Patent 6,475,510

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.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, a process is disclosed herein for the manufacturing of bite-dispersible tablets containing one or more medicaments, or active ingredients/agents, which will disperse easily, and quickly, after a gentle bite when taken orally.

It has now been found that by properly selecting a combination of commonly used excipients, such as xylitol and directly compressible mannitol, maltodextrin or sorbitol, preparing dry granules thereof, and subsequently blending these granules with additional excipients, in an extragranular admixture, a bite-dispersible tablet can be produced which rapidly disintegrates in the oral cavity without water. It will be recognized by the skilled artisan that the proportions of the above noted excipients may need to be "fine tuned" for each medicament, or combination of medicament, such as those disclosed herein.

The process herein comprises:

(1) blending intragranular components together which 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 excipients, and a combination of a waxy material and a taste-masking agent, which may include an intense sweetener, preferably BMI-60 or Neohesperidine; 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 compacting or slugging, milling and sieving as may be required; and

(3) preparing a compression mix by blending the intragranular dry granules from step (2) with any necessary or desired extragranular excipients as will be described herein; and

(4) compressing the mixture from step (3) into tablets.

The resulting tablets have been found to have a low friability, so that they can be readily packaged into bottles or blisters using conventional equipment.

The desired fraction of the dry granulation mixture, produced in step 2 above, may optionally be heat treated (Thermal Infusion Process, TIPped) following procedures well known in the art, such as those described in U.S. Pat. No. 5,690,959 prior to blending with additional excipients and compressing into tablets.

Steps # 1 and 2 above provide for substantially taste-masked granules of a medicament, while Steps # 3 and 4 result in the desired bite-dispersible tablet. In an alternative embodiment of the present invention, instead of the taste-masked granules produced in Step # 2, commercially available taste-masked granules of medicaments, such as polymer coated granules from Eurand America or microencapsulated Descote.RTM. granules, or any other suitable polymer coated medicament, may instead be blended with the excipients and flavors and compressed into bite-dispersion tablets following Steps # 3 and 4.

It is recognized that there are many suitable means for producing taste-masked intragranular medicaments for use in the intragranular component mix. Often the polymer coated granules, or microencapsulated granules of the active ingredients, may be active agents which have a bitter, or unpleasant taste. These medicaments may be coated, for instance, with separate layers of polymers, such as methacrylate ester copolymers, as taught in U.S. Pat. No. 5,578,316. Suitable coating materials described in this application include a wide range of copolymers, such as those available under the tradename 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 mix. These additives include plasticizers are employed to assist in the film forming characteristics of the polymeric coating and also to provide greater integrity and elasticity to the films coat. Exemplary of plasticizers that may be employed 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 may be from 5% to about 30% by weight of the dry polymers.

Suitably the desired excipients for use in the intragranular admixture of process step (i) above 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 does require in the intragranular mixture, a component which is a waxy material, and a second component which is either an intense sweetener, such as those derived from fruit flavonoids, or a taste masking agent such as the lipoproteins and phospholipids derived from soy lecithin, which are further described herein. As noted above, the admixture may optionally comprise additionally flavoring agents, and a distintegrent. If, however, the intragranular mixture uses a polymer coated granule of a pharmaceutically active agent, or a commercially available taste-masked granule of a pharmaceutically active ingredient is used instead, it is recognized that the waxy material and the second component are not necessary and may therefore be optionally included.

Suitable waxy materials for use herein include, but are not limited to, the mono-, di- or tri- C_10-30 aliphatic esters of glycerol, preferably glycerol palmito-stearate or glyceryl behenate; the high molecular weight (C_10-30) straight chain aliphatic alcohols, such as stearyl alcohol or cetyl alcohol; and mixtures of high molecular weight aliphatic acids and esters; or combinations thereof Preferably, the waxy material is stearyl alcohol or cetyl alcohol, or is glycerol palmito-stearate or glyceryl behenate.

Suitable taste-masking agents which may be incorporated in the intragranular formulation preferably include the lipoproteins and phospholipids derived from soy lecithin, such as BMI-60, a fractionated product from soy lecithin from Kao Corporation. However, other suitable components for taste-masking of active ingredients include, but are not limited to, synthetic or naturally occurring waxes such as Compritol.RTM. or Precirol.RTM. (glyceryl behenate or glycerol palmito-stearate, from Gattefosse s.a., France), cetyl alcohol or carnauba wax. It is noted that the waxy material and the taste-masking agents may be the same agents for use in the intragranular admixture, such as in the case of use of the synthetic or naturally occurring waxes noted above; or may be a combination thereof

Suitable sweetener agents for use in the intragranular formulation preferably include the intense sweeteners derived from fruit flavonoids, such as Neohesperidine DC from EM Industries, Inc. Suitably the required second component in the intragranular admixture may be either be the above noted taste-masking agent, the intense sweetner or a combination thereof Preferably the second component is either BMI-60 or Neohesperidine DC, a combination of these two products.

Suitably, the waxy material, in combination with BMI-60 or Neohesperidine DC, is present at a level of from about 1% to about 30%, preferably from about 3% to about 20% by weight of composition. In the intragranular admixture if the first and second component are present it is preferably from about 0.5 to about 2% w/w of the formulation. Alternatively, the waxy material to the taste-masking/sweetener ratio will vary in these formulations from about 20:1 to about 5:1 (total formulation).

The waxy material, taste-masking agents and sweetener agents noted herein for use in the intragranular component mix may also be optionally used in the extragranular admixture.

Suitable active ingredients for incorporation into the bite-dispersion tablets of the present invention include the many bitter, unpleasant tasting, or numbing effects of drugs which include, but are 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, amoxycillin, and erythromycin; acetaminophen; aspirin; caffeine, dextromethorphan, diphenhydramine, bromopheniramine, chloropheniramine, theophylline, spironolactone, NSAIDS's such as ibuprofen, ketoprofen, naprosyn, and nabumetone; 5HT4 inhibitors, such as granisetron, or ondansetron; seratonin re-uptake inhibitors, such as paroxetine, fluoxetine, and sertraline; vitamins such as ascorbic acid, vitamin A, and vitamin D; dietary minerals and nutrients, such as calcium carbonate, calcium lactate, etc., or combinations thereof.

The above drugs are not limiting but merely exemplary of unpleasant tasting drugs that may be employed in this invention. Additionally, other compounds such as the nonsteriodal anti-inflammatory drugs (NSAIDs), such as naprosyn, i.e. the propionic acid derivatives, are a preferred embodiment of this invention. Suitably, these agents, in particular the anti-inflammatory agents, may also be combined with other active therapeutic agents, such as various steroids, decongestants, antihistamines, etc., as may be appropriate.

The inactive ingredients or excipients, optionally used in the intragranular admixture and the required extragranular admixtures, include the pharmaceutically acceptable excipients such as xylitol [a sweetening agent (2.5 times as sweet as mannitol) with a large negative heat of solution--153 J/g)], fructose, sorbitol (heat of solution:--111 J/g), mannitol (heat of solution:--121 J/g), and maltodextrin.

Suitable flavoring agents for use herein include, but are not limited to, wintergreen, orange, grapefruit, and cherry-raspberry. If the intragranular mixture does not contain a polymer coated active ingredient than preferably the mixture includes a flavouring agent. Further, if a flavouring agent is present in the extragranular mix 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 (both intra and extra-granular) such as, but not limited to, sodium starch glycolate [Explotab.RTM.], crosslinked polyvinylpyrrolidone [Crospovidone b.RTM.], corn starch, acacia, Croscarmellose of sodium [Ac-di-sol.RTM.], sodium carboxymethylcellulose, veegum, alginates. Preferably the disintegrant is sodium starch glycolate, or corn starch.

While a disintegrant is an optional component in the intragranular mix, it is preferably corn starch or acacia, with the drug to disintegrant ratio of about 50:1 to 20:1.

While a disintegrant is also an optional component in the extragranular mix, it is preferably sodium starch glycolate (Explotab), Croscarmellose of sodium (Ac-Di-Sol) or crosslinked polyvinylpyrrolidone (Crospovidone), and is present in about 1-4% wt. of formulation.

The formulation may also optionally contain suitable lubricants, (both intra and extra-granular) 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 talc. 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 composition. Suitably, the lubricant is present in the extra-granular mix.

In addition to these above noted excipients, the formulation may also contain high surface area ingredients such as talc, acacia, corn starch, magnesium trisilicate or magnesium aluminum silicate. Suitably, the high surface area materials are present at a level from about 1% to about 10% by weight of composition, preferably from about 2% to about 6% by weight of composition.

The formulation may also include coloring agents, or pigments, such as FD&C or D&C approved lakes and dyes, 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. Suitably, the lubricant is present in the extra-granular mix.

Additional other conventional pharmaceutical diluents or excipients may be also be included, as needed, in either the intragranular or extragranular admixture. Suitable excipients which may be employed include, for example, fillers, binders, lubricants, binders, compression aids, and wetting agents. To further assist patient compliance, the formulation may also contain sweeteners such as aspartame, sodium cyclamate and sodium saccharinate; and flavorants such as those noted above.

The present invention provides for a method of manufacturing bite-dispersion tablets which are capable of rapid operation, is cost effective, and suitable particularly to moisture/heat sensitive medicaments.

Another aspect of this invention, as compared to other fast-dispersion technologies, is that no specialized manufacturing or packaging equipment is required to manufacture these tablets.

Suitably, the tablets of the present invention include:

a) 1-60 parts of at least one medicament; and

b) 10-90 parts, preferably 15-85 parts of xylitol; and

c) 0.5-20 parts, preferably 1.0-20 parts of a waxy material, such as glyceryl behenate (Compritol.RTM.), or glycerol palmitostearate (Precirol.RTM.); and

d) optionally, 0.5-7 parts, more preferably 1.0-4.0 parts of an intense sweetener/taste masking agent such as Neohesperidine or BMI-60 (the actual range depending upon the bitterness of the medicament).

The xylitol content in the formulations may vary significantly depending on the medicament; for example, 1 part of Granisetron hydrochloride to 90 parts of xylitol, preferably to 40-70 parts of xylitol, depending on the required dose; 1 part of Paroxetine hydrochloride to 15 parts of xylitol, preferably to 4-10 parts of xylitol; 1 part of Acetaminophen to 6 parts of xylitol, preferably to 2-4 parts of xylitol; 1 part of Ibuprofen to 6 parts of xylitol, preferably to 2-4 parts of xylitol; 1 part of Cimetidine free base to 6 parts of xylitol, preferably to 2-4 parts of xylitol; 5 parts of Calcium Carbonate to 1 part of xylitol, preferably 2 parts of Calcium Carbonate to 3-2 parts of xylitol; per total weight of formulation. Preferably, parts are ratios determined by w/w % of the total formulation.

The medicament, waxy material and sweetener/taste masking agent are blended together with suitable additional excipients, preferably roller compacted and milled, to produce palatable granules, this admixture is also referred to herein as the intragranular component. These intragranular components, or for instance, commercially available microencapsulated granules of the medicament, are then blended with additional excipients including xylitol, flavors and a lubricant (also referred to herein as the extragranular components) and compressed into fast dispersing tablets.

The taste-masked drug granule to xylitol ratio 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 strength of the dosage form and/or the extent of bitterness associated with the medicament.

The drug to xylitol ratio, if present, in the intragranular component of the tablet formula varies from about 1:30 to 10:1, preferably from about 1:20 to 3:1, depending on the strength of the dosage form and/or the extent of bitterness associated with the medicament.

The drug to 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 bitterness of the medicament. The ratio of the taste-masked granule (steps #1 and 2) to xylitol in the extragranular mix 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 fast-dispersing pharmaceutical tablet for oral administration which tablet has a structure comprising compacted granulates; the granulates comprising a medicament together with a combination of a waxy material and a taste-masking agent, optionally with an intense sweetner, and/or flavoring agent; and optionally a pharmaceutically acceptable excipent selected from xylitol, mannitol, maltodextrin, or sorbitol, or a combination thereof, the granulates being compacted together into a tablet form together with extragranular components which are a disintegrant, a sweetner and/or taste-masking agent, and a pharmaceutically acceptable excipent selected from xylitol, mannitol, maltodextrin, or sorbitol, or a combination thereof

Preferably, the medicament in the tablet as noted above, is an analgesic, antacid, antiemetic, anti-inflammatory agent, arthritis medication, calcium supplement, antihistamine, decongestant, or a mixture thereof.

Preferably, the tablet granulates further comprise an intragranular pharmaceutically acceptable excipiewhich is xylitol, and an extragranular granular excipient is xylitol.

Preferably the granulates include an intense sweetener which is derived from fruit flavonoids; or a taste masking agent of a lipoprotein or acidic phospholipids derived from soy lecithin. More preferably, the phospholipid is derived from a fractionated product derived from soy lecithin.

Preferably, the granulate waxy material comprises a synthetic or naturally occurring wax, or a mono-, di- or tri- C₁₀ -C₃₀ aliphatic ester of glycerol, such as glycerol palmito-stearate or glyceryl behenate. Or the waxy material may comprise a high molecular weight (C10-C30) straight chain aliphatic alcohol, or mixtures of high molecular weight aliphatic acids and esters, such as stearyl alcohol or cetyl alcohol.

Preferably, the waxy material is in combination with BMI-60 or Neohesperidine DC and is present at a level of from about 1% to about 30%, preferably from about 3% to about 20% by weight of 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 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 wherein the high surface area material is acacia.

The granulates may further comprises a flavoring agent, or the extragranular component may further comprises a flavoring agent, or a combination thereof

In the process of making the tablets preferably, the granualtes are optionally subjected to heat treatment prior to being compacted with the extragranular components.

Claim 1 of 101 Claims

What is claimed is:

1. A process for the preparation of a fast dispersing tablet for oral administration, which process comprises:

(i) admixing together intragranular components which are at least one pharmaceutically active ingredient, one or more pharmaceutically acceptable excipients which are xylitol, directly compressible mannitol, maltodextrin and sorbital, or a combination thereof; a waxy material which is a synthetic or natural wax, a mono-, di- or tri-(C_10-30) aliphatic esters of glycerol, a (C_10-30) straight chain aliphatic alcohol, a (C_10-30) aliphatic acid, and a (C_10-30) aliphatic ester, or combinations thereof; an intense sweetener or taste-masking agent; and optionally a disintegrant; and

(ii) preparing the admixture of step (i) for compression by dry granulation, slugging, roller compacting, milling or sieving, or combinations thereof; and

(iii) blending the product of step (ii) with an extragranular component which comprises a pharmaceutically acceptable excipient of xylitol, directly compressible mannitol, maltodextrin or sorbitol, or a combination thereof; and optionally a sweetener or taste-masking agent;

(iv) compressing into tablets.

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