WO2004096175A2

WO2004096175A2 - Taste masked microcapsules and processes for their preparation

Info

Publication number: WO2004096175A2
Application number: PCT/IB2004/001266
Authority: WO
Inventors: Kamal Mehta; Rajeev Shanker Mathur; Sanjeev Kumar Sethi; Rajiv Malik
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-04-30
Filing date: 2004-04-27
Publication date: 2004-11-11
Also published as: WO2004096175A3

Abstract

The invention relates to compositions and methods for taste-masking bitter, unpleasant tasting medicaments. The invention further relates to taste-masked coated granules of a bitter pharmaceutical agent that can be reconstituted as a liquid suspension. The taste-masked pharmaceutical granule composition includes a core, a first coating layer and a second coating layer. The core includes one or more bitter tasting pharmaceutically active agents, one or more hydrocolloid materials, and, optionally, one or more flavoring agents. The first coating layer includes one or more hydrophobic materials and covers at least a portion of the core. The second coating layer includes one or more enteric film forming polymers and one or more waxy materials and covers at least a part of the first coating layer.

Description

TASTE MASKED COMPOSITIONS AND PROCESSES FOR THEIR PREPARATION

Technical Field of the Invention

The invention relates to compositions and methods for taste-masking bitter, unpleasant tasting medicaments. The invention further relates to taste-masked coated granules of a bitter pharmaceutical agent that can be reconstituted as a liquid suspension.

Background of the Invention

A wide variety of pharmaceutically active agents exhibit the undesirable characteristic of having a bitter taste either during or immediately after oral administration. Among the pharmaceutical agents with this characteristic are acetaminophen, ampicillin, azithromycin, chlo heniramine, cimetidine, dextromethorphan, diphenhydramine, erythromycin, clarithromycin, ibuprofen, penicillin, phenylbutazone, psuedoephedrine, cefuroxime axetil, cepfodoxime proxetil, ranitidine, spironolactone and theophylline. The azalide antibiotics, such as azithromycin, and the erythrolide antibiotics, such as clarithromycin, are two particularly bitter tasting classes of pharmaceutical agents.

Administration as an oral dosage form is generally the preferred route of administration of many of the pharmaceutical agents listed above because such a dosage form provides for easy, low-cost administration. However, ensuring patient compliance can sometimes be a complicating factor when a patient has to swallow a tablet, capsule or suspension. Patients give many reasons for their refusal or inability to accept oral administration of a medicinal dosage form, including unattractive presentation, overly large size, bad taste or simple fear that an unchewed dosage form may catch in the throat. Patients who have difficulties with oral dosage forms often exhibit a gag reflex that effectively prevents oral administration. This problem is common in, but not specific to, children. The bitter taste and flavor of a pharmaceutical agent in a liquid suspension is inevitably detected during the drinking process or immediately after swallowing. Additionally, the bitterness of a bitter pharmaceutical agent in a tablet, capsule, suspension or other oral dosage form may be detected upon administration if the bitter active agent is brought into contact with the taste buds, such as occur if the dosage form is left too long in the mouth before swallowing, by inadvertent chewing of the dosage form, or by some other means of release of the bitter pharmaceutical agent. Chewable tablets have been shown to increase patient compliance in both children and others who have a problem swallowing whole tablets or capsules. However, quite often a pharmaceutical agent is so bitter-tasting that it cannot be tolerated when chewed, and the unpleasant taste or aftertaste imparted by the bitter active agent will cause patients to avoid taking the oral dosage form.

Conventionally, sweeteners and flavorants have been used in taste-masking. These agents generally work by providing a secondary flavor to the composition. This technique is sometimes able to mask mildly bitter pharmaceuticals, but the traditional sweeteners generally are not effective in masking the bitter taste and flavor of extremely bitter pharmaceutical agents such as azithromycin, clarithromycin, roxithromycin and the like.

Alternative approaches that have been used to mask the bitter flavor of certain phamiaceuticals include microencapsulating the unpleasant tasting active agent in a coating of ethyl cellulose or a mixture of ethyl cellulose and hydroxypropyl cellulose or other cellulose derivatives to provide chewable taste-masked dosage forms. These approaches however, suffer from the disadvantage that the polymer coating releases the active agent in an inconsistent fashion and may not provide immediate (or timely) release. Further, the use of these cellulose derivatives is quite often insufficient to provide adequate taste-masking of potently bitter active agents.

Moreover, the coatings are only suitable for storage when the foraiulation is stored in a dry forai. After reconstitution, stability of the drug in the suspension can pose a problem for the formulator. The reconstituted suspension should ideally be stable for the entire period of treatment.

Erythromycin and its derivatives are known for their extremely bitter taste. In particular, 6-0-methoxyerythromycin A (clarithromycin) which has been disclosed in U.S. Patent No. 4,331 ,803 is among the most bitter pharmaceutical agents known.

The aforementioned bitter taste of clarithromycin poses a serious patient compliance problem unless formulated in an oral dosage form in which the bitter taste is masked or reduced.

Summary of the Invention In one general aspect there is provided a taste-masked pharmaceutical granule composition. The composition includes a core, a first coating layer and a second coating layer. The core includes one or more bitter tasting phannaceutically active agents, one or more hydrocoUoid materials, and, optionally, one or more flavoring agents. The first coating layer includes one or more hydrophobic materials and covers at least a portion of the core. The second coating layer includes one or more enteric film forming polymers and one or more waxy materials and covers at least a part of the first coating layer. Embodiments of the composition may include one or more of the following features.

For example, the core may include an inert substrate layered with the active agent, the hydrocoUoid material and the flavoring agent. The inert core may be insoluble, soluble or commercially available. The insoluble inert core may be selected from one or more of dicalcium phosphate, macrocrystalline cellulose or combinations thereof. The soluble inert core may be selected from one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose, and combinations thereof. The commercially available inert core may be selected from one or more of sugar spheres, non-pareil seeds, celpheres and combinations thereof. The core may be made of the pharmaceutically active agent. The core may be prepared by one or more of extrusion, extrusion-spheronization, wet granulation, and granulation in a fluidized air bed.

The bitter tasting pharmaceutically active agent may be selected from one or more of antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, central nervous system stimulants, antihistaminics, anti-asthmatics, anti-tussives, nutritional supplements and vegetable extracts. The bitter tasting pharmaceutically active agent may be an antibiotic. The antibiotic may be a macrolide antibiotic. The macrolide antibiotic may be clarithromycin. The core may be about 2.0% to about 70% of the active ingredient in relation to the total weight of the coated granules. The size of the core may be between about 50 μm and about 500 μm.

The flavoring agent may be one or more of cherry, strawberry, peppermint, vanilla, chocolate, and spearmint. The hydrocoUoid material may be one or more of gums, pectin, alginates, starch, cellulose and cellulose derivatives. The gums may be one or more of xanthan gum, gum acacia, tragacanth gum, guar gum, and karaya gum. The cellulose derivatives may be one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxy ethyl cellulose. The core may further include one or both of binders and disintegrants. The binders may be one or more of methylcellulose, hydroxypropyl methyl cellulose, gelatin, polyvinypyrrolidone, ethyl cellulose, tragacanth, and gum arabic. The disintegrant may be one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, and low- substituted hydroxypropyl cellulose.

The hydrophobic material may be selected from one or more of vegetable and animal oils, fatty acids, glyceryl esters of fatty acids, triglycerides, polyethylene glycols of various molecular weights and mixtures thereof. The first coating layer may further include a lubricant. The lubricant may be one or more of talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, and beeswax. The first coating layer may be about 2% w/w to about 40% w/w of the total composition.

The enteric film forming polymer may be one or more of cellulose phthalates, poly (methyl) acrylates and acrylic acid polymers. The cellulose phthalate may be one or more of hydroxypropyl methylcellulose phthalate and cellulose acetate phthalate. The waxy material may be one or more of fatty acids, glyceryl esters of fatty acids, and polyethylene glycols.

Either or both of the first coating layer and the second coating layer may further include one or more additional pharmaceutically inert excipients. The pharmaceutically inert excipients may be one or both of plasticizers and lubricants. The plasticizers may be one or more of propylene glycol, triethylene glycol, oleic acid, ethylene glycol monooleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebaccate, and acetyl triethyl citrate.

The coating may be applied to the core using any conventional coating technique. Either or both of the first coating layer and the second coating layer may be applied to the core using one or more of spray coating in a coating pan, spray coating in a fluid bed processor, and dip coating. Either or both of the first coating layer and the second coating layer may be applied to the core as a solution or suspension in a solvent. The solvent may be one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof.

In another general aspect there is provided a process for preparing a taste-masked pharmaceutical granule composition. The process includes preparing a suspension/solution, layering over a core, applying a first coating layer, applying a second coating layer, and drying. The suspension/solution includes one or more pharmaceutically active agents, one or more hydrocoUoid materials, and, optionally, one or more flavoring agents in a solvent. The suspension/solution is layered over inert cores and dried. Applying the first coating layer includes applying the coating over at least a portion of the cores and drying. The first coating layer includes a hydrophobic material. Applying the second coating layer includes forming coated granules by applying a second coating layer over at least a portion of the first coating layer. The second coating layer includes one or more enteric polymers and one or more waxy materials. The coated granules are then dried. Embodiments of the process may include one or more of the following features or those described above. For example, the solution/suspension may further include one or more binders and disintegrants. The bitter tasting pharmaceutically active agent may be selected from one or more of antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, central nervous system stimulants, antihistaminics, anti-asthmatics, anti- tussives, nutritional supplements and vegetable extracts. In particular, the antibiotic may be clarithromycin.

The flavoring agent may be one or more of cherry, strawberry, peppermint, vanilla, chocolate, and spearmint. The hydrocoUoid material may be one or more of gums, pectin, alginates, starch, cellulose and cellulose derivatives. The hydrophobic material may be selected from one or more of vegetable and animal oils, fatty acids, glyceryl esters of fatty acids, triglycerides, polyethylene glycols of various molecular weights and mixtures thereof.

The first coating layer may further include one or more lubricants. The lubricant may be one or more of talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, and beeswax. The first coating layer may be about 2% w/w to about 40% w/w of the total composition.

The enteric film forming polymer may be one or more of cellulose phthalates, poly (methyl) acrylates and acrylic acid polymers. The waxy material may be one or more of fatty acids, glyceryl esters of fatty acids, and polyethylene glycols. Either or both of the first coating layer and the second coating layer may further include one or more additional pharmaceutically inert excipients. Applying either or both of the first coating layer and the second coating layer may include using one or more of spray coating in a coating pan, spray coating in a fluid bed processor, and dip coating. Either or both of the first coating layer and the second coating layer may be applied to the core as a solution or suspension in a solvent. The process may further include using the taste-masked granules to prepare one or more of dry syrups, sachets, tablets and powders that can be reconstituted before usage. The reconstituted suspension may be stable for at least 14 days.

The reconstitutable dry formulation may further one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may be one or more of sweeteners, coloring agents, thickening agents, pH modulators, preservatives, opacifiers and flavoring agents. The sweeteners may be one or more of aspartame, saccharose, acesulfame, sodium glycyrrhizinate and mixtures thereof. The opacifiers may be one or both of titanium oxide and opadry. In another general aspect there is provided a process for preparing a taste-masked pharmaceutical granule composition. The process includes granulating, applying a first coating layer, applying a second coating layer, and drying. Granulating includes granulating one or more bitter tasting pharmaceutically active agents, one or more hydrocoUoid materials, and one or more flavoring agents to form granules. The first coating layer is coated over at least a portion of the cores and dried. The first coating layer includes one or more hydrophobic materials. Applying the second coating layer includes forming coated granules by applying a second coating layer over at least a portion of the first coating layer. The second coating layer includes one or more enteric polymers and one or more waxy materials. The coated granules are then dried. Embodiments of the process may include one or more of the following features or those described above. For example, the solution/suspension may further include one or more binders and disintegrants. The bitter tasting pharmaceutically active agent may be selected from one or more of antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, central nervous system stimulants, antihistaminics, anti-asthmatics, anti- tussives, nutritional supplements and vegetable extracts, hi particular, the antibiotic may be clarithromycin.

The flavoring agent may be one or more of cherry, strawberry, peppermint, vanilla, chocolate, and spearmint. The hydrocoUoid material may be one or more of gums, pectin, alginates, starch, cellulose and cellulose derivatives. The hydrophobic material may be selected from one or more of vegetable and animal oils, fatty acids, glyceryl esters of fatty acids, triglycerides, polyethylene glycols of various molecular weights and mixtures thereof. The first coating layer may further include one or more lubricants. The lubricant may be one or more of talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, and beeswax. The first coating layer may be about 2% w/w to about 40% w/w of the total composition. The enteric film forming polymer may be one or more of cellulose phthalates, poly

(methyl) acrylates and acrylic acid polymers. The waxy material may be one or more of fatty acids, glyceryl esters of fatty acids, and polyethylene glycols.

Either or both of the first coating layer and the second coating layer may further include one or more additional pharmaceutically inert excipients. Applying either or both of the first coating layer and the second coating layer may include using one or more of spray coating in a coating pan, spray coating in a fluid bed processor, and dip coating. Either or both of the first coating layer and the second coating layer may be applied to the core as a solution or suspension in a solvent.

The process may further include using the taste-masked granules to prepare one or more of dry syrups, sachets, tablets and powders that can be reconstituted before usage. The reconstituted suspension may be stable for at least 14 days.

The reconstitutable dry formulation may further one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may be one or more of sweeteners, coloring agents, thickening agents, pH modulators, preservatives, opacifiers and flavoring agents. The sweeteners may be one or more of aspartame, saccharose, acesulfame, sodium glycyrrhizinate and mixtures thereof. The opacifiers may be one or both of titanium oxide and opadry.

In another general aspect there is provided a method for the treatment of a patient in need thereof. The method includes administering a taste-masked pharmaceutical granule composition to the patient. Thee composition includes a core, a first coating layer and a second coating layer. The core includes one or more bitter tasting pharmaceutically active agents, one or more hydrocoUoid materials, and, optionally, one or more flavoring agents. The first coating layer covers at least a portion of the core and includes one or more hydrophobic materials. The second coating layer covers at least a portion of the first coating layer and includes one or more enteric film forming polymers and one or more waxy materials. Embodiments of the method may include one or more of the following features or those described above. For example, the bitter tasting pharmaceutically active agent may be selected from one or more of antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, central nervous system stimulants, antihistaminics, anti-asthmatics, anti- tussives, nutritional supplements and vegetable extracts. In particular, the antibiotic may be clarithromycin.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims. Detailed Description of the Invention

As evident from the description of the prior art above, it is evident that there still exists a need to develop a pharmaceutical composition of a bitter tasting drug in which the bitter taste is reduced or eliminated and the composition is sufficiently stable to preserve the taste masking effect for a period of at least equal to 14 days after reconstitution. The inventors have surprisingly discovered a method of obtaining granules or pellets that contain a bitter tasting pharmaceutically active agent but nonetheless are palatable and possess high stability in the aqueous suspending medium. The granules or pellets include a core that includes a bitter tasting pharmaceutically active agent, a hydrocoUoid, and, optionally, a flavoring agent. The core is coated with at least two separate layers of polymers, among which the first coating includes a hydrophobic material and the second coating includes an enteric film forming polymer associated with a waxy material. The unpleasant or objectionable taste associated with a pharmaceutically active agent can be effectively reduced by maintaining the pharmaceutically active agent, the hydrocolloidal, and the flavoring agent in relatively close physical contact with one another in the oral dosage form. Although not wishing to be bound by any particular theory, it is believed that such relatively close physical contact facilitates dissolution of the pharmaceutically active agent and flavorant at relatively similar rates, thereby maximizing the extent to which the pharmaceutically active agent and flavorant are present together at any relevant point in time within the oral cavity. Coating of a hydrophobic component or material and a waxy component or material reduces the wetting properties of the drug, which result in stability enhancement and non availability of pharmaceutically active agent in solution - ultimately resulting in less bitterness. In addition to this, the coating of an enteric film-forming polymer and waxy material helps in imparting elasticity, thereby aiding in filling the granules or pellets into sachets.

The core may be selected from pharmaceutically inert insoluble or soluble materials. Alternatively, the inert core may also be a commercially available product. The insoluble inert cores are composed of dicalcium phosphate, microcrystalline cellulose and the like, either alone or in combination. The soluble inert cores are composed of sugar selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose and mixtures thereof. Commercially available inert cores are selected from sugar spheres, non-pareil seeds, celpheres and mixtures thereof. The cores may be of any geometric shape, although spheres are preferred for the ease of uniform coating.

Alternatively, the core can be prepared with the pharmaceutically active agent itself. The cores can be prepared by extrusion, extrusion-spheronization, wet granulation or granulation in fluidized air bed.

According to one embodiment, the core comprises an inert core material layered with a solution or suspension containing pharmaceutically active agent, a hydrocoUoid and, optionally, a suitable flavoring agent.

According to another embodiment, the core comprises the pharmaceutically active ingredient, a hydrocoUoid and, optionally, a flavoring agent.

The pharmaceutically active agent includes one or more pharmaceutically active compounds, wherein at least one has a bitter taste. Without being limiting, the active compound(s) may be selected from antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, stimulants of central nervous system, antihistaminics, anti- asthmatics, anti-tussives, nutritional supplements and vegetable extracts.

In particular, the pharmaceutically active compound is selected from a group comprising macrolide antibiotics, for example, erythromycins and compounds derived thereof, such as azithromycin, clarithromycin, roxithromycin and other compounds.

The granules comprise about 2% to 70% of the active ingredient in relation to the total weight of the coated granules.

The granules containing the active ingredient can have any suitable size, but preferably the distribution of size of the core may vary from about 50 μm to about 500 μm. Suitable flavoring agents may include but are not limited to cherry, strawberry, peppermint, vanilla, chocolate, spearmint and mixtures thereof.

Suitable hydrocolloids include natural and synthetic polymers which can form a colloidal solution in aqueous systems, for example, gum, pectins, alginates, starch, cellulose and cellulose derivatives. Gums may be selected from one or more of xanthan gum, gum acacia, tragacanth gum, guar gum, karaya gum, and mixtures thereof. Cellulose derivatives maybe selected from one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxy ethyl cellulose and mixtures thereof. The core may additionally comprise binders and disintegrants. Suitable binders may be selected from methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, ethylcellulose, tragacanth, gum arabic and mixtures thereof. Suitable disintegrants may be selected from sodium starch glycolate, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose. The first hydrophobic coating is intended to increase the stability of the granules or pellets in suspension. This coating includes one or more hydrophobic materials or components and optionally a lubricant.

The hydrophobic component may include vegetable and animal oils (one or more of unhydrogenated, hydrogenated, or partially hydrogenated); fatty acids; glyceryl esters of fatty acids; triglycerides; and polyethylene glycols (PEG) of various molecular weights such as PEG 600, PEG 2000, PEG 6000, PEG 8000 and mixtures thereof.

Suitable lubricants may be selected from talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, beeswax and mixtures thereof.

The first hydrophobic coating makes up about 2% w/w to about 40% w/w of the total composition.

The second coating layer comprises one or more enteric polymers and waxy materials or components associated with it. The enteric polymers may be selected from cellulose phthalates, e.g., chemically modified cellulose phthalates such as hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate and poly (meth) acrylates and other acrylic acid polymers, commercially available as Eudragits. The waxy material or component may be selected from fatty acids, glyceryl esters of fatty acids, polyethylene glycols and mixtures thereof. The coating layers may additionally contain pharmaceutically inert excipients such as plasticizers and lubricants. Suitable plasticizers include propylene glycol, triethylene glycol, oleic acid, ethyleneglycol monoleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebaccate, acetyl triethylcitrate , castor oil and mixtures thereof. The pharmaceutically active agent layer (in the embodiments that include the inert core), first coating layer and the second coating layer can be applied to the core as a solution/suspension in a suitable solvent, using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor or dip coating. Alternatively, the coating can also be performed using hot melt technique wherever possible.

Following the application of the coatings, the granules are subjected to a drying step. For example, the granules are dried in a rotor granulator or fluidized bed processor at a temperature between about 45°C and about 80°C. An anti-adherent or anti-static agent may be added after the granules have been dried to reduce flow related problems and to eliminate excess moisture which may develop from condensation due to climatic changes during ' shipping and storing.

Suitable anti-adherents or anti-static agents include silicon dioxide, talc, magnesium stearate, calcium stearate, stearic acid and combinations thereof.

The solvents used for forming a solution/suspension of the coating material may be selected from methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.

The taste-masked formulations are capable of being administered either as coated granules, pellets or beads, or as orodispersible tablets, fast-crumbling multiparticulate tablets, or as a liquid suspension or emulsion. In any of these dosage forms, the present compositions provide the substantial benefit that the bitter taste and aftertaste of bitter pharmaceutical agents are effectively masked such that the patient does not detect the bitter flavor. Further, the taste-masking component of the present invention does not adversely alter intended medicinal effect(s) of the pharmaceutical agent of the composition.

The coated granules may be used for preparing dry syrups, sachets, tablets and powders that can be reconstituted before usage by adding a liquid, e.g., water or any other aqueous liquid, to obtain a suspension or emulsion that is pharmaceutically administrable. The reconstitutable compositions prepared from granules are stable during storage and the suspensions, once reconstituted in the multidose bottle, present a masked taste during the entire period of treatment.

The reconstitutable compositions contain, in addition to the coated granules or pellets, excipients that confer special organoleptic characteristics and microbiological stability.

These excipients may be selected from sweeteners, coloring agents, thickening or suspending agents, disintegrants, pH modulators, antioxidants, preservatives, opacifiers, antistatic agents and flavoring agents.

Suitable sweeteners may be selected from aspartame, saccharose and its derivatives, acesulfame, neohesperidine, dihydrochalcone, polyols, sodium glycyrrhizinate or their mixtures.

Suitable opacifiers include Opadry® OYB and titanium oxide.

Suitable thickening or suspending agents include gums, starches, dextrins, cellulose ethers, alginates, carbomers, gelatin or their mixtures thereof. Gums may be selected from xanthan gum, guar gum, tragacanth gum and the like. Cellulose ethers may be selected from hydroxy ethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, methyl cellulose, hydroxypropyl methylcellulose and mixtures thereof.

Suitable disintegrants may be selected from amongst cross-linked sodium carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, low- substituted hydroxy propyl cellulose and carboxy methyl starch.

Suitable antistatic agents may be selected from amongst precipitated or colloidal silicon dioxide and talc.

Suitable pH modulators include citric acid, sodium bicarbonate, sodium citrate, trisodium citrate, tribasic sodium phosphate, sodium chloride and the like. Suitable preservatives include sodium benzoate, sodium sorbate, potassium sorbate, p- hydroxybenzoate and the like.

Suitable colors and flavors may be selected from any FDA approved colors or^' flavors which are compatible with the active compound and other excipients of the formulation.

Suitable antioxidants include butylated hydroxyanisole, butylated hydroxytoluene or propyl gallate or a mixture thereof. The dry granular material for reconstitution is prepared by mixing it homogeneously in any suitable conventional equipment used for mixing. The equipment may be selected, for example, from amongst hammer mills, ribbon mixers, vertical mixers and other blenders.

The following examples further illustrate the scope of the present inventions and are not intended to limit the scope of the inventions.

EXAMPLE 1

PREPARATION OF CLARITHROMYCIN COATED GRANULES:

Procedure: Hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, sodium croscarmellose, flavor and alginic acid were dispersed in purified water. Clarithromycin was added to the solution and the resulting suspension was stirred for 45 minutes.

Sucrose spheres were loaded in a fluid bed processor and the drug suspension was sprayed onto these spheres. Following the layering step, the spheres or granules were subjected to drying at a temperature between 45°C to about 55°C to remove the solvent. Coating I: Hydrogenated vegetable oil and polyethylene glycol 6000 were dissolved in methylene chloride and into which talc was then dispersed. This coating was then sprayed onto the drug-layered granules and these granules were dried to prevent agglomeration.

Coating II: Hydroxypropyl methyl cellulose phthalate and stearic acid were dissolved in a mixture of acetone and purified water. Coating II was sprayed onto the granules obtained after layering with Coating I.

The granules were finally dried at 40°C for 12 hours and were mixed with colloidal silicon dioxide

EXAMPLE 2 PREPARATION OF CLARITHROMYCIN COATED GRANULES :

Procedure:

Hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, sodium croscarmellose, flavor, alginic acid, clarithromycin and sucrose were mixed and granulated with purified water.

The granulated mass was passed through an extruder and the resulting extrudes were spheronized in a spheronizer.

Coating I: Hydrogenated vegetable oil and polyethylene glycol 6000 were dissolved in methylene chloride and talc was dispersed in it. This coating was then sprayed onto the drug layered granules and these granules were dried to prevent agglomeration.

The granules were finally dried at 40°C for 12 hours and were mixed with colloidal silicon dioxide.

Preparation of blend for suspension

Aspartame, citric acid, monosodium citrate, xanthan gum, sodium benzoate, sodium chloride, colloidal silicon dioxide, and flavors were sifted through a # 40 mesh screen and mixed for 20 minutes. Clarithromycin coated granules (obtained in Examples 1 and 2) and sucrose were sifted through a # 20 mesh screen and mixed with other ingredients for 30 minutes.

The dry blend for suspension was subjected to stability studies. The blend obtained in Example 1 was stored for 3 months at 40°C and 75% relative humidity. Samples were withdrawn at 0 and 3 month intervals, hi vitro dissolution of the dry blend was carried out in 900 ml of phosphate buffer (pH 6.8) at 50 rpm. The results of this dissolution are presented in Table 1.

Table 1. In vitro dissolution of the dry blend of Example 1 at 50 rpm/ 900 ml / phosphate (buffer pH 6.8)

The samples withdrawn were reconstituted in purified water to formulate a suspension. This was analyzed for drug content and pH at 0 and 14 days after reconstitution. These results are presented in Tables 2 and 3.

Table 2. Drug content of reconstituted clarithromycin suspension of Example 1

Table 3. pH of reconstituted clarithromycin suspension of Example 1

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, taste-masked granules can be similarly prepared for azithromycin, roxithromycin, fexofenadine, ranitidine, cefuroxime axetil, ibuprofen and other bitter tasting pharmaceutical active agents. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

Claims

We claim 1. A taste-masked pharmaceutical granule composition comprising: a. a core comprising one or more bitter tasting pharmaceutically active agents, one or more hydrocoUoid materials, and, optionally, one or more flavoring agents; b. a first coating layer comprising one or more hydrophobic materials and covering at least a portion of the core; and c. a second coating layer comprising one or more enteric film forming polymers and one or more waxy materials and covering at least a part of the first coating layer.

2. The composition according to claim 1 wherein the core comprises an inert substrate layered with the active agent, the hydrocoUoid material and the flavoring agent.

3. The composition according to claim 2 wherein the inert core is insoluble, soluble or commercially available.

4. The composition according to claim 3 wherein the insoluble inert core is selected from one or more of dicalcium phosphate, microcrystalline cellulose or combinations thereof.

5. The composition according to claim 3 wherein the soluble inert core is selected from one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose, and combinations thereof.

6. The composition according to claim 3 wherein the commercially available inert core is selected from one or more of sugar spheres, non-pareil seeds, celpheres and combinations thereof.

7. The composition according to claim 1 wherein the core comprises the phannaceutically active agent.

8. The composition according to claim 1 wherein the core is prepared by one or more of extrusion, extrusion-spheronization, wet granulation, and granulation in a fluidized air bed.

9. The composition according to claim 1 wherein the bitter tasting pharmaceutically active agent is selected from one or more of antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, central nervous system stimulants, antihistaminics, anti-asthmatics, anti-tussives, nutritional supplements and vegetable extracts.

10. The composition according to claim 9 wherein the bitter tasting pharmaceutically active agent comprises an antibiotic.

11. The composition according to claim 10 wherein the antibiotic comprises a macrolide antibiotic.

12. The composition according to claim 11 wherein the macrolide antibiotic comprises clarithromycin.

13. The composition according to claim 1 wherein the core comprises about 2.0% to about 70% of the active ingredient in relation to the total weight of the coated granules.

14. The composition according to claim 1 wherein the size of the core is between about 50 μm and about 500 μm.

15. The composition according to claim 1 wherein the flavoring agent comprises one or more of cherry, strawberry, peppermint, vanilla, chocolate, and spearmint.

16. The composition according to claim 1 wherein the hydrocoUoid material comprises one or more of gums, pectin, alginates, starch, cellulose and cellulose derivatives.

17. The composition according to claim 16 wherein the gums comprise one or more of xanthan gum, gum acacia, tragacanth gum, guar gum, and karaya gum.

18. The composition according to claim 16 wherein the cellulose derivatives comprise one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxy ethyl cellulose.

19. The composition according to claim 1 wherein the core further comprises one or both of binders and disintegrants.

20. The composition according to claim 19 wherein the binders comprise one or more of methylcellulose, hydroxypropyl methyl cellulose, gelatin, polyvinypyrrolidone, ethyl cellulose, tragacanth, and gum arabic.

21. The composition according to claim 19 wherein the disintegrant comprises one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, and low- substituted hydroxypropyl cellulose.

22. The composition according to claim 1 wherein the hydrophobic material comprises one or more of vegetable and animal oils, fatty acids, glyceryl esters of fatty acids, triglycerides, polyethylene glycols of various molecular weights and mixtures thereof.

23. The composition according to claim 22 wherein the first coating layer further comprises a lubricant.

24. The composition according to claim 23 wherein the lubricant comprises one or more of talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, and beeswax.

25. The composition according to claim 1 wherein the first coating layer comprises about 2% w/w to about 40% w/w of the total composition.

26. The composition according to claim 1 wherein the enteric film forming polymer comprise one or more of cellulose phthalates, poly (methyl) acrylates and acrylic acid polymers.

27. The composition according to claim 26 wherein the cellulose phthalate comprises one or more of hydroxypropyl methylcellulose phthalate and cellulose acetate phthalate.

28. The composition according to claim 1 wherein the waxy material comprises one or more of fatty acids, glyceryl esters of fatty acids, and polyethylene glycols.

29. The composition according to claim 1 wherein either or both of the first coating layer and the second coating layer further comprises one or more additional pharmaceutically inert excipients.

30. The composition according to claim 29 wherein the pharmaceutically inert excipients comprise one or both of plasticizers and lubricants.

31. The composition according to claim 30 wherein the plasticizers comprise one or more of propylene glycol, triethylene glycol, oleic acid, ethylene glycol monooleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebaccate, and acetyl triethyl citrate.

32. The composition according to claim 1 wherein the coating is applied to the core using any conventional coating technique.

33. The composition according to claim 1 wherein either or both of the first coating layer and the second coating layer are applied to the core using one or more of spray coating in a coating pan, spray coating in a fluid bed processor, and dip coating.

34. The composition according to claim 1 wherein either or both of the first coating layer and the second coating layer are applied to the core as a solution or suspension in a solvent.

35. The composition according to claim 34 wherein the solvent comprises one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof.

36. A process for preparing a taste-masked pharmaceutical granule composition, the process comprising: a. preparing a suspension/solution of one or more pharmaceutically active agents, one or more hydrocoUoid materials, and, optionally, one or more flavoring agents in a solvent; b. layering the suspension/solution over inert cores and drying; c. applying a first coating layer over at least a portion of the cores and drying, the first coating layer comprising a hydrophobic materials; d. forming coated granules by applying a second coating layer over at least a portion of the first coating layer, the second coating layer comprising one or more enteric polymers and one or more waxy materials; and e. drying the coated granules.

37. The process of claim 36, wherein the solution/suspension further comprises one or more binders and disintegrants.

38. The process according to claim 36 wherein the bitter tasting pharmaceutically active agent is selected from one or more of antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, central nervous system stimulants, antihistaminics, anti- asthmatics, anti-tussives, nutritional supplements and vegetable extracts.

39. The composition according to claim 38 wherein the antibiotic comprises clarithromycin.

40. The process according to claim 36 wherein the flavoring agent comprises one or more of cherry, strawberry, peppermint, vanilla, chocolate, and spearmint.

41. The process according to claim 36 wherein the hydrocoUoid material comprises one or more of gums, pectin, alginates, starch, cellulose and cellulose derivatives.

42. The process according to claim 36 wherein the hydrophobic material comprises one or more of vegetable and animal oils, fatty acids, glyceryl esters of fatty acids, triglycerides, polyethylene glycols of various molecular weights and mixtures thereof.

43. The process according to claim 36 wherein the first coating layer further comprises one or more lubricants.

44. The process according to claim 43 wherein the lubricant comprises one or more of talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, and beeswax.

45. The process according to claim 36 wherein the first coating layer comprises about 2% w/w to about 40% w/w of the total composition.

46. The process according to claim 36 wherein the enteric film forming polymer comprise one or more of cellulose phthalates, poly (methyl) acrylates and acrylic acid polymers.

47. The process according to claim 36 wherein the waxy material comprises one or more of fatty acids, glyceryl esters of fatty acids, and polyethylene glycols.

48. The process according to claim 36 wherein either or both of the first coating layer and the second coating layer further comprises one or more additional pharmaceutically inert excipients.

49. The process according to claim 36 wherein applying either or both of the first coating layer and the second coating layer comprises using one or more of spray coating in a coating pan, spray coating in a fluid bed processor, and dip coating.

50. The process according to claim 36 wherein either or both of the first coating layer and the second coating layer are applied to the core as a solution or suspension in a solvent.

51. The process according to claim 36 further comprising using the taste-masked granules to prepare one or more of dry syrups, sachets, tablets and powders that can be reconstituted before usage.

52. The process according to claim 51 wherein the reconstituted suspension is stable for at least 14 days.

53. The process according to claim 51 wherein the reconstitutable dry formulation further comprises one or more pharmaceutically acceptable excipients.

54. The process according to claim 53 wherein the pharmaceutically acceptable excipients comprise one or more of sweeteners, coloring agents, thickening agents, pH modulators, preservatives, opacifiers and flavoring agents.

55. The process according to claim 54 wherein the sweeteners comprise one or more of aspartame, saccharose, acesulfame, sodium glycyrrhizinate and mixtures thereof.

56. The process according to claim 54 wherein the opacifiers comprise titanium oxide and opadry.

57. A process for preparing a taste-masked phannaceutical granule composition, the process comprising: a. granulating one or more bitter tasting pharmaceutically active agents, one or more hydrocoUoid materials, and one or more flavoring agents to form granules; b. applying a first coating layer to at least a portion of the granules and drying, the first coating layer comprising one or more hydrophobic materials, c. forming coated granules by applying a second coating layer over at least a portion of the first coating layer, the second coating comprising one or more enteric polymers and one or more waxy materials; and d. drying the coated granules.

58. The process of claim 57 wherein the solution/suspension further comprises one or more binders and disintegrants.

59. The process according to claim 57 wherein the bitter tasting pharmaceutically active agent is selected from one or more of antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, central nervous system stimulants, antihistaminics, anti- asthmatics, anti-tussives, nutritional supplements and vegetable extracts.

60. The composition according to claim 57 wherein the antibiotic comprises clarithromycin.

61. The process according to claim 57 wherein the flavoring agent comprises one or more of cherry, strawberry, peppermint, vanilla, chocolate, and spearmint.

62. The process according to claim 57 wherein the hydrocoUoid material comprises one or more of gums, pectin, alginates, starch, cellulose and cellulose derivatives.

63. The process according to claim 57 wherein the hydrophobic material comprises one or more of vegetable and animal oils, fatty acids, glyceryl esters of fatty acids, triglycerides, polyethylene glycols of various molecular weights and mixtures thereof.

64. The process according to claim 57 wherein the first coating layer further comprises one or more lubricants.

65. The process according to claim 64 wherein the lubricant comprises one or more of talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, and beeswax.

66. The process according to claim 57 wherein the first coating layer comprises about 2% w/w to about 40% w/w of the total composition.

67. The process according to claim 57 wherein the enteric film forming polymer comprise one or more of cellulose phthalates, poly (methyl) acrylates and acrylic acid polymers.

68. The process according to claim 57 wherein the waxy material comprises one or more of fatty acids, glyceryl esters of fatty acids, and polyethylene glycols.

69. The process according to claim 57 wherein either or both of the first coating layer and the second coating layer further comprises one or more additional phanriaceutically inert excipients.

70. The process according to claim 57 wherein applying either or both of the first coating layer and the second coating layer comprises using one or more of spray coating in a coating pan, spray coating in a fluid bed processor, and dip coating.

71. The process according to claim 57 wherein either or both of the first coating layer and the second coating layer are applied to the core as a solution or suspension in a solvent.

72. The process according to claim 57 further comprising using the taste-masked granules to prepare one or more of dry syrups, sachets, tablets and powders that can be reconstituted before usage.

73. The process according to claim 72 wherein the reconstituted suspension is stable for at least 14 days.

74. The process according to claim 72 wherein the reconstitutable dry formulation further comprises one or more pharmaceutically acceptable excipients.

75. The process according to claim 74 wherein the pharmaceutically acceptable excipients comprise one or more of sweeteners, coloring agents, thickening agents, pH modulators, preservatives, opacifiers and flavoring agents.

76. A method for the treatment in a patient in need thereof, the method comprising administering a taste-masked pharmaceutical granule composition to the patient, the composition comprising: a. a core comprising one or more bitter tasting pharmaceutically active agents, one or more hydrocoUoid materials, and, optionally, one or more flavoring agents; b. a first coating layer over at least a portion of the core, the first coating layer comprising one or more hydrophobic materials; and c. a second coating layer over at least a portion of the first coating layer, the second coating layer comprising one or more enteric film forming polymers and one or more waxy materials.

77. The method according to claim 76 wherein the bitter tasting pharmaceutically active agent is selected from one or more of antacids, anti-infectives, antibiotics, anxiolytics, neuroleptics, psychotropics, central nervous system stimulants, antihistaminics, anti- asthmatics, anti-tussives, nutritional supplements and vegetable extracts.

78. The method according to claim 77 wherein the antibiotic comprises clarithromycin.