from about 3% to about 7% by weight of the gum base layer.

The tablet layer, as well as the gum layer, may contain a binder or bulking agent. Preferred bulking agents are those having good organoleptic properties and a negative heat of solution.

The binder is useful to disperse the drug with the remaining components of the respective layer. In addition, such substances may be good disinteg rants, glidants and lubricants. Such substances are especially preferred where the nicotine base is used as the drug.

Binders may be used in an amount of up to 60 weight percent and preferably about 10 to about 40 weight percent of either the tablet layer or gum layer. Examples of binders include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxymethyl cellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids and bentonites.

The binder may further be a crystalline cellulosic derivative, such as microcrystalline cellulose, or polyvinyl pyrrolidone. Microcrystalline celluloses typically have a mean particle size of about 15 to 250 μm. Suitable microcrystalline celluloses include those commercial pharmaceutically accepted qualities, such as Avicel®, Vivacel®, and Emcocel®.

The binder may be combined with the medicament and water or suitable solvent to form a binder liquid. The solvent may serve as a solubilizing agent or a recrystallization agent. Suitable solvents include mono-alcohols, such as ethanol and isopropanol, as well as polyhydric alcohols.

The binder liquid may then be sprayed onto any of the other components which constitute the tablet layer.

Upon dissolution with the saliva, the bulking agent (which constitutes the remainder of the tablet layer) may absorb heat and render a cooling sensation. Suitable bulking agents include sugars such as invert sugars and/or polyol sugars, for example, sucrose, fructose, lactose, dextrose, sorbitol, mannitol, maltitol, xylitol, isomalt, glucose syrup, maltitol syrup or eritrithol.

The medicament may be incorporated into the tablet layer neat. Alternatively, the active medicament may be modified to impart taste masking or other desirable attributes to the tablet layer. For example, the medicament may be taste masked using an ion exchange resin, a salt, or by other conventional means known in the art. Such modifications may affect the rate of absorption of the medicament within the patient.

The tablet layer quickly disintegrates and may contain any bio-effecting medicament capable of being conducted from the mouth to the digestive system for absorption through the stomach or intestines and/or systemic distribution from the mouth into the bloodstream . For instance, the drug may be a nutritive or functional ingredient (such as a mineral, vitamin, amino acid, or dietary supplement) or a pharmaceutical agent such as an analgesic, antipyretic, anti-arrhythmic, appetite suppressant, anti-inflammatory, coronary dilator, cerebral dilator, peripheral vasodilator, anti-infective, psychotropic, anti-manic, stimulant, antihistamine, laxative, decongestant, gastro-intestinal sedative, sexual dysfunction agent, anti-diarrheal agent, anti-anginal substance, vasodilator, anti-hypertensive agent, vasoconstrictor, migraine treating agent, antibiotic, tranquilizer, antipsychotic, anti-tumor drug, anticoagulant and antithrombotic agent, hypnotic, sedative, anti-emetic, anti-nauseant, anticonvulsant, neuromuscular agent, hyper and hypoglycemic agent, thyroid and antithyroid agent, diuretic, antispasmodic, uterine relaxant, anti-obesity agent, anabolic agent, erythropoietic agent, anti-asthmatic, expectorant, cough suppressant, mucolytic, anti- uricemic agent, dental vehicle such as casein glyco-macro-peptide (CGMP), breath freshener, antacid, anti-diuretic, anti-flatuent, betablocker, teeth whitener and combination thereof. The medicament may further be any enzyme, co-enzyme, protein, energy booster, or fiber.

In a preferred mode, the drug is a nicotine source such as nicotine base and the drug delivery system is used in the treatment of individuals who opt to ingest caffeine or nicotine by other than conventional means. For instance, a nicotine containing drug delivery system may serve to assist the individual in the cessation of smoking especially where there is a fast onset of nicotine craving.

Since the inventive drug delivery system contains at least two distinct layers, it is possible to use two incompatible interacting agents since one agent may be placed in one layer and the second agent in the other layer. For instance, it is often desirable to use a nicotine salt, such as nicotine bitartrate, sulfate, tartrate, phthalate, lactate, citrate, or polacrilex, as the source of nicotine in the drug delivery system since such nicotine salts are generally more stable than nicotine base. The nicotine salt must first be converted to nicotine base in-situ before absorption can occur. In some instances, therefore, it is desirable to incorporate a base, such as sodium bicarbonate, in the drug delivery system since conversion of nicotine salt to nicotine base proceeds more quickly at increased pH. Due to the relative instability of nicotine base, it is preferred that the conversion of nicotine salt to nicotine base occurs in the mouth. For this to occur, it is preferred to incorporate the nicotine base in the gum layer and the nicotine salt in the tablet layer. Upon contact with saliva, the reaction of the nicotine base and nicotine salt proceeds quickly. In a preferred mode, the drug delivery system contains at least one of the components selected from:

A. antimicrobial agents, such as triclosan, cetyl pyridium chloride, domiphen bromide, quaternary ammonium salts, zinc compounds, sanguinarine, fluorides, alexidine, octonidine, and EDTA;

B. non-steroidal anti-inflammatory drugs, such as aspirin, acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium, naproxen, tolmetin sodium, and indomethacin;

C. anti-tussives, such as benzonatate, caramiphen edisylate, menthol, dextromethorphan hydrobromide, theobromine and chlophedianol hydrochloride;

D. decongestants, such as pseudoephedrine hydrochloride, phenylepherine, phenylpropanolamine, and pseudoephedrine sulfate;

E. anti-histamines, such as brompheniramine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchlorpheniram ine maleate, diphenhydramine hydrochloride, diphenylpyraline hydrochloride, azatadine meleate, diphenhydramine citrate, doxylamine succinate, promethazine hydrochloride, pyrilamine maleate, tripelennamine citrate, triprolidine hydrochloride, acrivastine, loratadine, brompheniramine, and dexbrompheniramine;

F. expectorants, such as guaifenesin, ipecac, potassium iodide, and terpin hydrate;

G. anti-diarrheals, such a loperamide;

H. hydrogen antagonists, such as famotidine, and ranitidine;

I. proton pump inhibitors, such as omeprazole, and lansoprazole;

J. general nonselective CNS depressants, such as aliphatic alcohols, and barbiturates;

K. general nonselective CNS stimulants such as caffeine, nicotine, strychnine, picrotoxin, and pentylenetetrazol;

L. drugs that selectively modify CNS function such as phenyhydantoin, phenobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, diazepam, benzodiazepines, phenacemide, pheneturide, acetazolamide, sulthiame, and bromide;

M. antiparkinsonism drugs such as levodopa, and amantadine;

N. narcotic-analgesics such as morphine, heroin, hydromorphone, metopon, oxymorphone, levorphanol, codeine, hydrocodone, xycodone, nalorphine, naloxone, and naltrexone;

O. analgesic-antipyretics such as salycilates, phenylbutazone, indomethacin, and phenacetin; P. psychopharmacological drugs such as chlorpromazine, methotrimeprazine, haloperidol , clozapine, reserpine, imipramine, tranylcypromine, phenelzine, and lithium; and Q. sexual dysfunction agents, such as sildenafil citrate, tadalafil, vardenafil HCI, etc.

In another preferred mode, the tablet layer contains one or more cough/cold/allergy/sinus/flu medications, and other over-the-counter medications. A common active ingredient in such medications is dextromethorphan.

The tablet layer further may contain dextrose or maltose or syrup components, such as corn syrup high in dextrose or maltose. The gum layer, upon dissolution of the saliva-activated drug, renders a more lasting flavor that continues to increase salivation and bathe the throat. The chewing action further facilitates opening of the Eustachian tubes. Children and other individuals who loathe taking tablet medication may thus find the drug delivery system of the invention more palatable and acceptable.

The present invention further has particular applicability with end users who have difficulty swallowing or are reluctant to take conventional medicament forms. For instance, a patient receiving psychotropic drugs, particularly a patient in a mental institution, often attempts to hold a conventional tablet or capsule concealed within his mouth rather than swallow it. The patient may then surreptitiously remove the tablet or capsule when medical personnel are not present. The preferred dosage forms according to this aspect of the present invention are substantially resistant to such concealment, inasmuch as the active ingredient will disintegrate rapidly even if concealed within the mouth.

The amount of active ingredient present in the chewing gum-containing drug delivery system may depend on the bio-effecting desired result and the actual medicament used. The quantity of active ingredient in the drug delivery system is that amount sufficient to elicit the required or desired response when administered.

For example, some active ingredients have high functional activity at very low doses such as micronutrients of vitamins and minerals, such as calcium, iron, selenium, zinc, magnesium, phosphorus, iodine, manganese, iron, boron or copper, molybdenum, potassium, chromium, vanadium or fluoride, whereas others such as dextrose are beneficial to the body in much higher amounts. For instance, where the active ingredient is a vitamin or mineral, the amount is preferably at least about 10% of the United States Recommended Daily Allowance ("RDA") of that particular ingredient. For example, if an intended ingredient were vitamin C, then an effective amount of vitamin C would include an amount of vitamin C sufficient to provide 10% or more of the RDA. Typically, where the drug delivery system includes a mineral or vitamin, it will incorporate higher amounts, preferably about 100% or more of the applicable RDA.

Typically, the amount of active ingredient is from up to 1x10^"8 to 15, typically between from about 1x10^'6 to about 0.5, weight percent of the quick disintegrating tablet layer. The mass of the tablet layer is less than about 2.0 g, preferably less than about 1.5 g. At least about 95 weight percent of the drug delivery system disintegrates in the mouth of the patient within 0.5 seconds to 1 minute. The drug delivery system then becomes a normal cohesive chewing gum.

The dosage form of the drug delivery system and the active ingredient in the tablet layer is substantially completely disintegrated in the patient's mouth by contact with saliva requiring little to no chewing. Disintegration may be assisted by the incorporation within the tablet layer or the gum layer of a salivary stimulating agent (i.e., food acids, such as citric, mallic, tartaric, etc.) or a disintegration agent, thus further promoting the disintegration process. The amount of disintegration agent in the layer is that effective to aid in the rapid and complete disintegration of the drug delivery system when orally administered. In general, the amount of disintegration agent, when present, ranges from about 5 to about 50% by weight of the requisite layer and is dependent on the effectiveness of the chosen disintegrant.

Suitable disintegration agents include starches, such as starch glycolate, corn starch, potato starch and modified starches thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose, alginates, gums such as agar, guar, locust bean, karaya, pecitin, tragacanth, and croscarmellose and effervescents such as sodium bicarbonate in combination with citric or tartaric acids, ion exchange resins, crosslinked polyvinylpyrrolidone and modified celluloses.

Either the tablet layer or gum layer may further contain other desirable additives for complementary benefits, such as organoleptic agents, teeth whiteners, vitamins, mineral supplements, breath fresheners, stabilizers, disintegration agents, taste-masking or blocking substance such as an ion exchange resin, salt, processing agents such as digestive and metabolic aids or adjuvants, colorants or flavorants, preservatives, dispersing agents, and pH modifiers. One or all of these additives may be chosen so as to provide a positive organoleptic sensation to the patient which is both pleasant and enjoyable to the end user.

Where desired to be used, the amount of such additives may range from about 0.1 to about 50 weight percent of the total weight of the layer in which they are to be incorporated. Typically, the amount of such additives is less than 10, usually less than 5, weight percent of the total weight of the layer in which they are to be incorporated.

Suitable colorants may include titanium dioxide, and dyes suitable for food and drugs such as those known as F. D. & C. and D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, etc.

Flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, almond oil and cassia oil, coffee, vanilla, licorice and menthol. Also useful as flavors are citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired.

Sweeteners such as sugar or aspartame, as well as organoleptic agents such as menthol, are further typically included as flavorant. Other sweeteners include, but are not limited to, solid natural or synthetic sweetener such as amino acid based sweeteners, dipeptide sweeteners, especially aspartame, glycyrrhizin, saccharin and its salts, acesulfame salts, cyclamates, steviosides, talin and dihydrochalcone compounds. Other sweeteners include mono-, di-, tri- and polysaccharides and natural and synthetic non-saccharide-based sweeteners such as isomalt, xylitol and sorbital and mixtures thereof.

The drug delivery system can be manufactured by conventional techniques such as wet granulation, dry granulation, or direct compression. In direct compression, the drug delivery system may be prepared on a tablet press. Although it is not required, the tablet layer is compressed on the first rotation. In the second rotation, the gum layer is applied on the compacted tablet layer and the product is compressed so that the gum layer is bound onto the compacted tablet layer.

The tablet press typically comprises a die and a punch wherein the material to be tableted is deposited into a cavity, and one or more punch members are then advanced into the cavity and brought into intimate contact with the material to be pressed, whereupon compressive force is applied. The material is thus forced into conformity with the shape of the punches and the cavity. The tablet is then ejected.

Components to be incorporated in the drug delivery system may further be pretreated to form granules that readily lend themselves to tableting by granulation. Such methods include those processes for size enlargement whereby small particles are gathered together into larger, permanent aggregates to yield a free-flowing composition having a consistency suitable for tableting. Granulation may be accomplished by agitation in mixing equipment or by compaction, extrusion or globulation.

The drug delivery system of the invention normally further contains a lubricant in either the tablet layer or gum layer. Without the use of an effective lubricant, tableting by use of high speed equipment is often difficult. Granulations are further difficult to lubricate due to both the nature of the raw materials and the requirement that the tablets quickly disintegrate.

Suitable lubricants are those capable of reducing the friction arising at the interface of the drug delivery system (especially the gum layer) and the die wall during compression and ejection. Lubricants may also serve to prevent sticking to the punch and, to a lesser extent, the die wall as well. Lubricants further include anti-adherents, such as talc, which function during ejection.

Intrinsic lubricants incorporated in the tablet layer or gum layer include magnesium, calcium and zinc salts of stearic acid. Other intrinsic lubricants include hydrogenated and partially hydrogenated vegetable oils, animal fats, polyethylene glycol, polyoxyethylene monostearate, talc, light mineral oils, sodium benzoate, sodium lauryl sulfate and magnesium oxide. Typically the total amount of lubricant in the tablet layer or gum layer is up to 5 weight percent and preferably between about 0.5 and about 2.0 weight percent based on the total weight of the respective layer.

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An extrinsic lubricant may further be directly applied to the tableting tool surface in the form of a film, as by spraying onto the die cavity and/or punch surface.

The size of the tablet layer is also dependent upon the amount of material used. Circular, disk-like tablets desirably have diameters of about 11/16 inch (= 1.75 cm) or less, whereas elongated tablets desirably have a long dimension of about 7/8 inch (= 2.22 cm) or less.

Either layer or both layers of the drug delivery system may include surface markings, cuttings, grooves, letters, and/or numerals for the purpose of decoration and/or identification.

Many shapes and sizes of the drug delivery system may be made by varying the shape of the die and punch, e.g., circular, briquette, pillow, etc. The drug delivery system may be shaped as lamellae wherein one of the layers is stacked on top of the other. Alternatively, the gum layer may encapsulate the tablet layer, or vice versa. Conventional methods of encapsulation known in the art may be employed.

Where the tablet layer is the outer layer of the drug delivery system, the tablet layer may contain a protective layer which shields the medicament from contact with the outside environment. A protective layer may surround the gum layer. The protective material is such that it does not greatly delay disintegration of the delivery system.

The protective material may be formed from those polymers conventionally utilized in the art as protective materials for particulates. Among these are cellulosic materials such as naturally occurring cellulose and synthetic cellulose derivatives, acrylic polymers, and vinyl polymers. Other suitable polymers include proteinaceous materials such as gelatin, polypeptides, and natural and synthetic shellacs and waxes. When used, preferred protective materials include ethylcellulose, methylcellulose, carboxymethylcellulose and acrylic resins. The protective layer may further be used in combination with release promoters to facilitate the quick release of the saliva activated medicament. Such release promoters include soluble polymers and, in particular, polyfunctional alcohols such as mannitol, as well as magnesium oxide.

Once introduced into the patient, the tablet layer containing the medicament rapidly disintegrates. The gum layer forms a chewable bolus upon disintegration of the tablet layer.

The drug delivery system of the invention offers several advantages over those of the prior art. Most notably, the medicament typically does not become incorporated into the gum layer upon activation with saliva because the tablet layer disintegrates quickly. This phenomenon is attributable to the components comprising the tablet layer being capable of rapid disintegration.

Examples: The following examples will illustrate the practice of the present invention in a preferred embodiment. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification and practice of the invention as disclosed herein. It is intended that the specification, together with the examples, be considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow. All parts are given in terms of weight units except as may otherwise be indicated. DC Chewing gum powder in the examples refers to a directly compressible over the counter chewing gum powder and is commercially available from Roquette America.

Example 1 : A quick disintegrating tablet layer is prepared from the components set forth in Table 1A:

Table 1A

A liquid binder is first prepared by combining the oily liquid nicotine base and microcrystalline cellulose in water for a total volume of 50 ml at room temperature. The binder is then sprayed onto the mannitol and sodium starch glycolate, menthol flavoring, aspartame, talc, and stearic acid are then added. The composition is dried at elevated heat and then sized to an average particle size of 200 microns.

A gum layer is prepared from the components set forth in Table 1 B:

Table 1 B

The DC chewing gum powder, talc, menthol flavoring and aspartame are mixed together at room temperature. The magnesium stearate is then added to the blend and mixing is continued. The layers are filled into the die of a tablet press comprising a shaped die and punch and compressed by the punch being lowered under pressure which is maintained on the powder until the particles bond together and are sufficiently compacted to form the tablet. The tablet is then ejected. The process renders a quick disintegrating drug delivery system having stabilized nicotine which is rapidly absorbed by the end user.

Example 2: A tablet layer is prepared using the components set forth in Table 2A:

Table 2A

The nicotine bitartrate, microcrystalline cellulose, mannitol, croscarmellose, flavoring, and aspartame are mixed at room temperature. The layer is then sized to 200 microns by hammer mill. The magnesium stearate is then mixed with the sized tableting components.

A gum layer is prepared from the components set forth in Table 2B in accordance with the procedures of Example 1 :

Table 2B

The drug delivery system is then made by compression in accordance with the procedures set forth in Example 1. The nicotine in the resulting drug delivery system is quick dissolving upon activation with saliva.

Example 3: A tablet layer is prepared using the components and procedure set forth in Example 2. A gum layer is then prepared using the components set forth in Table 3A:

Table 3A

The DC chewing gum powder, talc, sodium bicarbonate, flavoring agent and aspartame are first mixed at room temperature, followed by the addition of magnesium stearate. Mixing is then continued.

The two layers are then compressed into a bilayered drug delivery system using a tablet press.

Example 4: Example 4 illustrates a two-layered cough-cold delivery system which is particularly acceptable to children in strawberry and grape flavors. The active ingredients are set forth below wherein Tables 4A, 5A, 6A, and 7A represent the tablet layer for the strawberry system and Tables 4B, 5B, 6B, and 7B represent the tablet layer for the grape system. The gum layers for the strawberry system and the grape system are set forth in Tables 8 and 9, respectively.

Table 4A ingredient mg/tablet %(w/w)

7.5 mg dextromethorphan HBr (46 % in a taste masked medium) 16.3 1.63

Table 5A

Table 6A

Table 7A

Table 4B

Table 5B

Table 6B

Table 7B

Table 8

1 kg of the tablet layer material is compounded by blending the active ingredient (dextromethorphan HBr, diphenhydramine HCI, pseudoephedrine HCl and/or chlorpheniramine maleate) and dextrose at room temperature until the components are adequately admixed. All other excipients (other than magnesium stearate) are then added to the admixture and blending is continued. Magnesium stearate is then added to the admixture and blended.

The gum layer is prepared by blending together all of the excipients (absent magnesium stearate) in a vessel at room temperature. Magnesium stearate is then added to the admixture and the blending is continued.

A Carver press having a 5/8" (= 5/8 inch = 1.59 cm) round, flat faced, bevel edged shape tooling is used to compact a 1 g tablet with about 1 ton of pressure. 1 g of gum layer is then added and compressed under similar pressure.

From the foregoing, it will be observed that numerous variations and modifications may be effected without departing from the true spirit and scope of the novel concepts of the invention.

Claims

Claims:

1. A multi-layered drug delivery system containing at least one gum layer and at least one quick disintegrating tablet layer, the tablet layer containing a therapeutically effective amount of a medicament.

2. The multi-layered drug delivery system of Claim 1 , wherein the medicament is an antimicrobial, non-steroidal anti-inflammatory, anti-tussive, decongestant, anti-histamine, expectorant, anti-diarrheal, hydrogen antagonist, proton pump inhibitor, general nonselective central nervous system depressant, general nonselective central nervous system stimulant, drug which selectively modifies the central nervous system function, antiparkinsonism drug, narcotic-analgesic, analgesic-antipyretic, sexual dysfunction agent or a psychopharmacological drug.

3. The multi-layered drug delivery system of Claim 1 , wherein the medicament is a nicotine releasing agent.

4. The multi-layered drug delivery system according to any one of Claims 1-3, wherein the gum layer contains a natural or synthetic gum base.

5. The multi-layered drug delivery system of Claim 4, wherein the gum base is chicle, jelutong, gutta percha, guayle, lechi de caspi gum, soh gum, siak gum, kahau gum, sorwa gum, balata gum, pendare gum, Malaya gum, peach gum, natural cauchouc, dammar, mastlix, crown gum or a mixture thereof.

6. The multi-layered drug delivery system of Claim 4, wherein the gum base is a butadiene- styrene copolymer, isobutylene-isoprene copolymer, polyethylene, polyisobutylene or a mixture thereof.

7. The multi-layered drug delivery system according to any one of Claims 1-6, wherein the multi-layered drug delivery system is prepared by compressing the gum layer and the tablet layer in solid form for a time sufficient for the gum layer and the tablet layer to bind together and form a compacted drug delivery system.

8. The multi-layered drug delivery system according to any one of Claims 1-7, wherein the tablet layer and/or gum the tablet layer contains a stabilizer, sweetener, disintegration agent, processing aid, lubricant, flavorant, and/or colorant.

9. The multi-layered drug delivery system according to any one of Claims 1-8, wherein the gum layer further contains a binder or bulking agent.

10. The multi-layered drug delivery system of Claim 9, wherein the bulking agent is an invert or polyol sugar.

11. The multi-layered drug delivery system of Claim 9, wherein the binder is a cellulosic material.

12. The multi-layered drug delivery system of Claim 11 , wherein the binder is microcrystalline cellulose.

13. The multi-layered drug delivery system of Claim 1 , wherein the medicament is a nutritive or functional ingredient or a pharmaceutical.

14. The multi-layered drug delivery system of Claim 2, wherein the medicament is dextromethorphan bromide.

15. The multi-layered drug delivery system of Claim 3, wherein the nicotine releasing agent is nicotine base or a nicotine salt.

16. The multi-layered drug delivery system of Claim 15, wherein the tablet layer contains nicotine salt and the gum layer contains a base capable of reacting with the nicotine salt or capable of facilitating conversion of the nicotine salt to nicotine base.

17. The multi-layered drug delivery system of Claim 16, wherein the base capable of reacting with the nicotine salt is sodium bicarbonate.

18. The multi-layered drug delivery system of Claim 2, wherein the drug delivery system is a cough, cold, allergy or sinus delivery system.

19. A method of delivering a medicament to a human patient comprising introducing into the mouth of the patient a drug delivery system containing at least two distinct layers, wherein at least one of the layers is a tablet layer containing at least one medicament and at least one of the layers is a gum layer.

20. The method of Claim 19, wherein the medicament is absorbed by a buccal, gastrointestinal or sublingual route.