MXPA00006094A - Process for manufacturing bite-dispersion tablets - Google Patents

Abstract

This invention relates to a method for the manufacture of Bite-dispersion tablets which disperse easily and quickly in the oral cavity, after a gentle bite, without the aid of water, and if necessary includes masking the bitter taste of medicaments. The process comprises preparing a dry granulation of one or more of medicaments blended with suitable excipients, flavors and a combination of a waxy material and phospholipid (BMI-60) or an intense sweetener derived from fruit flavonoids (Neohesperidine) for taste-masking and compressing into tablets which can be packaged in bottles or blisters using conventional equipment.

Description

PROCEDURE FOR THE MANUFACTURE OF TABLETS WITH DISPERSION TO THE MORDISCO FIELD OF THE INVENTION The present invention relates to a method for the manufacture of bite dispersion tablets (fast dispersion) containing flavored masked medicaments for oral administration without water.

BACKGROUND OF THE INVENTION Drug tablets developed for the treatment of various diseases are the most preferred dosage forms based on ease of administration and compliance by the patient. However, most medications have a bitter taste, and people who take these medications orally experience some discomfort or pain. To avoid this bitter taste, the medications are therefore swallowed. However, infants and the elderly experience some difficulty swallowing. In this way, two problems are faced, namely, the suppression of the bitter taste and the rapid disintegration of the tablets in the oral cavity to avoid difficulty in swallowing. The following methods have been used to mask the taste of the pharmaceutical compounds, namely the addition of sweetener or flavors, microencapsulation and coating of medicaments with materials, generally polymers, soluble in the stomach. The patent of E.U.A. 5,260,072 discloses a method for making chewable tablets of masked flavored medicaments, whereby flavored masking is achieved by rotogranulating the active material with a binder and carrier material, and coating the rotogranulations with an acetate taste masking polymer blend. of cellulose, or butyrate-cellulose acetate and polyvinylpyrrolidone. Alternative methods of the prior art (US 5,084,278) include microencapsulating the core of the tablet containing bitter active agents with polymers such as copolymers of methyl methacrylate and ethyl cellulose. Drug absorption products with complex silicates such as aluminum magnesium silicate, magnesium trisilicate or cation exchange resin have also been proposed (see USP 3,085,942, 3,140,978, 4,711, 744, 5,219,563 and WO 96/39126). WO 96/23494 discloses a taste masking method by wet granulation of the active medicament, a silicate adsorbate and a weak base such as calcium carbonate which acts as a dissociating agent, and compressing the granulation into tablets. US 5,275,823 discloses a method for preparing chewable tablets containing unpleasant-tasting drugs such as cimetidine, by coating cimetidine with Eudragit E100 and incorporating certain water insoluble hygroscopic substances such as Al / Mg antacids as external excipients. The main drawback of the methods described above is that the tablets still need to be swallowed, and the complete release of the active drug can take up to 2 hours, depending on the polymer system used therein. Japanese Patent Nos. 55-8966 and 62-265234 describe the addition of lecithin (phosphatidylcholine) and cephalin individually, or in combination with lecithin. Japanese Patent No. 55-108254 proposes the use of an absorbent material. The patent of E.U.A. 5,407,921 discloses a method for suppressing bitter taste by adding an acid phospholipid or an acid lysophospholipid. Bitter substances are commonly hydrophobic, and it is thought that hydrophobic interactions with receptor sites lead to their binding. Y. Katsuragi et al. [Pharm. Research Vol. 12, 658-662, 1995; Nature, 365: 213-214, 1993; Brain Research, 713, 240-245, 1996; Biochimica et Biophysica Acta, 1289, 322-328, 1996] describe the use of PA-LG or PA-LA lipoproteins composed of phosphatidic acid (PA) and β-lactoglobin (LG) and PA and α-lactalbumin, respectively. These lipoproteins being hydrophobic, reversibly suppress the responses of target sites for bitter substances. The patent of E.U.A. 5,407,921 describes the addition of lysophospholipid or acid phospholipid to suppress bitter taste. It has been found that these methods are insufficient to give the desired suppression of the bitter taste of certain pharmaceutical agents. Technologies for producing tablets that disintegrate rapidly in the oral cavity have also been described in the literature. These include immediate disintegration tablets (WOW ®) from Yamanouchi Pharmaceuticals Company of Japan; fast dissolving tablets (WO 95/33446) from Procter & Gamble Company; Lyoc® by Laboratoire Farmalyoc; OraSolv masked tablets with fast-dissolving taste from Cima Labs Inc .; ProTharharm FlashTab tablets; freeze-dried dosage forms of rapid bubble dissolution (Zydis®) from RP Scherrer; and Fuisz Technologies quick dissolution tablets, all of which involve laborious manufacturing procedures. In addition, these tablets need to be packed in special packages. The WOWTAB technology, described above (Japanese Patent Nos. 6-010112, 6-086652, 6-0616), comprises coating a pharmaceutically active ingredient and mannitol / lactose with maltose, initially changing from a crystalline state to an amorphous state, and then granulating These granules are compressed into porous tablets at very low compression forces. When subjected to high humidity, the maltose absorbs moisture until recrystallized; therefore, the residual moisture in the formulation is removed before packing. It was found that the tablets of hardness 3-5 kP obtained in this way, require special packing to avoid friction during storage / transport. The technology described in the patent application WO 95/33446 of Procter & Gamble comprises forming a non-breakable drug matrix by first dissolving / dispersing in water a flavor masking agent such as xanthan gum, methyl methacrylate copolymer, etc., and a pharmaceutically active agent, and then extracting the moisture and mixing with a vehicle orally acceptable (effervescent) such as sodium bicarbonate, and compressing into tablets. Moisture and heat sensitive active agents can not be processed, so the process is time consuming and expensive. Cima's instant dispersion technology is based on compressing commercially available microencapsulated medications into soft friable tablets. The procedure is thus complicated and expensive, and also requires strict environmental controls (< 20 ° C / 10% relative humidity and tablet hardness of -1-2.5 kP), and also specialized packaging. Lyoc technology involves freezing a suspension of a drug and excipients in preformed bubbles. Obviously, this technology is not suitable for most active ingredients. In addition, the technology requires specialized equipment and is expensive. Flash Tab is an instantaneous dispersion system that involves coating a drug with an Eudragit polymer (methyl methacrylate copolymer) to provide for rapid release of the drug into the stomach, and formulating this microencapsulated drug with an effervescent pair to produce an instant dispersion tablet. The microencapsulation system usually uses an undesirable solvent-based manufacturing process, and the cost of the goods is high. The patent of E.U.A. 5,407,921 discloses a method for suppressing the bitter taste of materials that will be placed in the oral cavity, such as food, beverages and medications. The process described in WO 94/08576 (Glaxo Group Limited) consists in first encapsulating ranitidine or a suitable salt form in a polymer matrix such as ethylcellulose, or using molten wax material such as Carnauba wax, tristearate or tripalmitate of glyceryl (fatty acids, esters and straight-chain saturated or unsaturated alcohols of high molecular weight), to obtain substantially insipid ranitidine granules with a drug content of about 20% w / w, granulate said granules with xylitol, flavor, etc., compress into chewable tablets or disperse on the basis of molten triglyceride suppository and theobromine oil, and prepare molds in tablet form. In any case, the procedure is laborious and expensive. There is a need for a rapid and cost-effective procedure for producing tablets containing medicaments, facilitating oral administration (rapid disintegration in the mouth without water), and masking with taste of any bitter-tasting ingredient.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a fast dispersion tablet, also referred to as a bite dispersible tablet, containing an active ingredient. The pharmaceutically acceptable fast dispersion tablet formulation of the present invention has a structure comprising compacted granulates; these granulates comprise a medicament together with a combination of a waxy material and an intense sweetener and / or a taste masking agent, a pharmaceutically acceptable excipient selected from xylitol, mannitol, maltodextrin or sorbitol, or a combination thereof; and optionally a flavoring and disintegrating agent; the granulates being compacted together in the form of a tablet together with extragranular components which are a disintegrant, a sweetener and / or flavor masking agent, and a pharmaceutically acceptable excipient selected from xylitol, mannitol, maltodextrin or sorbitol, or a combination thereof. same. Another aspect of the present invention is a process for the preparation of bite dispersion or rapid dispersion tablets for oral administration, which process comprises: A. Manufacturing of masked flavored granules: (i) mixing at least one pharmaceutically active ingredient , with one or more pharmaceutically acceptable excipients selected from the group consisting of xylitol, directly compressible mannitol, maltodextrin or sorbitol; a waxy material; an intense sweetener or flavor masking agent; and optionally a disintegrant and a flavoring agent; and (ii) preparing the mixture of step (i) for compression by dry granulation [such as by force beating or roll compaction], grinding and sieving; and B. Fabrication of bite dispersion tablets: (iii) mixing the product of step (i) with additional pharmaceutically acceptable excipients comprising xylitol, mannitol, maltodextrin or sorbitol, optionally including a flavoring agent, a sweetener / masking agent flavor, and a disintegrant; and (iv) compressing the mixture from step (iii) into tablets.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is described herein a process for the manufacture of bite dispersion tablets containing one or more drugs, or active agents / ingredients, which will disperse easily and rapidly after a soft bite when Ingest orally. It has now been found that by suitably selecting a combination of commonly used excipients such as xylitol and directly compressible mannitol, maltodextrin or sorbitol, preparing dry granules thereof, and subsequently mixing these granules with additional excipients, in an extragranular mixture, an dispersible tablet by bite that disintegrates rapidly in the oral cavity without water. It will be recognized by those skilled in the art that the proportions of excipients described above may need to be "refined" for each drug, or combination of medication, such as those described herein. The method of the present invention comprises: (1) mixing intragranular components that include one or more medicaments (also referred to herein as active agents or active ingredients), individually or in combination, together with any suitable or desired excipient, and a combination of a waxy material and a taste masking agent, which may include an intense sweetener, preferably BMI-60 or Neohesperidin; and optionally may include one or more additional flavoring agents and a disintegrant; and (2) preparing a dry granulation mixture by techniques well known in the art, such as by roller compaction or force beating, grinding and sieving, as required; and (3) preparing a compression mixture by mixing the intragranular dry granules of step (2) with any necessary or desired extragranular excipients, as will be described herein; and (4) compressing the mixture of step (3) into tablets.

It has been found that the resulting tablets have low friability, so that they can be easily packaged in jars or bubbles using conventional equipment. The desired fraction of the dry granulation mixture, produced in step 2 above, can be optionally treated with heat (Thermal Infusion Process, TIPped) following procedures well known in the art, such as those described in the patent of E.U.A. 5,690,959 before mixing it with additional excipients and compressing it into tablets. Steps 1 and 2 above provide substantially masked granules with a flavor of a medicament, while steps 3 and 4 result in the tablet dispersible by desired bite. In an alternative embodiment of the present invention, instead of the flavored masked granules produced in step 2, flavored commercially available flavored drug granules, such as granules coated with Eurand America polymer or microencapsulated Descote® granules, or any other suitable drug or polymer coated, can be mixed with excipients and flavors, and tablets in bite dispersion tablets following steps 3 and 4. It is recognized that there are many suitable means to produce masked intragranular drugs with flavor for use in the intragranular component mixture. Frequently, the polymer-coated granules or microencapsulated granules of the active ingredients can be active agents that have a bitter or unpleasant taste. These medicaments can be coated, for example, with separate polymer layers, such as methacrylate ester copolymers, as described in US Pat. 5,578,316. Suitable coating materials described in this application include a wide range of copolymers, such as those available under the trade name of Eudragit. These copolymers are manufactured and marketed by Rohm Pharma of Darmstadt, Germany. It is recognized that these polymeric aqueous dispersions may also contain additives such as plasticizers, pigments, talc and the like, which may be included for use herein in the intragranular mixture. These additives include plasticizers that are used to facilitate the film-forming characteristics of the polymeric coating, and also to provide greater integrity and elasticity to the coating of the films. Examples of plasticizers that can be used in the coatings of this invention are triethyl citrate, triacetin, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate, vinyl pyrrolidone and propylene glycol. The amount of plasticizer present in the aqueous dispersion can be from 5% to about 30% by weight of the dry polymers. Conveniently, the excipients desired for use in the intragranular mixture of step (i) of the above process include, but are not limited to, xylitol, directly compressible mannitol, maltodextrin or sorbitol; or a combination thereof, preferably xylitol. However, the extragranular mixture requires the use of certain pharmaceutically acceptable excipients, and these excipients may be selected from xylitol, directly compressible mannitol, maltodextrin or sorbitol; or a combination thereof, preferably xylitol. The present invention requires in the intragranular mixture, a component that is a waxy material, and a second component that is an intense sweetener, such as those derived from fruit flavonoids, or a taste masking agent such as lipoproteins and phospholipids. soy lecithin derivatives, which are also described herein. As described above, the mixture may optionally comprise flavoring agents, and a disintegrant. However, if the intragranular mixture uses a polymer-coated granule of a pharmaceutically active agent, or a masked, commercially available flavored granule of a pharmaceutically active ingredient is used, it is recognized that the waxy material and the second component are not necessary, and can therefore optionally be included. Waxy materials suitable for use herein include, but are not limited to, glycerol C al-3α aliphatic mono-, di- or tri-esters, preferably glycerol palmito stearate or glyceryl behenate.; high molecular weight straight chain aliphatic alcohols (C10.30) such as stearyl alcohol or cetyl alcohol; and mixtures of esters and high molecular weight aliphatic acids; or combinations thereof. Preferably, the waxy material is stearyl alcohol or cetyl alcohol, or is glycerol palmitostearate or glyceryl behenate. Suitable taste masking agents that can be incorporated into the intragranular formulation preferably include lipoproteins and phospholipids derived from soy lecithin, such as BMI-60, a fractionated product of soy lecithin from Kao Corporation. However, other components suitable for masking the taste of the active ingredients include, but are not limited to, synthetic or naturally occurring waxes, such as Compritol® or Precirol® (glyceryl behenate or glycerol palmito-stearate, from Gattefosse SA, France). ), cetyl alcohol or carnauba wax. It is noted that the waxy material and the taste masking agents may be the same agents that are used in the intragranular mixture, such as in the case of the use of the synthetic or naturally occurring waxes described above; or it can be a combination of them. Sweetening agents suitable for use in the intragranular formulation preferably include the intense sweeteners derived from fruit flavonoids, such as Neohesperidin DC from EM Industries, Inc. Conveniently, the second component required in the intragranular mixture may be the taste masking agent. described above, the intense sweetener, or a combination thereof. Preferably, the second component is BMI-60 or Neohesperidin DC, or a combination of these two products.

Conveniently, the waxy material, in combination with BMI-60 or Neohesperidin DC, is present at a level of from about 1% to about 30%, preferably from about 3% to about 20% by weight of the composition. In the intragranular mixture, if the first and second components are present, they are preferably from about 0.5 to about 2% w / w of the formulation. Alternatively, the ratio of waxy material: sweetening / taste-masking agent will vary in these formulations from about 20: 1 to about 5: 1 (total formulation). The waxy material, taste masking agents and sweetening agents described above for use in the intragranular component mixture can also be optionally used in the extragranular mixture. The active ingredients suitable for incorporation into the bite dispersion tablets of the present invention include the many numbing or unpleasant or bitter taste effects of drugs including, but not limited to, histamine H2 antagonists, such as cimetidine, ranitidine , famotidine, nizatidine, etinidine, lupitidine, nifenidine, niperotidine, roxatidine, sulfotidine, tuvatidine and zaltidine; antibiotics such as penicillin, ampicillin, amoxicillin and erythromycin; acetaminophen; aspirin; caffeine, dextromethorphan, diphenhydramine, bromopheniramine, chlorpheniramine, theophylline, spironolactone, NSAIDs such as ibuprofen, ketoprofen, naprosin and nabumetone; 5HT inhibitors such as granisetron or ondansetron; serotonin reuptake inhibitors such as paroxetine, fluoxetine and sertraline; vitamins such as ascorbic acid, vitamin A and vitamin D; minerals and dietary nutrients such as calcium carbonate, calcium lactate, etc., or combinations thereof. The above drugs are not limiting, but only examples of unpleasant-tasting drugs that can be used in this invention. In addition, other compounds such as nonsteroidal anti-inflammatory drugs (NSAIDs), such as naprosin, ie, propionic acid derivatives, are a preferred embodiment of this invention. Conveniently, these agents, in particular the anti-inflammatory agents, can also be combined with other active therapeutic agents such as various steroids, decongestants, antihistamines, etc., as appropriate. The inactive ingredients or excipients that are optionally used in the intragranular mixture and the extragranular mixtures required include pharmaceutically acceptable excipients such as xylitol [a sweetening agent (2.5 times as sweet as mannitol) with a large heat of negative solution, -153J / g)], fructose, sorbitol (heat of solution: -111 J / g), mannitol (heat of solution: -121 J / g), and maltodextrin. Flavoring agents suitable for use herein include, but are not limited to, wintergreen, orange, grapefruit and cherry / raspberry. If the intragranular mixture does not contain an active ingredient coated with polymer, preferably the mixture includes a flavoring agent. In addition, if a flavoring agent is present in the extragranular mixture, it should be present from about 0.5 to about 3% w / w of the total tablet formulation. The formulation may optionally contain suitable disintegrants (intra- and extragranular) such as, but not limited to, sodium starch glycolate [Explotab®], cross-linked polyvinylpyrrolidone [Crospovidone b®], corn starch, acacia, croscarmellose sodium [Ac-di-sof), sodium carboxymethylcellulose, veegum and alginates. Preferably, the disintegrant is sodium starch glycolate or corn starch. Although a disintegrant is an optional component in the intragranular mixture, it is preferably maize or acacia starch, the drug: disintegrating ratio being about 50: 1 to 20: 1. Although a disintegrant is also an optional component in the extragranular mixture, it is preferably sodium starch glycolate (Explotab), croscarmellose sodium (Ac-Di-Sol) or interlaced polyvinylpyrrolidone (Crospovidone), and is present in about 1-4% by weight of the formulation. The formulation may also optionally contain suitable lubricants (intra- and extragranular) such as, but not limited to, magnesium stearate, stearic acid and its pharmaceutically acceptable alkali metal salts, calcium stearate, sodium stearate, Cab-O -Sil, Syloid, sodium lauryl sulfate, sodium chloride, magnesium lauryl sulfate or talcum. Preferably, a suitable lubricant is magnesium stearate or stearic acid. The amount of lubricant present in the total formulation may be from about 0.5 to about 2.0 by weight of the composition. Conveniently, the lubricant is present in the extragranular mixture. In addition to these excipients described above, the formulation may also contain high surface area ingredients such as talc, acacia, corn starch, magnesium trisilicate or aluminum-magnesium silicate. Conveniently, high surface area materials are present at a level of from about 1% to about 10% by weight of the composition, preferably from about 2% to about 6% by weight of the composition. The formulation may also include coloring agents, or pigments, such as FD &ampoules and dyes; C or D &C approved, iron oxide and titanium dioxide. The amount of pigment present may be from about 0.1% to about 2.0% by weight of the composition. The formulation may also contain suitable lubricants in the intra and extra granular mixtures such as, but not limited to, magnesium stearate or stearic acid. Conveniently, the lubricant is present in the extragranular mixture. Additional conventional pharmaceutical diluents or excipients may also be included, as necessary, in the intragranular or extragranular mixture. Suitable excipients that can be used include, for example, fillers, binders, lubricants, compression aids and wetting agents. To further facilitate compliance by the patient, the formulation may also contain sweeteners such as aspartame, sodium cyclamate and sodium saccharinate; and flavorings such as those described above. The present invention provides a method for manufacturing bite dispersion tablets, which is capable of operating rapidly, is cost effective and particularly suitable for moisture / heat sensitive medicaments. Another aspect of this invention, comparatively with other rapid dispersion technologies, is that specialized packaging or manufacturing equipment is not required to manufacture these tablets. Conveniently, the tablets of the present invention include: a) 1-60 parts of at least one medicament; and b) 10-90 parts, preferably from 15 to 85 parts of xylitol; and c) 0.5-20 parts, preferably 1.0-20 parts of a waxy material such as glyceryl behenate (Compritol®) or glycerol palmito-stearate (Precirol®); and d) optionally, from 0.5 to 7 parts, more preferably from 1.0 to 4.0 parts of an intense taste / sweetener masking agent such as Neohesperidin or BMI-60 (the actual scale depending on the bitter taste of the medicament).

The content of xylitol in the formulations can vary significantly, depending on the medication; for example, 1 part of Granisetron hydrochloride per 90 parts of xylitol, preferably up to 40 to 70 parts of xylitol, depending on the dose required; 1 part of Paroxetine hydrochloride per 15 parts of xylitol, preferably up to 4 to 10 parts of xylitol; one part acetaminophen per 6 parts xylitol, preferably 2 to 4 parts xylitol; 1 part of buprofen per 6 parts of xylitol, preferably up to 2 to 4 parts of xylitol; 1 part of free base of cimetidine per 6 parts of xylitol, preferably up to 2 to 4 parts of xylitol; 5 parts of calcium carbonate per 1 part of xylitol, preferably 2 parts of calcium carbonate per 2 to 3 parts of xylitol; by total weight of the formulation. Preferably, the parts are ratios determined in percent w / w of the total formulation. The medicament, the waxy material and the taste-masking / sweetening agent are mixed together with suitable additional excipients, and preferably are roller compacted and ground, to produce pleasant-tasting granules; this mixture is also referred to herein as the intragranular component. These intragranular components, or for example, the microencapsulated granules of the commercially available medicament, are then mixed with additional excipients including xylitol, flavors and a lubricant (also referred to herein as the extragranular components), and compressed into fast dispersion tablets. .

The ratio of flavored masked drug granules: xylitol in the extragranular component of the tablet formula varies from about 1: 10 to 3: 1, preferably from about 1: 5 to 2: 1, depending on the diet regimen. dosage form and / or the degree of bitter taste associated with the medicament. The drug: xylitol ratio, if present in the intragranular component of the tablet formula, ranges from about 1: 30 to 10: 1, preferably from about 1: 20 to 3: 1, depending on the regime of the dosage form and / or the degree of bitter taste associated with the medicament. The ratio of drug: waxy material (if present) in the intragranular composition varies from about 10: 1 to 1: 30, preferably from about 5: 1 to 1: 20, depending on the dose and the bitter taste of the medication. The ratio of masked flavored granule (steps numbers 1 and 2): xylitol in the extragranular mixture, varies from about 1: 10 to 3: 1, preferably from about 4: 1 to 1: 1. Another aspect of the present invention is the novel formulation for a rapid dispersion pharmaceutical tablet for oral administration, which tablet has a structure comprising compacted granules; the granules comprising a medicament together with a combination of a waxy material and a taste masking agent, optionally with an intense sweetener, and / or flavoring agents; and optionally a pharmaceutically acceptable excipient selected from xylitol, mannitol, maltodextrin or sorbitol, or a combination thereof; the granulates being compacted together in the form of a tablet together with the extragranular components which are a disintegrant, a sweetener and / or taste masking agent, and a pharmaceutically acceptable excipient selected from xylitol, mannitol, maltodextrin or sorbitol, or a combination of the same. Preferably, the medicament in the tablet as described above is an analgesic, antacid, anti-emetic, anti-inflammatory agent, anti-arthritis medication, calcium supplement, antihistamine, decongestant, or a mixture thereof. Preferably, the granules of the tablet further comprise a pharmaceutically acceptable intragranular excipient such as xylitol, and an extragranular granular excipient such as xylitol. Preferably, the granulates include an intense sweetener which is derived from fruit flavonoids; or a flavor masking agent of a lipoprotein or acid phospholipids derived from soy lecithin. More preferably, the phospholipid is derived from a fractionated product derived from soy lecithin. Preferably, the granulated waxy material comprises a synthetic or naturally occurring wax, or a C10-C30 aliphatic mono-, di- or tri-ester glycerol, such as glycerol palmito stearate or glyceryl behenate. Or the waxy material may comprise a high molecular weight straight chain aliphatic alcohol (C 10 -C 30), or mixtures of esters and high molecular weight aliphatic acids such as stearyl alcohol or cetyl alcohol. Preferably, the waxy material is in combination with BMI-60 or Neohesperidin DC, and is present at a level of from about 1% to about 30%, preferably from about 3% to about 20% by weight of the composition. The granulates may further comprise a high surface area material comprising acacia or corn starch, or a combination thereof, at a level of from about 1% to about 10%, preferably from about 2% to about 6%. % by weight of the composition. Preferably, the tablets may also comprise a high surface area material comprising acacia or corn starch, or a combination thereof, at a level of from about 1% to about 10% in the extragranular component of the formulation, preferably where the high surface area material is acacia. The granulates may further comprise a flavoring agent, or the extragranular component may comprise a flavoring agent, or a combination thereof. In the process for making the tablets, preferably the granulates are optionally subjected to heat treatment before being compacted with the extragranular components.

EXAMPLES OF BIT DISPERSION TABLET FORMULATIONS Examples of typical formulations of bite dispersion tablets are illustrated in the following sections. These examples are neither exhaustive nor limited in scope.

EXAMPLE 1 Mix 80 g of granisetron hydrochloride with 68 g of xylitol, 4 g of Neohespiridine and 8 g of Compritol (glyceryl behenate), and grind the mixture using a micropulverizer. Prepare the following dry granulation formulation by mixing: Intraqranular mixture Inqredient% w / w Granitetron 11.2 ground mixture Xylitol 71.0 Maltodextrin 15.0 Flavoring agent 1.0 Aspartame (sweetener) 0.2 Compritoi ™ (glyceryl behenate) 1.6 Roll, grind and sift to produce # 30-80 mesh granules. Prepare the following compression mixture and compress tablets of 1.0 mg (free base of granisetron) to weigh 100 mg and hardness of 1-2 kP: Ingredient% in w / w Sifted granules 20.0 Xylitol 64.6 Maltodextrin 10.0 Sodium starch glycolate 3.0 Flavoring agent 0.5 Aspartame 0.3 Compritol ™ 16 Total 100.0 It was found that the tablets produced in this way are easily dispersed in the mouth with a fresh sensation, after a mild bite. These tablets met the uniformity requirements of USP content and also exhibited excellent friability (0.3% in 3 minutes or 75 revolutions), not requiring special packing for transportation and distribution.

EXAMPLE 2 Preparation of the following mix formulation in roller compactor: Intragranular mixture Ingredient% w / w paroxetine 50.0 Xylitol paroxetine 21.5 Flavoring agent 1.0 BMI-60 (phospholipid) 1.5 Aspartame 1.0 Precirol ™ (glycerol palmito-stearate) 25.0 Total 100.0 Compact the mixture with a roller, grind and sift to produce # 30-80 mesh granules, and heat with 45 to 48 ° C for 15 minutes. Prepare the following compression mixture and compress in dispersion tablets by bite with a concentration of 30 mg and weight of 200 mg: Ingredient% w / w treated granules 38.1 Xylitol 39.1 Mannitol spray-dried 13.8 Acacia 5.0 Flavoring agent 1.0 BMI-60 1.0 Aspartame 1.0 Compritol ™ 1.0 Total 100.0 Flavored masked tablets produced in this way are quickly dispersed in the mouth with a fresh sensation, after a mild bite. Tablets that have a hardness of 1-3 kP and acceptable friability do not require special packing for transport.

EXAMPLE 3 Preparation of the following mix formulation in roller compactor: Intragranular mixture Ingredient% w / w Acetaminophen 60.0 Xylitol 11.5 Flavoring agent 1.0 BMI-60 (phospholipid) 1.5 Aspartame 1.0 Precirol ™ 25.0 Total 100.0 Compact the mixture with rollers, grind and sift to produce # 40-80 mesh granules, and heat treat at 45 to 48 ° C for 15 minutes. Prepare the following compression mixture and compress in dispersion tablets by bite with a concentration of 80 mg and weight of 350 mg: Ingredient% w / w treated granules 38.1 Xylitol 39.1 Mannitol spray-dried 12.0 Corn starch 5.0 Ac-Di-Sol (croscarmellose sodium) 1.8 Flavoring agent 1.0 BMI-60 1.0 Aspartame 1.0 Precirol ™ 1.0 Total 100.0 The masked tablets produced in this way quickly disperse in the mouth with a fresh sensation, after a mild bite. Tablets that have a hardness of 1-3 kP and an acceptable friability (0.4% in 3 minutes) do not require special packing for transport.

EXAMPLE 4 Weigh ingredients, sift excipients and prepare the following compaction mixture for roller compaction: Extragranular blend Ingredient% w / w Cimetidine free base 55.0 Xylitol 14.5 Orange flavor 2.0 BMI-60 2.0 Precirol ™ 25.0 Aspartame 0.5 Mint flavor 1.0 Total 100.0 Weigh ingredients, sift excipients and prepare the next compression mixture and compress the intragranular mixture with compression (extragranular mixture) in cimetidine dispersion tablets by bite with a concentration of 200 mg and weight of 750 mg.

Extragranular blend: Ingredient% in w / w Sifted granules 48.5 Xylitol 31.8 Mannitol SD 9.1 BMI-60 1.0 Corn starch 5.0 Ac-Di-Sol 1.8 Aspartame 0.5 Mint flavor 1.5 Compritol ™ 0.8 Total 100.0 Flavored masked tablets produced in this way are quickly dispersed in the mouth with a fresh sensation, after a mild bite. Tablets that have a hardness of 2-3 kP and an acceptable friability (0.5% in 3 minutes) do not require special packing for transport.

EXAMPLE 5 Weigh ingredients, sift excipients, and prepare the following compression mixture, and compress into dispersion acetaminophen tablets by bite with a concentration of 250 mg and weight of 800 mg: Intragranular mixture: Ingredient% in w / w Granules Unbound * 52.1 Xylitol 26.0 Mannitol SD 12.1 BMI-60 2.0 Corn starch 3.0 Ac-Di-Sol 1.8 Aspartame 0.5 Flavoring agent 1.7 Compritol ™ 0.8 Total 100.0 * 60% Masked Flavored Acetaminophen Granules Descote®, manufactured by Particle Dynamics, St. Louis, MO 63144.

Flavored masked tablets produced in this way are quickly dispersed in the mouth with a fresh sensation, after a mild bite. Tablets that have a hardness of 2-3 kP and an acceptable friability (0.5% in 3 minutes) do not require special packing for transport.

EXAMPLE 6 Weigh ingredients, sift excipients, and prepare the following compaction mixture for roller compaction: Extragranular blend: Ingredients% w / w Calcium carbonate 70.0 Xylitol 16.0 Precirol ™ 10.0 BMI-60 1.5 Aspartame 1.0 Flavoring agent 1.5 Total 100.0 Compact the mix with roller, grind and sift to produce # 30-80 mesh granules. Prepare the following compression mixture, and compress in dispersion tablets by bite with a concentration of 500 mg and weight of 1.1 g: Ingredient% in w / w Sifted granules 64.9 Xylitol 16.2 Mannitol SD 9.1 BMI-60 2.0 Corn starch 3.0 Ac-Di-Sol 1.8 Aspartame 0.5 Flavoring agent 1.7 Compritol ™ 08 Total 100.0 Flavored masked tablets produced in this way are quickly dispersed in the mouth with a fresh sensation, after a mild bite. Tablets that have a hardness of 2-3 kP and an acceptable friability (0.5% in 3 minutes) do not require special packing for transport.

EXAMPLE 7 In an example of the alternative mode using pre-flavored masked granules, the following example is prepared. The ingredients are weighed, the excipients are screened, the next compression mixture is prepared and compressed into bite dispersion ibuprofen tablets with a concentration of 250 mg and a weight of 1.0 g: Ingredient% in w / w Cimetidine granules * 35.7 Xylitol 40.2 Mannitol SD 11.5 BMI-60 2.0 Corn starch 5.0 Ac-Di-Sol 1.8 Aspartame 1.0 Flavoring agent 2.0 Compritol ™ 0.8 Total 100.0 * Microcap cimetidine granules 60% masked with flavor, manufactured by Eurand America, Vandalia, Ohio.

Flavored masked tablets produced in this way are quickly dispersed in the mouth with a fresh sensation, after a mild bite. Tablets that have a hardness of 2-3 kP and acceptable friability (1.2% in 3 minutes) do not require special packing for transport.

EXAMPLE 8 The preparation of the following formulation can be done using a roller compactor: Intraqranular mixture: Ingredient% w / w Paroxetine hydrochloride 80.0 Xylitol 11.0 Flavoring agent 2.0 BMI-60 (phospholipid) 2.0 Aspartame 1.0 Precirol (glycerol palmito-stearate) 4.0 Total 100.0 Compact the mix with roller, grind and sift to produce # 30-80 mesh granules. These sieved granules are coated in a particle bed / fluid bed granulator with a solution of Eudragit E100 polymer dissolved in a mixture of ethyl alcohol and purified water. Prepare the following compression mixture, and compress in dispersion tablets by bite with a concentration of 30 mg and weight of 125.0 mg: Ingredient% in w / w treated granules 38.1 Xylitol 39.1 Mannitol spray-dried 13.8 Acacia 5.0 Flavoring agent 1.0 BMI-60 1.0 Aspartame 1.0 Compritol 1.0 Total 100.0 Flavored masking tablets produced in this way quickly disperse in the mouth with a fresh sensation , after a soft bite. Tablets that have a hardness of 1-3 kP and acceptable friability do not require special packing for transport.

All publications including, but not limited to, patents and patent applications cited in this specification are incorporated herein by reference as if each individual publication was specifically and individually indicated to be incorporated herein by reference, as described in more detail later. The foregoing description fully describes the invention, including preferred embodiments thereof. Modifications and improvements of the modalities specifically described herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest extent. Therefore, the examples herein should be considered only as illustrative, and in no way as a limitation on the scope of the present invention. The embodiments of the invention in which an exclusive property or privilege is claimed, are defined as follows.

Claims (53)

NOVELTY OF THE INVENTION CLAIMS

1. - A method for the preparation of fast dispersion tablets for oral administration, characterized in that said method comprises: (i) mixing together intragranular components which are at least one pharmaceutically active ingredient, one or more pharmaceutically acceptable excipients which are xylitol, mannitol directly compressible, maltodextrin or sorbitol, or a combination thereof; a waxy material; an intense sweetener or flavor masking agent; and optionally a disintegrant; and (i) preparing the mixture of step (i) for compression by dry granulation, force beating, roller compaction, milling or sieving, or combinations thereof; and (iii) mixing the product of step (ii) with an extragranular component comprising a pharmaceutically acceptable excipient of xylitol, directly compressible mannitol, maltodextrin or sorbitol, or a combination thereof; and optionally a taste masking / sweetening agent and a flavoring agent; and (iv) compress into tablets.

2. The method according to claim 1, further characterized in that the pharmaceutically acceptable intragranular excipient is xylitol.

3. The process according to claim 1 or 2, further characterized in that the extragranular granular excipient is xylitol.

4. The method according to claim 1, further characterized in that the drug is an antidepressant, analgesic, antacid, antiemetic, anti-inflammatory agent, anti-arthritis medication, calcium supplement, antihistamine, a decongestant, serotonin reuptake inhibitor or a 5HT4 inhibitor, or a mixture thereof.

5. The process according to claim 1, further characterized in that the intragranular sweetener is derived from fruit flavonoids.

6. The method according to claim 1, further characterized in that the intragranular component is a taste masking agent of lipoprotein or acid phospholipids derived from soy lecithin.

7. The process according to claim 6, further characterized in that the phospholipid is derived from a fractionated product derived from soy lecithin.

8. The process according to claim 1, further characterized in that the waxy material comprises a synthetic or naturally occurring wax, or a C10-C30 aliphatic mono-, di- or tri-ester glycerol.

9. - The method according to claim 8, further characterized in that the waxy material is glycerol palmitostearate or glyceryl behenate.

10. The process according to claim 1, further characterized in that the waxy material comprises a straight chain aliphatic alcohol of high molecular weight (C10-C30), or mixtures of esters and aliphatic acids of high molecular weight.

11. The process according to claim 9, further characterized in that the waxy material is stearyl alcohol or cetyl alcohol.

12. The process according to any of claims 1, or 7 to 11, further characterized in that the waxy material is in combination with BMI-60 or Neohesperidin DC and is present at a level of about 1% to about 30% , preferably from about 3% to about 20% by weight of the composition.

13. The process according to claim 1, further characterized in that the intragranular dry granules are optionally subjected to heat treatment before mixing them with the extragranular components.

14. The process according to claims 1 or 13, further characterized in that the dry granules granules are mixed with xylitol as an extragranular excipient, and compressed into fast dispersion tablets.

15. - The method according to claim 14, further characterized in that the dried granules are optionally mixed with a high surface area material comprising acacia or corn starch, or a combination thereof, at a level of about 1% to about 10%.

16. The process according to claim 15, further characterized in that the high surface area material is from about 2% to about 6% by weight of the composition.

17. The method according to claim 16, further characterized in that the high surface area material is in the extragranular mixture of the composition.

18. The process according to any of claims 15 to 17, further characterized in that the high surface area material is acacia.

19. The process according to claim 15, further characterized in that the material of high surface area is corn starch included in the intragranular mixture at a level of about 1% to about 10% by weight of the total composition.

20. The process according to claim 15, further characterized in that the high surface area material is aluminum magnesium silicate or magnesium trisilicate, and is from about 1% to about 4% by weight of the composition.

21. - The method according to claim 1, further characterized in that the intragranular component includes a flavoring agent.

22. The method according to claim 1, further characterized in that the extragranular component includes a flavoring agent.

23. A method for the preparation of fast dispersion tablets for oral administration, further characterized in that said method comprises: (i) mixing together intragranular components that include at least one microencapsulated pharmaceutically active ingredient, and optionally one or more pharmaceutically acceptable excipients , a waxy material; an intense sweetener or flavor masking agent; and a disintegrant; (ii) preparing the mixture of step (i) for compression by dry granulation, force tapping, roller compaction, milling or sieving, or combinations thereof; (iii) mixing the product of step (i) with an extragranular component comprising a pharmaceutically acceptable excipient selected from the group consisting of xylitol, directly compressible mannitol, maltodextrin or sorbitol; and optionally a taste masking / sweetening agent and a flavoring agent; and (iv) compress into tablets.

24. The method according to claim 23, further characterized in that the microencapsulated active ingredients are coated with a polymer which is soluble, is expandable, and releases the drug in the stomach.

25. The method according to claim 24, further characterized in that the active ingredient is a propionic acid NSAID, or a H2 receptor antagonist or proton pump inhibitor.

26. The process according to any of claims 23 to 25, further characterized in that the pharmaceutically acceptable extragranular excipient is xylitol.

27. The process according to any of claims 23 to 26, further characterized in that the mixture includes a taste masking agent of lipoprotein or acid phospholipids derived from soy lecithin.

28. The process according to claim 27, further characterized in that the phospholipid is derived from a fractionated product derived from soy lecithin.

29. The method according to claim 26, further characterized in that the mixture includes BMI-60.

30.- A rapidly dispersed pharmaceutical tablet formulation having a structure comprising compacted granulates; the granulates comprising a medicament together with a combination of a waxy material and a taste masking agent or an intense sweetener, optionally with a flavoring agent, and a pharmaceutically acceptable excipient selected from xylitol, mannitol, maltodextrin or sorbitol, or a combination thereof. same; the granulates being compacted together in the form of a tablet together with extragranular components which are a disintegrant, a sweetener and / or flavor masking agent, and a pharmaceutically acceptable excipient selected from xylitol, mannitol, maltodextrin or sorbitol, or a combination thereof. same.

31. The tablet formulation according to claim 30, further characterized in that the drug is an antidepressant, analgesic, antacid, antiemetic, anti-inflammatory agent, anti-arthritis medication, calcium supplement, antihistamine, a decongestant, reuptake inhibitor of serotonin or a 5HT4 inhibitor, or a mixture thereof.

32. The tablet according to claim 30, further characterized in that the granulates further comprise a pharmaceutically acceptable intragranular excipient which is xylitol.

33. The tablet according to any of claims 30 to 32, further characterized in that the extragranular granular excipient is xylitol.

34. The tablet according to claim 30, also characterized because the intense sweetener is derived from fruit flavonoids.

35. The tablet according to claim 30, further characterized in that the granulated component is a taste masking agent of a lipoprotein or acid phospholipids derived from soy lecithin.

36. The tablet according to claim 35, further characterized in that the phospholipid is derived from a fractionated product derived from soy lecithin.

37. The tablet according to claim 30, further characterized in that the waxy material comprises a synthetic or naturally occurring wax, or a glycerol C10-C30 aliphatic mono-, di- or tri-ester.

38. The tablet according to claim 37, further characterized in that the waxy material is glycerol palmitostearate or glyceryl behenate.

39.- The tablet according to claim 30, further characterized in that the waxy material comprises a straight chain aliphatic alcohol of high molecular weight (C10-C30), or mixtures of esters and aliphatic acids of high molecular weight.

40.- The tablet according to claim 39, further characterized in that the waxy material is stearyl alcohol or cetyl alcohol.

41. The tablet according to claim 30, further characterized in that the waxy material is in combination with BMI-60 or Neohesperidin DC, and is present at a level of about 1% to about 30%, preferably about 3% to about 20% by weight of the composition.

42.- The tablet according to claim 30, further characterized in that the granulates are optionally subjected to thermal treatment before being compacted with the extragranular components.

43.- The tablet according to claim 30 or 42, further characterized in that the granulates further comprise a high surface area material comprising acacia or corn starch, or a combination thereof, at a level of about 1. % to approximately 10%.

44. The tablet according to claim 43, further characterized in that the high surface area material is from about 2% to about 6% by weight of the composition.

45.- The tablet according to claim 30, further characterized in that it comprises a high surface area material comprising acacia or corn starch, or a combination thereof, at a level of about 1% to about 10% in the extragranular component of the formulation.

46.- The tablet according to claim 45, further characterized in that the high surface area material is acacia.

47. - The tablet according to claim 46, further characterized in that the granulate further comprises a flavoring agent.

48. The tablet according to claim 30, further characterized in that the extragranular component further comprises a flavoring agent.

49. A pharmaceutically acceptable rapid dispersion tablet for oral administration, characterized in that it comprises: a) 1-60 parts of at least one medicament; b) 10-90 parts of xylitol; c) 0.5-20 parts of a waxy material selected from glyceryl behenate or glycerol palmito-stearate; and d) optionally, from 0.5 to 7 parts of a flavor masking agent and / or intense sweetener.

50.- The tablet according to claim 49, further characterized in that the intense sweetener and / or taste masking agent is Neohesperidin or BMI-60.

51. The tablet according to claim 49, further characterized in that the xylitol is present in an amount of 15 to 85 parts.

52. The tablet according to claim 49, further characterized in that the waxy material is present in an amount of 1.0 to 20 parts.

53. The tablet according to any of claims 49 to 52, further characterized in that the drug is an antidepressant, analgesic, antacid, anti-emetic, anti-inflammatory agent, anti-arthritis drug, calcium supplement, antihistamine, a decongestant, inhibitor of the reuptake of serotonin or a 5HT4 inhibitor, or a mixture thereof.