The present invention discloses coating compositions with taste masking property, comprising a blend of pH sensitive polymers and optionally a pH independent polymer or a blend of the pH sensitive polymer and pH independent polymer used for taste masking of highly bitter drugs. The pH sensitive polymers used comprise the acid soluble polymers and the enteric polymers. The process for the preparation of taste masked pharmaceutical compositions of the bitter drugs comprising the said coating compositions is disclosed. The concomitant use of the polymers inhibits the release of the bitter drug at the pH of saliva. The said coating compositions deliver substantial amount of the bitter drug immediately with improved palatability.

SUMMARY OF THE INVENTION

Accordingly the present invention relates to a coating composition for the taste masking of pharmaceutical compositions containing a bitter drug, wherein the said coating composition comprises an acid soluble or swellable polymer in combination with one or more enteric coating polymers as pH dependent polymer and/or pH independent polymers: wherein said acid soluble or swellable polymer has a formula: P[A.sub.(x)B.sub.(y)C.sub.(z)] wherein P is polymer comprising (A) a hydrophobic monomer, (B) a basic monomer and (C) a hydrophilic monomer where, (x)=30-95%,(y)=5-70%,(z)=0-60%, all expressed in terms of w/w such that x+y+z=100%.

The acid soluble or swellable polymer in coating composition comprises of methyl methacrylate, hydroxy ethyl methacrylate and vinyl pyridine in the range of 50-75%, 15-35% and 5-15% w/w respectively.

In one of the embodiments of the present invention the coating composition comprises essentially of polymeric blends wherein one of the polymer is acid soluble or swellable polymer.

In another embodiment the coating composition used for the taste masking comprises the blend of acid soluble or swellable polymer and the enteric polymer.

In yet other embodiment of the present invention the coating composition used for the taste masking comprises the blend of acid soluble or swellable polymer, enteric and pH independent polymer.

In yet another embodiment of the present invention the coating composition used for the taste masking comprises the blend of acid soluble or swellable polymer and pH independent polymers.

The embodiment of the present invention which comprises essentially acid soluble or swellable polymer in coating composition wherein the monomer composition of the said polymer is methyl methacrylate, hydroxy ethyl methacrylate and vinyl pyridine in the range 50-75%, 15-35% and 5-15% w/w respectively.

In yet another embodiment of the invention, the coating composition comprises blend of pH dependent polymer, wherein the other polymer is selected from the group consisting of enteric polymers like the cellulosic esters viz cellulose acetate phthalate, hydroxymethyl cellulose phthalate, cellulose trimellitate, hydroxymethyl cellulose acetate succinate, resins like shellac and polymethacrylates viz copolymers of methylmethacrylate-methacrylic acid and, methacrylic acid-ethyl acrylate. The pH independent polymers are cellulosic ethers such as ethyl cellulose, methyl cellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, carboxy methyl cellulose, and proteins like prolamine, zein.

In the embodiment of the present invention the coating composition used in taste masked composition has a ratio of the acid soluble or swellable polymer to enteric polymer, in the range 1:0.1 to 1:5.

Further in the embodiment of the present invention the coating composition used in taste masked composition has a ratio of pH dependent polymer to pH independent polymer, in the range 1:0.05 to 1:5.

In yet another embodiment of the present invention a pharmaceutical composition comprising a coating composition and macrolide antibiotic drug is selected from the group consisting of erythromycin, azithromycin and clarithromycin, fluroquinolones selected from the group consisting of ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin and norfloxacin, cephalosporins selected from the group consisting of cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal, and anti-inflammatory and analgesic drugs selected from the group consisting of ibuprofen and diclofenac sodium; and COX 2 inhibitors selected from the group consisting of etoricoxib and celecoxib; antibistamic drugs selected from the group consisting of chlorpheniramine maleate, oxazolidinones selected from the group consisting of linezolid and other drug like dextromethorphan.

In the embodiment of the present invention the coating composition used in taste masked composition has the ratio of acid soluble or swellable polymer to pH independent polymer as 1:0.1 to 1:5.

In another embodiment of the present invention the pharmaceutical composition comprises a drug or its pharmaceutically acceptable salt or ester or amide and the polymer coating composition wherein the drug is a macrolide antibiotic selected from the group consisting of erythromycin, azithromycin and clarithromycin, fluroquinolones selected from the group consisting of ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin and norfloxacin, cephalosporins selected from the group consisting of cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal, and anti-inflammatory and analgesic drugs selected from the group consisting of ibuprofen and diclofenac sodium and COX 2 inhibitors selected from the group consisting of etoricoxib and celecoxib, antihistamic drugs selected from the group consisting of chlorpheniramine maleate, oxazolidinones selected from the group consisting of linezolid and other drug like dextromethorphan.

In yet other embodiment of the present invention the total polymer to drug ratio in the pharmaceutical composition is in the range 0.1:1 to 4:1 by weight.

In another embodiment of the invention the composition comprises drug in the form of the microparticles, either dispersed within polymer matrix or coated by the polymer.

The pharmaceutical composition as disclosed comprises the microparticles, which can be formulated in a pharmaceutically acceptable dosage form. The pharmaceutical composition does not release drug at pH of saliva from the oral dosage form but rapidly releases substantial amount of the drug immediately at pH.ltoreq.3 found in the stomach. The pharmaceutical composition can be formulated as liquid orals comprising dry syrup and suspension or as solid dosage form like chewable, effervescent, rapidly disintegrating or dispersible tablets.

Accordingly the pharmaceutical composition is obtained by dispersion or coating of the bitter drug in the matrix of coating composition of polymers by any of the known techniques like microencapsulation, spray drying, fluid bed processing, co precipitation in a non solvent or by tray drying method. The taste masked composition in particulate form as of the present invention comprising the blend of acid soluble or swellable polymer and the enteric polymer can be suspended using the reconstitution medium of pH 3.5 to 5.

The taste masked coated composition in the particulate form comprising the blend of acid soluble or swellable polymer, enteric and pH independent polymer can be suspended using the reconstitution medium of pH 3.5 to 5.

The taste masked coated composition in particulate form comprises of the blend of acid soluble or swellable polymer and pH independent polymer and can be suspended in reconstitution medium of pH>3.5. The pharmaceutical composition comprises the drug itself or its pharmaceutically acceptable salt or an ester or an amide.

Accordingly, in the present invention the process for preparation of drug microparticles is by microencapsulation using an emulsification solvent evaporation method comprising dissolving the polymer constituting the polymer blend in an organic solvent selected from acetone, methanol, dichloromethane and a mixture of methanol and dichloromethane in the ratio 1:1 to 1:1.5, or a mixture of acetone and methanol in the ratio 1:1 or a mixture of acetone methanol and dichloromethane in the ratio 1:1:0.1, adding the drug to the polymer solution to obtain a solution or a dispersion, adding this organic phase to light liquid paraffin-containing span 85 in an amount of 0.1 to 1% w/w, continuously stirring the mixture mechanically at a rate of about 500-1000 rpm and at a temperature of about 25.degree. C. for a period of about 3-5 hrs and then separating the microparticles by filtration and washing the separated microparticles with petroleum ether or n hexane and drying at a temperature of about 27.degree. C. under vacuum for up to 24 hours.

Accordingly the coating compositions of the present invention provide the taste masked pharmaceutical compositions which do not release the drug in the saliva and which release the drug without any delay at the pH of stomach and the coating compositions are not soluble in water. Further the increase in the polymeric coating does not alter the release and provides better protection in the reconstitution medium.

DETAILED DESCRIPTION OF THE INVENTION

Mostly medicaments are administered via the oral route for the ease and convenience of the patients. The disadvantage of this is that in certain dosage forms where the drug is extremely bitter, it causes discomfort and the compliance of the patients is adversely affected. This effect is profound in the case of the pediatric and geriatric patients and where the drugs are formulated as the liquid orals or other preparations like the rapidly disintegrating, dispersible or chewable tablets for ease of swallowing. The taste masking techniques are hence applied extensively to improve the palatability of the dosage forms.

The present invention provides oral pharmaceutical compositions, which effectively mask the bitter, unpleasant and otherwise undesirable taste of the active ingredient. More specifically the invention relates to the use of the coating compositions, which mask the bitter taste of the drugs and also release a substantial amount of drug upon administration without delay.

Taste masked compositions making use of the synthetic acid soluble polymers and their applications in various pharmaceutical compositions providing substantial immediate release without causing any delay in the absorption of the active ingredient are disclosed in patent applications PCT/IN03/00390 and PCT/IN03/00392. The use of these polymers is effective in taste masking of the drugs to be used in the oral dosage forms like the liquid orals and the solid dosage forms like the chewable, dispersible, rapidly disintegrating tablets. The advantage of these polymers is that they are insoluble at the near neutral pH and are soluble at the acidic pH so that the release of the drug in the stomach is not affected. Further the polymers disclosed in these applications showed no negative interaction with the drugs as shown by the use of Eudragit E in presence of the drug Cefuroxime axetil. The polymer compositions disclosed in these applications are very useful for the taste masking of bitter drugs since they release the drug in gastric pH without any delay and prevent the leaching at the pH of saliva. The polymer compositions disclosed in these applications are very useful for taste masking of the solid dosage forms like the conventional film coated tablets, the rapidly disintegrating tablets and the chewable tablets and the dispersible tablets where the amount of the polymer required is comparatively less.

Depending on the type of dosage form the amount of the polymer required for imparting palatability will vary. Further the dose of the active ingredient will also affect the performance of the polymer coating. In some cases where the dose is higher, the amount of polymer required to provide effective coating may be more. The liquid dosage forms like dry syrup and suspensions require a more uniform and complete polymer coat to impart taste masking effect and the polymer requirement is higher as compared to the conventional solid dosage forms. In the case of the liquid dosage forms, the polymer has to provide taste masking effect by preventing leaching of the drug from the formulation during the reconstitution period. However in certain drugs, which are extremely bitter and may remain palatable for a short period but may release some of the drug later, in such a case higher loading of the polymer is required to provide the desired taste masking effect. Further during swallowing, if any particles are retained in mouth, then the polymer coating should prevent the leaching of the drug from the coated particles and also if these particles get chewed, the polymer coating should prevent the bitter taste in the mouth. Such situations are commonly found in the pediatric patients. So the amount of the polymeric coating has to be higher to impart the desired palatable characteristic.

The maximum permissible amount of a polymer in a formulation is decided on the basis of the safety and maximum potency of the polymer. This restricts the total amount of the polymer to be used in a formulation. The present invention discloses the use of the blends of the polymeric coatings such that the blend masks bitter taste of the drug and when used concomitantly the amount of the individual polymer component falls within the safe acceptable limits. The polymer blends used are such that the taste masking effect is not compromised and the amount of the polymer blend is sufficient to provide better barrier to leaching of the drug in the liquid oral preparation. Further these compositions can be used in the solid dosage forms. The advantage of using the polymer blends comprising the acid soluble or swellable polymer in conjunction with the other pH dependent polymers and the pH independent polymers is that the acid soluble polymer dissolves or swells in the acidic environment of the stomach and causes the release of the drug without delay.

The coating compositions disclosed in the patent applications PCT/IN03/00390 and PCT/IN03/00392 are very useful for the drugs which have better absorption from the stomach. However the drugs, which are absorbed all along the gastrointestinal tract, need polymeric coatings, which will release the drug even in the intestinal region. So there is a need to develop the coating compositions, which release the drug in stomach and other parts of the gastrointestinal tract. The use of the enteric polymers, delays the release till the dosage form reaches the intestine. However the coating compositions disclosed in the present invention overcome the limitation by releasing the substantial amount of drug in the gastric region and the remaining drug in the intestinal region. Further the commercially available reverse enteric polymer Eudragit E cannot be used in combination with the other enteric polymers like hydroxy propyl methylcellulose phthalate and Eudragit L as there is precipitation of polymers in presence of the organic solvents. The coating compositions containing the acid soluble or swellable polymer as disclosed in the present invention do not precipitate in presence of Eudragit L, hydroxy propyl methyl cellulose phthalate and cellulose acetate phthalate.

This type of coating composition as disclosed in the present application has advantage over the other earlier methods disclosed in prior art employing the blends of the enteric polymers or the blends of the enteric polymer and the pH independent polymers like the cellulose ethers which retards the release of the drug in the stomach. Further the coating compositions of the present invention can be used for a variety dosage forms.

One of the advantages of the coating composition used, as disclosed in the present application is that the coating composition essentially incorporates the synthetic acid soluble polymer such that it dissolves or swells thereby releasing the drug in the stomach and thus there is no delay in the drug release. The acid soluble or swellable polymer as disclosed in the application PCT/IN03/00390 and PCT/IN03/00392 has a formula P[A.sub.(x)B.sub.(y)C.sub.(z)] wherein P is the acid soluble or swellable polymer comprising (A) a hydrophobic monomer, (B) a basic monomer and (C) a hydrophilic monomer and (x)=30-95%, (y)=5-70%, (z)=0-60%, all expressed in terms of w/w such that x+y+z=100%. The acid soluble pH sensitive polymer comprises of essentially a hydrophobic monomer, a basic monomer and optionally a hydrophilic monomer.

The acid soluble or swellable polymer used in coating composition comprises of methyl methacrylate, hydroxy ethyl methacrylate and vinyl pyridine in the range of 50-75%, 15-35% and 5-15% w/w respectively.

The coating composition as disclosed in the present application comprises essentially of the acid soluble polymer as one of the polymers in the polymeric blends.

The coating composition used for the taste masking application as disclosed in the present invention comprises of the blend of acid soluble or swellable polymer and the enteric polymer or a blend of acid soluble or swellable polymer, enteric and optionally pH independent polymers or a blend of acid soluble or swellable polymer and pH independent polymers.

The pH dependent polymers in coating composition wherein the other polymer is selected from the group consisting of enteric polymers like the cellulosic esters like cellulose acetate phthalate, hydroxymethyl cellulose phthalate, cellulose trimellitate, hydroxymethyl cellulose acetate succinate, resins like shellac and polymethacrylates like copolymers of the methylmethacrylate--methacrylic acid and, methacrylic acid-ethyl acrylate preferably enteric polymers like the cellulosic esters viz cellulose acetate phthalate, hydroxymethyl cellulose phthalate reisns like shellac and polymethacrylates like copolymers of the methylmethacrylate--methacrylic acid.

The pH independent polymer in coating composition comprises cellulosic ethers like ethyl cellulose, methylcellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methylcellulose, carboxy methylcellulose, and proteins like prolamine, zein preferably cellulosic ethers like ethyl cellulose and proteins like prolamine and zein.

The present invention also provides for the taste masking of bitter drugs like macrolide antibiotics such as erythromycin, azithromycin and clarithromycin, fluroquinolones such as ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin and norfloxacin, cephalosporins such as cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal and anti-inflammatory and analgesic drugs such as ibuprofen, diclofenac sodium and COX 2 inhibitors like etoricoxib and celecoxib, antihistamic drugs like chlorpheniramine maleate, oxazolidinones like linezolid and other drug like dextromethorphan.

The drug itself or its pharmaceutically acceptable salt or ester or amide may be used in the present invention. The drugs preferred for the practice of present invention can be chosen from a wide range comprising cefuroxime axetil, ciprofloxacin, celecoxib and clarithromycin. As a representative bitter drug the cephalosporin antibiotic cefuroxime axetil is chosen but the invention is not restricted to the drug only it can be used in relation to a wide range of the drugs which require to be taste masked.

The pharmaceutical composition described herein has the total polymer to drug ratio for optimal taste masking bitter drug in the range 0.1:1 to 4:1 by weight. More preferably the ratio of the total polymer to drug is 0.5:1 to 3:1 by weight. The coating composition used for the taste masking has a ratio of the acid soluble or swellable polymer to enteric polymer in the range of 1:0.1 to 1:5.

The coating composition used for the taste masking has a ratio of pH dependent polymer to pH independent polymer is in the range of 1:0.05 to 1:5.

The coating composition used for the taste masking has a ratio of the acid soluble or swellable polymer to pH independent polymer in the range of 1:0.1 to 1:5.

The invention comprises development of a taste masked formulation using the blend of various polymers in varying proportions, the said composition is in the form of microparticles wherein the drug is dispersed in the polymer matrix or coated by the polymer coating. The coatings are capable of masking the bitterness and maintain the palatability of the pharmaceutical composition while still providing immediate release and bioavailability upon exposure to the pH levels found in the stomach of a human.

The taste-masked particles obtained as described in the invention can be optionally blended with other pharmaceutically acceptable excipients such as flavors, sweeteners, suspending agents and or preservatives and formulated as dry syrup or compressed into fast disintegrating, effervescent or chewable tablets.

The mean particle size of the microcapsules will be in the range of about 30 to 1000 microns, most preferably in the range of up to 500 microns.

In another feature of the present invention the pharmaceutical composition may be obtained by coating the drug using pH sensitive polymer either by microencapsulation, spray drying, fluid bed processing, co-precipitation in a non solvent or by tray drying method.

In still another feature the taste masking compositions are made by microencapsulation of the drug in the polymer matrix. The microencapsulation of the bitter drugs can be obtained by emulsification, solvent evaporation or solvent traction and spray drying of the drug polymer solution or dispersion of drug in polymer solution. If the drug is not soluble in the polymer solution then it is dispersed in the polymer solution uniformly with the help of the dispersing agents like the surfactants. The preferred surfactants are the nonionic surfactants belonging to the class of SPAN and TWEEN. Preferably the solvent is selected such that the drug and the polymer are both soluble in the solvent. In another feature of the present invention the solvents chosen for the solubilization of the drug and polymer are alcohols like methanol, ethanol, isopropanol, butanol, chlorinated hydrocarbons like dichloromethane, chloroform, ketones like methyl ethyl ketone, methyl iso-butyl ketone and acetone. Preferably the solvents used to dissolve the drug and polymers are methanol, acetone and dichloromethane and a mixture of methanol and dichloromethane in the ratio 1:1 to 1:1.5, or a mixture of acetone and methanol in the ratio 1:1 or a mixture of acetone methanol and dichloromethane in the ratio 1:1:0.1

The taste-masked microcapsules of the bitter drug can be obtained by microencapsulation by emulsification solvent evaporation technique. The dispersed phase is the organic solvent containing the drug and polymer and the dispersion medium is the liquid paraffin. The polymer blend is dissolved in the organic solvent. The drug is added to the polymeric solutions resulting in a solution or a dispersion. The organic phase is then added into light liquid paraffin-containing span 85 (0.1 to 1% w/w). A constant mechanical stirring rate of 1000 rpm and at room temperature is maintained for 3-4 hours. The solvent is allowed to evaporate and the microspheres so obtained are separated by filtration, washed by petroleum ether or by n hexane and dried under vacuum for up to 24 hours.

Alternately the taste masked micro particles can be obtained by spray drying or fluid bed coating of the drug particles. The taste masked particles and granules obtained may be mixed with the flavoring agents such as natural or artificial flavors, citric and tartaric acids, sweeteners such as sucrose, saccharin and aspartame, and other pharmaceutically acceptable excipients to be formulated as conventional, chewable or dispersible tablets, dry syrups, suspensions, sachets or any other suitable oral dosage form.

The present invention is more directed towards the taste masking of the liquid oral compositions suitable for the pediatric patients or those, who have a difficulty in swallowing the solid dosage form. The taste masked pharmaceutical composition can be prepared by reconstitution of the polymer coated drug particles in a suitable liquid vehicle as described below.

A taste masked composition in particulate form wherein the coating composition comprises of the blend of acid soluble or swellable polymer and the enteric polymer can be suspended using the reconstitution medium of pH 3.5 to 5.

A taste masked composition in particulate form wherein the coating composition comprises of the blend of acid soluble or swellable polymer, enteric and pH independent polymer can be suspended using the reconstitution medium of pH 3.5 to 5.

A taste masked composition in particulate form wherein the coating composition comprises of the blend of acid soluble or swellable polymer and pH independent polymer can be suspended using the reconstitution medium of pH>3.5.
 

Claim 1 of 31 Claims

1. A coating composition for the taste masking of pharmaceutical compositions containing a bitter drug, wherein said coating composition comprises an acid soluble polymer in combination with one or more enteric coating polymers as pH dependent polymer and/or pH independent polymers: wherein said acid soluble polymer has a formula: P[A.sub.(x)B.sub.(y)C.sub.(z)] wherein P is polymer comprising (A) a hydrophobic monomer, (B) a basic monomer and (C) a hydrophilic monomer and (x)=30-95%, (y)=5-70%, (z)=10-60%, all expressed in terms of w/w such that x+y+z =100%.
 

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