MX2008004381A - Oral composition containing a salivation inducing agent - Google Patents

Abstract

Oral dosage forms, and particles used therein, containing salivation inducing agents are disclosed. The salivation agents may be in the core of the dosage form and/or in coatings applied thereto, or alternatively may be within particles and/or the matrix of such dosage forms, in coatings applied to such particles, or on the surface of such coated particles. The particles may be produced into a tablet form, such as a chewable tablet form, that provides for the immediate release of the active ingredient. Other oral dosage forms include thin film strips, gummi, foam tabs, and lozenges.

Description

ORAL COMPOSITION CONTAINING AN INDUCTOR AGENT OF SALIVATION FIELD OF THE INVENTION This invention relates to oral compositions containing an active ingredient and a salivating agent. These compositions can be used for the preparation of dosage forms that can be conveniently administered without water.

BACKGROUND OF THE INVENTION Pharmaceutical elements that are intended for oral administration are typically provided in solid form such as tablets, capsules, pills, lozenges, or granules. The tablets are swallowed whole, chewed in the mouth, or dissolved in the oral cavity. Chewable tablets are typically made from a mixture that includes active drug particles, and other inactive ingredients (excipients), and are often used for the administration of pharmaceutical elements where it is impractical to provide a complete intake tablet. With chewable tablets, the act of chewing helps to break up the particles of the tablet as the tablet disintegrates and can increase the rate of absorption by the digestive tract. The tablets Chews are often used to improve drug administration in pediatric and geriatric patients. Various attempts have been made to improve the texture of the drug particles in order to prevent their adhesion to the oral mucosa after ingestion. For example, WO88 / 06893 describes an oral composition comprised of an active substance and a gelling or swelling agent capable of forming a viscous medium around the particles in an aqueous vehicle. Disadvantageously, said compositions must be disintegrated in water to form a liquid suspension before ingestion for purposes of facilitating rapid ingestion of the composition without chewing. The Patent of E.U.A. No. 6,709,678 has overcome the need to suspend the formulation in an aqueous vehicle prior to administration by coating its particles with a hydratable polymer and a salivating promoter agent. It may be desirable to have an oral dosage form that effectively increases the production of saliva during ingestion, which thus obviates the need for consumption with water and thus improves the ingestibility of said dosage forms.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides pharmaceutical compositions as described in the claims.

In accordance with this invention, various forms of pharmaceutical formulations can be made that have an immediate release profile using a salivating inducing agent. The initiation of an increased amount of saliva not only facilitates the ingestion of the dosage form, but is also provided for convenient ingestion without the need for water.

DETAILED DESCRIPTION OF THE INVENTION It is believed that one skilled in the art can use, based on the present disclosure, the present invention to its fullest extent. The following specific modalities should be considered as merely illustrative, and are not limiting of the remainder of the description in any way. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as is commonly understood by one skilled in the art to which the invention pertains. Also, all publications, patent applications, patents, and other references mentioned in the present invention are incorporated as references. As used in the present invention, all percentages are by weight unless otherwise specified.

Unless defined otherwise, all ranges provided in the present invention also explicitly include all combinations of intervals that may be formed by all numbers within the terminal points of the range. As used in the present invention, "injection molding" must mean a process for the formation of a dosage form in a desired shape and size wherein a flow material, which is a fluid or shape in a fluid state, enters a mold, then solidifies in the mold via a change in temperature (either positive or negative) before being removed from it. In contrast, "compression", as used in the present invention, should mean a process for the formation of a dosage form in a desired shape and size wherein a material is compacted towards a tablet between the surfaces of the punches via an increase in pressure before being removed from them. As used in the present invention, an "outer surface" of a portion is a surface that comprises part of the outer surface of the finished dosage form. As used in the present invention, the term "substantially covers" or "substantially continuous" means that the coating is generally continuous and generally encompasses the entire surface of the underlying core or layer, so that little or nothing of the active ingredient or underlying layer It is exposed.

As used in the present invention, the term "salivating agent" should mean an insipid compound having a salivary inducing value of at least about 10%, for example at least about 12% or at least about 16% or less about 18%, and which substantially excludes the following water soluble compounds: a) Water soluble acids such as tartaric acid, citric acid, malic acid, fumaric acid, and ascorbic acid; b) Water-soluble salts are such as sodium or potassium chloride, sodium or potassium acid tartrate, sodium acid citrate or sodium ascorbate; and c) water soluble substances having an osmotic action such as glucose, fructose, sucrose, xylitol, mannitol; sorbitol, maltitol and mixtures thereof. By "substantially excludes", it is understood that the resulting formulation contains less than about 0.1 percent, for example less than about 0.5 percent or less than about 0.01 percent or less than 0.001 percent of said water-soluble components. Examples of suitable salivary-inducing agents include, but are not limited to, those muscarinic acetylcholine insipidic receptor agonists such as pilocarpine and the compound that is commercially available from IFF under the tradename, "SN12011"; sigma sigma binders such as arylalkylamines wherein the alkyl group has from about 1 to about 8 carbons, ie, for example, N, N-disubstituted phenylalkylamines wherein the alkyl has from about 1 to about 8 carbons and N, N disubstituted 2-phenylcyclopropylamines; Spirooxathiolan-quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof. As used in the present invention, "tasteless" should mean the substantial absence of or non-substantial contribution to a sense of taste, sweetness, saltiness, bitterness or acidity. As used in the present invention, "salivating inducing value" is the amount of additional saliva, expressed in percentage terms, secreted in the mouth of a user who consumes a dosage form containing a compound that can be an inducing agent. of salivation in accordance with the test method set forth in example 3, in relation to the amount of saliva secreted in the mouth of a user who similarly consumes a tablet containing the same ingredients but without that compound, after a period about 30 seconds, for example after about 1 minute or about 3 minutes or about 5 minutes, after either having ingested the tablet or removing the tablet from the user's mouth. As used in the present invention, "sweetness index" is a term used to describe the sweetness level of the dosage form in relation to sucrose. Sucrose, defined as the standard, has a sweetness index of 1. For example, the sweetness indices of various known sweetening compounds are listed below: In one embodiment, the dosage form of the present invention can be provided with a sweetness index of less than about 0.6.

The addition of sweetening agent may increase the sweetness of the dosage form to at least about 0.9, for example at least about 1.0, ie at least about 1.5, or at least about 2.0. As used in the present invention, the term "dosage form" is applied to any form that can be ingepr which are designed to be chewed or to remain in the mouth of a user, as opposed to those forms that are designed to be immediately ingested after ingestion. Examples of suitable forms that can be ingested include, but are not limited to solid dosage forms having a liquid, powder or solid core; disintegrating tablets that can be chewed or oral tablets; thin strips; gummy tablets; foam tablets; and coated particles having the salivation inducing agent in the coating and / or granulation matrix. In one embodiment, the dosage forms are solid, semi-solid, or liquid compositions designed to contain a predetermined specific amount (ie, dose) of a certain ingredient, for example, an active ingredient as defined below. Suitable dosage forms are systems for administration of pharmaceutical drug, including those for oral administration, buccal administration, or mucosal administration; or compositions for the administration of minerals, vitamins and other nutraceuticals, oral care agents, flavorings, and the like. In one embodiment, the dosage forms of the present invention can be considered as solids; however, they may contain liquid or semi-solid components. In another embodiment, the dosage form is a system orally administered for the administration of a pharmaceutical active ingredient to the gastro-intestinal tract of a human. In yet another embodiment, the dosage form is an orally administered "placebo" system containing pharmaceutically inactive ingredients, and the dosage form is designed to have the same appearance as a particular pharmaceutically active dosage form, such as that which is it may be used for control purposes in clinical studies to evaluate, for example, the safety and efficacy of a particular pharmaceutically active ingredient. "Active ingredients", as used in the present invention, includes, for example, pharmaceutical elements, minerals, vitamins and other nutraceuticals, oral care agents, flavors and mixtures thereof. Suitable pharmaceutical elements include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, agents of the central nervous system, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, migraine preparations, products for motion sickness, mucolytics, muscle relaxants, preparations for osteoporosis, polydimethylsiloxanes, respiratory agents, sleep aids , agents for the urinary tract and mixtures thereof. Suitable agents for oral care include breath fresheners, dental whiteners, antimicrobial agents, dental mineralizers, tooth fall inhibitors, topical anesthetics, mucoprotectants, and the like. Suitable flavors include menthol, peppermint, peppermint flavors, fruit flavors, chocolate, vanilla, chewing gum flavors, coffee flavors, liqueur flavors, and combinations thereof and the like. Examples of suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, sodium dihydroxy aluminum carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenoftaleína, aloe, castor oil, ricinoleic oil, and dehydrocholic oil, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectants, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for H. pylori, such as clarithromycin, amoxycilin, tetracycline, and metronidazole; antidiarrheals, such as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such as ondansetron, analgesics, such as mesalamine. In one embodiment of the invention, the active ingredient can be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. In another embodiment, the active ingredient may be selected from analgesics , anti-inflammatories, and antipyretics: for example non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives: for example ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives: for example indomethacin, diclofenac, sulindac, tolmetin, and the like; phenamic acid derivatives: for example mefanamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodilic acid derivatives: for example diflunisal, flufenisal, and the like; and oxicams: for example piroxicam, sudoxicam, isoxicam, meloxicam, and the like. In one embodiment, the active ingredient is selected from NSADD derived from propionic acid: for example ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof. In another embodiment of the invention, the active ingredient can be selected from acetaminophen, acetylsalicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. In another embodiment of the invention, the active ingredient can be selected from pseudoephedrine, phenylephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, guaifenesin, astemizole, terfenadine, fexofenadine, loratadine, desloratidine, doxylamine, norastemizole, cetirizine, bezocaine, mixtures of the same and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. In another embodiment, the active ingredient may be methylphenidate, modafinil and other active agents suitable for attention deficit hyperactivity disorder or attention deficit disorder; oxybutynin; sidenefil; and cyclobenzaprine. Examples of suitable polydimethylsiloxanes, including but not limited to dimethicone and simethicone, are those described in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each are expressly incorporated herein by reference. As used in the present invention, the term "simileone" it refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone. The active ingredient or ingredients are present in the dosage forms of the present invention in a therapeutically effective amount, which is an amount that produces the desired therapeutic response after oral administration and can be readily determined by one skilled in the art. For the determination of such amounts, the particular active ingredient to be administered, the bioavailability characteristics of the active ingredient, the dosage regimen, the age and weight of the patient, and other factors, as known in the art, should be considered. In one embodiment, the dosage form comprises at least about 85 percent by weight of the active ingredient. The active ingredient or ingredients may be present in the dosage form in any form. For example, the active ingredient can be dispersed at the molecular level, for example molten or dissolved, within the dosage form, or it can be in the form of particles, which in turn can be coated or uncoated. If the active ingredient is in the form of particles, the particles (either coated or uncoated) typically have an average particle size of about 1 miera to about 2000 microns. In one embodiment, said particles are crystals having an average particle size of about 1 miera to about 300 micras. In yet another embodiment, the particles are granules or concentrates that have an average size of particle from about 50 microns to about 2000 microns, for example from about 50 microns to about 1000 microns or from about 100 microns to about 800 microns. In certain embodiments in which the modified release of the active ingredient is desired, the active ingredient may optionally be coated with a known coating that modifies the release. It advantageously provides an additional tool for modifying the release profile of the active ingredient from the dosage form. For example, the dosage form may contain particles coated with one or more active ingredients, in which the coating of the particle confers a release-modifying function, as is well known in the art. Examples of suitable coatings for particles that modify the release are described in U.S. Pat. Nos. 4,173,626; 4,863,742; 4,980,170; 4,984,240; 5,286,497; 5,912,013; 6,270,805; and 6,322,819. Commercially available active ingredients for modified release may also be employed. For example, acetaminophen particles, which are encapsulated with polymers that modify the release by a coacervation process, can be used in the present invention. Said acetaminophen encapsulated by coacervation is commercially available from, for example, Eurand America, Inc. or Circa Inc. If the active ingredient has a questionable taste, and the dosage form is intended to be chewed or disintegrated in the mouth before if ingested, the active ingredient may be coated with a taste masking coating, as is known in the art. Examples of suitable taste masking coatings are described in, for example, US Patents. Nos. 4,851, 226; 5,075,114; and 5,489,436. Suitable processes for the application of taste masking coatings to dosage forms are known in the art, and include, but are not limited to, fluid bed coating, coacervation, complex coacervation, spray drying and coagulation by spraying. Commercially available masked flavored active ingredients may also be employed. For example, acetaminophen particles, which are encapsulated with ethylcellulose or other polymers by a coacervation process, can be used in the present invention. Said acetaminophen encapsulated by coacervation is commercially available from Eurand America, Inc. or Circa Inc. The active ingredient or ingredients are typically capable of carrying out dissolution after contact with a fluid such as water, stomach acid, intestinal fluid or the Similar. In one embodiment, dissolution characteristics of the active ingredient satisfy the USP specifications for immediate release tablets containing the active ingredient. In embodiments in which it is desired that the active ingredient be absorbed into the systemic circulation of an animal, the active ingredient or ingredients must be capable of carrying out dissolution after contact with a fluid such as water, gastric fluid, intestinal fluid or the like. In one embodiment, the dissolution characteristics of the active ingredient satisfy the USP specifications for the immediate release tablets containing the active ingredient. For example, for tablets with acetaminophen, USP 24 specifies that the pH regulator with phosphate at pH 5.8, using the USP 2 instrument (pallets) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form was released from of this within the first 30 minutes after dosing, and for tablets with ibuprofen, USP 24 specific than the phosphate pH regulator at pH 7.2, using the USP 2 instrument (pallets) at 50 rpm, at least 80% of the ibuprofen contained in the dosage form was released from it within the first 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In another embodiment, the dissolution characteristics of the active ingredient can be modified: for example controlled, sustained, extended, delayed, prolonged, or delayed. The location of the agent for salivation within the dosage form is not critical, and will depend on, for example, the type of dosage form selected, the active agent selected, the desired processing steps, and the like. For example, the salivation agent may be in the core of a dosage form or one or more coatings applied to the core of the dosage form. In another embodiment, the salivating agent may be in coatings for granules of the active ingredient and / or in the granulation matrix thereof, which are then compacted or extruded to produce a dosage form.

In addition to the active ingredient and the salivating inducing agent, the dosage form may contain other optional ingredients including, but not limited to fillers, including water soluble compressible carbohydrates such as sucrose, mannitol, sorbitol, maltitol, xylitol, erythritol, lactose, isomait, lactitiol, dextrose, polydextrose, dextrose monohydrate, fructose, maltose and mixtures thereof; conventional dry binders including cellulose, cellulose derivatives, polyvinyl pyrrolidone, starch, modified starch, maltodextrin, and mixtures thereof, and in particular microcrystalline cellulose, maltodextrin, and starch; sweeteners including aspartame, acesulfame potassium, sucralose and saccharin; disintegrants such as microcrystalline cellulose, starch, sodium starch glycolate, crosslinked polyvinyl pyrrolidone, crosslinked carboxymethyl cellulose; preservatives, flavorings, acidulants, antioxidants, binders, surfactants, and coloring agents. The dosage forms of the present invention can be made by any methods known in the art. For example, conventional methods for tablet production include direct compression ("dry blending"), dry granulation followed by compression, and wet granulation followed by drying and compression. Other methods include the use of roller technology for compaction such as a kilosonicador or roller by dripping, or technologies of molding, casting, or extrusion. All of these methods are well known in the art, and are described in detail in, for example, Lachman, et al., "The Theory and Practice of Industrial Pharmacy, "Chapter 11, (3rd Ed. 1986), which is incorporated by reference in the present invention In the embodiments wherein the tablets are formed by the direct compression method, the desired mixture of active ingredients, salivating inducer agent, and optional ingredients are mixed, then a pre-determined volume of particles is filled into a die cavity of a rotary tablet press, which rotates continuously as part of a "die table" from Possessing the filling to a compaction position The particles are compacted between an upper punch and a lower punch to an ejection position, in which the resulting tablet is pressed from the die cavity by the lower punch and is guided to an ejection outlet by a stationary bar for "elimination." One embodiment of the present invention is directed toward a dosage form that a core substantially coated with a coating, wherein the coating is comprised of, based on the total weight of the coating, from about 0.01 percent to about 15 percent, for example, from about 0.1 percent to about 5 percent of a salivating inducer agent. Suitable ingredients for coatings and methods for application of such coatings to the tablet cores, such as, for example, by dip coating, spray coating, or injection molding, are known in the art and are described in, example, US Publications Nos. 20030072729, 0072731, and 0070584; and the Patents of E.U.A. Nos. 4,820,524, 5,228,916; and 6,837,696. Another embodiment of the present invention is directed to a chewable dosage form having particles of active agents that are optionally coated with a taste masking coating and / or a texture masking coating. Examples of suitable taste masking agents and / or texture masking agents are known in the art and are described in, for example, U.S. Pat. Nos. 4,851, 226, US 5,260,072 and US 5,075,114. In this embodiment, the salivation inducing agent may be present in the matrix in an amount, based on the total dry weight of the dosage form, from about 0.01 percent to about 10 percent, for example, about 0.05 percent. to approximately 5 percent. The salivation-inducing agent may also be within the particle of the granulated active agent, and / or within the coating applied to the particles in an amount, based on the total dry weight of the coated particle, from about 0.1 percent to about 25 percent. percent, for example, from about 0.1 percent to about 15 percent. In embodiments wherein the salivation inducing agent is applied to a particle of an active ingredient that has previously been coated with an initial taste masking coating and / or a texture masking coating, the dosage form contains, based on the dry weight total of the particle coated with a initial coating as well as a covering of the salivating inducing agent, from about 0.1 percent to about 25 percent, for example, from about 0.1 percent to about 15 percent of a salivating agent. Additional ingredients suitable for chewable dosage forms and methods for their preparation are well known in the art and are described in, for example, Patents of E.U.A. Nos. 6,277,409, US 6,270,790, and US 6,258, 381. For example, the chewable dosage form may contain an active ingredient, a salivating inducing agent, a sweetener such as sucrose, and any aforementioned compressible carbohydrate including, but not limited to to dextrose monohydrate, lactose, mannitol and xylitol. In embodiments where a chewable tablet is desired, the degree of compaction of the particle is controlled so that the resulting tablets are relatively soft, i.e. have a hardness of up to about 15 kilo-per square centimeter (kp / cm2), for example from about 1 kp / cm2 to about 10 kp / cm2 or from about 2 kp / cm2 to about 6 kp / cm2. "Hardness" is a term used in the art to describe diametral breaking strength as measured by a conventional pharmaceutical hardness evaluation equipment, such as a Schieuniger Hardness Tester. In order to compare values between different sizes of tablets, the breaking force is normalized for the breaking area (which can be calculated as the number of times the thickness of the diameter of the tablet). East normalized value, expressed in kp / cm2, is sometimes referred to in the art as tablet tensile strength. A general discussion on the hardness assessment of the tablet is found in Leiberman et al., Pharmaceutical Dosage Forms-Tablets, Volume 2, 2nd ed., Marcel Dekker Inc., 1990, pp. 213-217, 327- 329 (hereinafter "Lieberman"). In another embodiment, the dosage form can be comprised of a thin strip of film containing, based on the total dry weight of the dosage form, from about 0.1 percent to about 10 percent, for example, about 0.1 percent. one hundred to about five percent of a salivating agent. Suitable ingredients for thin strip dosage forms of film and methods for their products are well known in the art and are described in, for example, U.S. Pat. Nos. 6,177,096; 5,948,430; US 6,596,298 and US 6,419,903. As used in the present invention, "thin film strip" must mean a dosage form that rapidly disintegrates in the oral cavity subsequent to ingestion and which comprises at least one water-soluble polymer and optionally an active ingredient, wherein the thickness of the dosage form is less than 200 microns. In another embodiment, the dosage form may be comprised of a gummy dosage form containing, based on the total dry weight of the dosage form, from about 0.1 percent to about 10 percent, for example, about 0.1 percent. one hundred to about five percent of a salivating agent.

Suitable ingredients for rubbery dosage forms and methods for their products are well known in the art and are described in, for example, U.S. Pat. No. 6,432,442. As used in the present invention, "gummy" dosage forms must mean an edible dosage form suitable for human consumption having a gel-like matrix comprised of gelatin, one or more hydrocolloids, and an optional active ingredient, such as so that the dosage form is chewed and ingested in less than 20 seconds. Said gummy dosage forms may also optionally contain sweeteners, adjuvants and flavorings such as those mentioned above. In another embodiment, the dosage form may be comprised of a foaming tablet dosage form containing, based on the total weight of the dry dosage form, from about 0.1 percent to about 10 percent, eg, about 0.1. percent to about 5 percent of a salivating agent. Suitable ingredients for foam tablet dosage forms and methods for their products are well known in the art and are described in, for example, U.S. Pat. No. 6,090,401. As used in the present invention, "foam tablet" dosage forms must mean an edible dosage form suitable for human consumption having a ity of less than 0.40 grams per cubic centimeter comprising a polymeric foaming agent, such as, for example, hypromellose, a polysaccharide and optionally an active ingredient. Said dosage forms of foam tablet may also optionally contain sweeteners, adjuvants and flavorings such as those mentioned above. The specific embodiments of the present invention are illustrated by means of the following examples. This invention is not confined to the specific limitations set forth above in these examples, but rather to the scope of the appended claims. Unless stated otherwise, the percentages and relationships provided below are by weight.

EXAMPLES EXAMPLE 1 Preparation of chewable tablet without salivating agent A mixture for the chewable tablets was prepared using the materials described in Table 1.

TABLE 1 Formulation for chewable tablet The dextrose monohydrate was sieved through a 20 mesh screen, then approximately half was added to a plastic bottle. Sucralose powder, mint flavor, and crospovidone were sieved through a 50 mesh screen, then added to the plastic bottle. One half of the remaining portion of dextrose monohydrate was sieved through the 50 mesh screen, then added to the plastic bottle. All remaining dextrose monohydrate, not screened, was subsequently added to the plastic bottle. The components were mixed end to end in the plastic bottle for 3 minutes. Then the magnesium stearate was sieved through a 50 mesh screen and added to the bottle. The bottle was mixed end-to-end for an additional minute, then compressed to a hardness of approximately 6.3 klolopondios on a rotary tablet press equipped with a 1.6-centimeter flat-face round beveled edge tool.

EXAMPLE 2 Preparation of chewable tablet containing salivating agent A mixture for chewable tablets containing a salivating agent was prepared using the materials described in Table 2 below: TABLE 2 Formulation for chewable tablet The dextrose monohydrate was sieved through a mesh screen , then about half was added to a plastic bottle. Sucralose powder, mint flavor, crospovidone, and salivation inducing agent were then sieved through a 50 mesh screen and added to the plastic bottle. One half of the remaining portion of dextrose monohydrate was sieved through the 50 mesh screen, then added to the bottle.

After all the remaining dextrose monohydrate was added to the plastic bottle, the components were mixed end to end in the plastic bottle for 3 minutes. After the magnesium stearate was sieved through a 50 mesh screen, it was added to the bottle, which was mixed end-to-end for an additional minute. The mixture was then compressed to tablets with a hardness of approximately 6.3 kiloponds on a rotary tablet press equipped with a round 1.6-inch flat-face bevelled edge tool.

EXAMPLE 3 Method for determining salivation-inducing agent One panelist received a tablet, which was produced according to example 1, and he was instructed to chew the tablet and expectorate (instead of swallow) his saliva into a graduated cylinder as the tablet was slowly swallowed. At intervals of 30 seconds, two minutes, three minutes, and five minutes after the tablet was Ingested, the amount of expectorated saliva was measured. The panelist waited four hours, then repeated the procedure with a second tablet, which was produced according to example 2. Ten additional independent panelists repeated this procedure. The results are presented below in tables 3 and 4.

TABLE 3 Amount of expectorated saliva TABLE 4 Difference in the production of saliva This example showed that 8 of the 11 panelists had an increase in the generation of saliva with the second tablet, which contained a salivating agent, in relation to the first tablet that did not contain it. This example also showed that the second tablet, which contained the salivating inducing agent, generated an average excess of 18 percent more saliva than the amount generated by the first tablet, when the saliva generated from each tablet was measured 30 seconds after swallowing each respective tablet. For dosage forms that are designed to remain in the mouth of a user, such as a pill, this test can be modified from so that the user removes said dosage form from the mouth 30 seconds after placing it therein. The amount of saliva produced can then be measured for any interval after the dosage form is removed.

EXAMPLE 4 Production of the thin film dosage form containing salivating agent TABLE 5 Preparation of the thin film base * Deionized water removed after drying.

The materials in the aforementioned frame were processed to a thin film using the following procedure.

For each 10.0 grams of total materials for the thin film mixture in Table A, 90.0 grams of DI water was required to create a dispersion containing approximately 10% solids. The water was initially heated to 85 ° C. To prepare the thin film dosage form, sodium benzoate, flavor, sucralose, salivating agent and citric acid were added to the DI water until dissolved using a laboratory-scale mixer at 500 RPM. Then HPMC and carrageenan were added while mixing at 500 RPM. The acetaminophen was then added and dispersed while mixing. The mixture was then manually poured into pre-formed molds designed to produce thin film dosage forms having a thickness of about 70 microns and a dry weight of about 300.0 mg under a constant temperature of 10 ° C. The thin film dosage forms were then removed from the molds and dried at 50 ° C and at 40% relative humidity until the water was substantially removed.

EXAMPLE 5 Preparation of a solution for coating with salivating agent A solution for film coating is prepared by adding to a beaker containing ethanol and water purified in a weight ratio of 50:50 with respect to the following solid ingredients in order and under ambient conditions: hydroxypropylmethylcellulose (5 degrees Centipoise); polyethylene glycol 8000; and talcum powder. The finished solution contained 10.0% solids, relative to the total weight of the coating solution. The salivation-inducing agent is then added thereto and mixed at 500 RPM for 1 hour under ambient conditions. The solution was left deaerating for a minimum of 2 hours before its use. The final solution for coating contained the ingredients set forth below in Table 6 in amounts based on the percentage weight of the final coating solution: TABLE 6 Composition of the coating solution EXAMPLE 6 Preparation of calcium carbonate in granules containing coating with salivating agent The coating solution in Example 5 was applied to 500.0 g of calcium carbonate in granules using a Glatt GPC-3 Wurster fluid bed coating unit at a spray speed of approximately 10-15 g / min, pressurized air for atomization of approximately 2-2.5 bar, a product temperature of approximately 28-35 ° C, and an exit temperature of approximately 45 ° C until the granules were coated with 10.0% weight gain of the coating solution. The resulting coated granules contained, based on the total dry weight of the coated granules, 0.2% of the salivation-inducing agent. The granules were then formed into tablets via compression at a hardness of approximately 6.3 kiloponds on a rotary tablet press equipped with a round 1.6-inch flat-faced bevel edge tool.

EXAMPLE 7 Tablet containing salivating agent A tablet formulation containing a salivating agent was prepared using the materials described in the table TABLE 7 Formulation for tablet For each 1000.0 g of the heavy mixture from Table 7, 100.0 g of deionized water had to be added to process the pellets. The corn syrup, sucrose and water were added to a vessel, then added at a temperature of about 140 ° C with mixing. The dye and the citric acid were added thereto with mixed, then the resulting solution was heated with stirring until it reached 155 ° C. The mixture was then stirred from the heat, and allowed to cool to 120 ° C, at which point flavor and salivating agent were added thereto with mixing. The resulting mixture was then manually poured into preformed molds to form pellets and removed from them after reaching room temperature.

EXAMPLE 8 Anti-acid mastic tablet containing salivating agent A mixture for the antacid chewable tablets containing a salivating agent was prepared using the materials described in Table 8.

TABLE 8 Formulation for chewable tablet The dextrose monohydrate and calcium carbonate were screened through a 20 mesh screen, then about half was added to a plastic bottle. Sucralose powder, mint flavor, crospovidone, and salivation inducing agent were then sieved through a 50 mesh screen and added to the plastic bottle. One half of the remaining portion of dextrose monohydrate was then sieved through a 50 mesh screen. All remaining dextrose monohydrate and calcium carbonate were subsequently added to the plastic bottle. The components were mixed end to end in the plastic bottle for 3 minutes. He Magnesium stearate was then sieved through a 50 mesh screen and added to the bottle, and mixed end-to-end for an additional 1 minute. The resulting mixture was then compressed to tablets with a hardness of approximately 6.2 kiloponds on a rotary tablet press equipped with a round 1.6-inch flat-face bevel edge tool.

Claims (24)

NOVELTY OF THE INVENTION CLAIMS

1. - An oral dosage form comprised of: a) a nucleus; and b) a coating that substantially coats the core, wherein the coating contains, based on the total dry weight of the dosage form, from about 0.1 percent to about 10 percent of at least one salivation-inducing agent.

2. The oral dosage form according to claim 1, further characterized in that the salivation inducing agent is selected from the group consisting of muscarinic acetylcholine insipidic receptor agonists; N, N-disubstituted phenylalkylamines wherein the alkyl has from about 1 to about 8 carbons; Spirooxathiolane-Quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof.

3. The oral dosage form according to claim 1, further characterized in that the salivation-inducing agent is selected from the group consisting of pilocarpine; N, N-disubstituted 2-phenylcyclopropylamine; Spirooxathiolane-Quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof.

4. The oral dosage form according to claim 1, further characterized in that the salivary-inducing agent has a salivary inducing value of at least about 12%.

5. The oral dosage form according to claim 1, further characterized in that the active ingredient is a non-steroidal anti-inflammatory drug, acetaminophen, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, dimenhydrinate, meclizine, famotidine, loperamide, ranitidine, cimetidine, astemizole, loratadine, desloratadine, fexofenadine, cetirizine, antacids, oxybutynin, methylphenidate, pharmaceutically acceptable salts thereof, metabolites thereof, and mixtures thereof.

6. The oral dosage form according to claim 1, further characterized in that it satisfies the USP dissolution specification for immediate release tablets containing the particular active ingredient.

7. A particle comprising, based on the total dry weight of the particle: a) a core containing an active ingredient; and b) a coating layer that masks the texture substantially covering the core, and c) from about 0.1% to about 25% of a layer of the salivating agent that substantially covers the coating layer to mask the texture.

8. The particle according to claim 7, further characterized in that the salivation-inducing agent is selected at from the group consisting of muscarinic acetylcholine taste receptor agonists; N-disubstituted phenylalkylamines wherein the alkyl has from about 1 to about 8 carbons; Spirooxathiolane-Quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof.

9. The particle according to claim 8, further characterized in that the salivation-inducing agent is pilocarpine; N-disubstituted phenylcyclopropylamines; Spirooxathiolane-Quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof.

10. The particle according to claim 7, further characterized in that the salivary-inducing agent has a salivary inducing value of at least about 12%.

11. The particle according to claim 7, further characterized in that the active ingredient is a non-steroidal anti-inflammatory drug, acetaminophen, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, dimenhydrinate, meclizine, famotidine, loperamide, ranitidine, cimetidine, astemizole , loratadine, desloratadine, fexofenadine, cetirizine, antacids, oxybutynin, methylphenidate, pharmaceutically acceptable salts thereof, metabolites thereof, and mixtures thereof.

12. The particle according to claim 7, further characterized in that the particle satisfies the specification of USP solution for the immediate release tablets containing the particular active ingredient.

13. A chewable tablet comprised of the particles of claim 7.

14. An oral dosage form comprised of, based on the total dry weight of the dosage form, from about 0.1% to about 10% of an inducing agent. of salivation, wherein the dosage form is selected from the group consisting of a chewable tablet, thin film strip, foam tablet, and gummy.

15. The oral dosage form in accordance with the claim 14, further characterized in that the salivation-inducing agent is selected from the group consisting of muscarinic acetylcholine insipidic receptor agonists; N, N-disubstituted phenylalkylamines wherein the alkyl has from about 1 to about 8 carbons; Spirooxathiolane-Quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof.

16.- The oral dosage form in accordance with the claim 15, further characterized in that the salivation-inducing agent is selected from the group consisting of pilocarpine; N, N-disubstituted 2-phenylcyclopropylamines; Spirooxathiolane-Quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof.

17. The oral dosage form according to claim 14, further characterized in that the salivating inducing agent has a salivary-inducing value of at least about 12%.

18. The oral dosage form according to claim 14, further characterized in that the active ingredient is a non-steroidal anti-inflammatory drug, acetaminophen, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, dimenhydrinate, meclizine, famotidine, loperamide, ranitidine, cimetidine, astemizole, loratadine, desloratadine, fexofenadine, cetirizine, antacids, oxybutynin, methylphenidate, pharmaceutically acceptable salts thereof, metabolites thereof, and mixtures thereof.

19. The oral dosage form according to claim 14, further characterized in that the dosage form satisfies the USP dissolution specification for immediate release tablets containing the particular active ingredient.

20. A particle comprising, based on the total dry weight of the particle: a) a core containing an active ingredient; and b) a coating that substantially coats the core, said coating comprised of from about 0.1% to about 25% of a salivation-inducing agent.

21. The particle according to claim 20, further characterized in that the salivary-inducing agent is selected from the group consisting of muscarinic receptor agonists. tasteless acetylcholine; N, N-disubstituted phenylalkylamines wherein the alkyl has from about 1 to about 8 carbons; Spirooxathiolane-Quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof.

22. The particle according to claim 21, further characterized in that the salivation-inducing agent is selected from the group consisting of pilocarpine; N, N-disubstituted 2-phenylcyclopropylamines; Spirooxathiolane-Quinuclidine; Heliopsis longpipes root; cholinesterase inhibitors; and mixtures thereof.

23. The particle according to claim 20, further characterized in that the active ingredient is a non-steroidal anti-inflammatory drug, acetaminophen, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, dimenhydrinate, meclizine, famotidine, loperamide, ranitidine, cimetidine, astemizole , loratadine, desloratadine, fexofenadine, cetirizine, antacids, oxybutynin, methylphenidate, pharmaceutically acceptable salts thereof, metabolites thereof, and mixtures thereof.

24. A chewable tablet comprised of the particles of claim 20.