JP2007518670A - Flavor masked pharmaceutical composition comprising a bitter drug and a pH sensitive polymer - Google Patents

Abstract

  The present invention discloses a pharmaceutical composition comprising a pH sensitive polymer used for flavor masking of very bitter drugs. The pH sensitive polymer acts as a reverse enteric coating and dissolves within the acidic pH range of 1.0 to 3.0 normally found in the stomach, but is insoluble within the pH range of 3.5 to 7. Therefore, the release of the bitter drug is inhibited at the pH of the saliva and, in the case of liquid oral drugs, at the pH in the reconstitution medium.

Description

FIELD OF THE INVENTION The present invention relates to a flavor masked composition comprising a bitter drug and a pH sensitive polymer, and a method for making the same. The invention also relates to a process for producing a flavor masked pharmaceutical composition comprising a bitter drug and a pH sensitive polymer.

Background of the invention

  Although various delivery systems have been developed for different routes of administration, such as oral, parenteral, nasal and transdermal, the oral route remains of interest as drug delivery. The dosage form is easy, convenient, non-invasive, and is a well-known drug delivery method. Most of the prescription drugs are designed for oral application because they can be self-administered by the patient without hospitalization. Oral dosage forms are designed according to the nature of the drug, the type of use, and the need for any special effects. Common oral dosage forms include liquid mixtures such as solutions, solid dosage forms such as suspensions, tablets and capsules, and capsules with liquids. The solid dosage form is further improved depending on the desired therapeutic effect, eg, controlled, sustained or delayed release. However, extreme age patients, such as children and the elderly, often have difficulty swallowing solid oral dosage forms. For these patients, the drug is mostly in liquid dosage form, eg, in solutions, emulsions and suspensions. These dosage forms usually lead to considerable exposure of the active ingredient to taste buds, which is a very serious problem when the drug has an extremely unpleasant or bitter taste.

  The bitter taste of such drugs administered orally is inconvenient in some situations. Flavor is an important factor governing acceptance. The unpleasant flavor of the drug can cause difficulty in swallowing or cause the patient to avoid their medication, thus resulting in poor patient compliance. Conventional flavor masking techniques, such as the use of sweeteners, amino acids, flavoring agents, are often insufficient in flavor masking of very bitter drugs, where such very bitter drugs include, for example, quinine, Antibiotics such as barberin, celecoxib, etlicoxib, levofloxacin, such as ofloxacin, sparfloxacin, ciprofloxacin, cefuroxime axetil, erythromycin, and clarosromycin. As such, flavor masking techniques are considered important and have been developed by many researchers.

  The taste masking is mainly a problem when the drug is extremely unpleasant and bitter, which not only limits liquid oral compositions such as solutions, dry syrups and suspensions, but usually Difficulties are encountered between chewable or dispersible tablet dosage forms that lead to significant exposure of the active ingredient to miso. Depending on the type of dosage form, various methods are used to overcome the objectionable and bitter taste of the drug.

  International Patent Publication No. WO 03/13470 discloses the use of ammonium glycyridinate to taste mask a formulation comprising paroxetine formulated as a dispersed powder or formed as a dispersible or chewable tablet, and a dry mixture of glycyridinate. To do. International Patent Publication No. WO 03/11227 is a flavor masked composition for the delivery of ibuprofen, which causes throat snagging in the form of a chewable ibuprofen tablet with the polymer carbomer 934. Is disclosed. European Patent No. EP1219291 is an active ingredient acetaminophen chewable tablet, and texture masked particles, a flavor masking polymer, ethylcellulose, and a film-forming polymer, and hydroxypropyl methylcellulose, And polyethylene glycol 800, and those coated with acesulfame-K texture masking coating solution.

  In other Japanese Patent Application Publication No. 20022363066, the flavor masked pharmaceutical or food composition is disclosed to be suitable for formulation as a granule, tablet or chewable tablet. The flavor masked granules can be obtained by using a polymer such as ethyl cellulose or hydroxypropyl cellulose. European Patent No. EP 1166777 discloses yet another chewable tablet formed from flavor masked particles. The active ingredient ibuprofen is coated with the enteric polymer HPMCP and the insoluble film agent cellulose acetate, and a chewable tablet that does not irritate the throat is treated with aspartame, acesulfame K, Prepared from the coated particles by mixing with acid, granular mannitol, fumaric acid, microcrystalline cellulose, and perfume.

  Flavor masking technology extends to dispersible dosage forms and rapidly disintegrating tablets. International Patent Publication No. WO 01/58449 discloses a flavor masking agent comprising the wettable powder and tablet of paroxetine for immediate release of the drug and a methacrylic acid copolymer. The flavor masked composition was obtained by spray drying paroxetine and the polymer.

  International Patent Publication No. WO 02/64119 discloses an instant disintegrating tablet that provides a masking of bad taste in the oral cavity and quick absorption of the active ingredient from the tablet in the digestive tract. The disclosure is limited to drugs that are poorly soluble in water under neutral or alkaline conditions, but are highly soluble in water and give an unpleasant flavor under acidic conditions. The physicochemical properties of different drug molecules are different and so many systems would not be suitable for the drug being water soluble. International Patent Publication No. WO 01/52848 is a flavor masked oral formulation of linezolid, by microencapsulating antibiotics by solvent coacervation of ethylcellulose with an optional seal coat of shrack and functional Disclosed are such formulations that can be formulated as suspensions, fast disintegrating, foaming or chewable tablets by further coating the particles with the polymer Eudragit L30D. The formulated microcapsules are suspended in an aqueous medium prior to oral administration to pediatric and elderly patients who have been found to be unwilling and / or difficult to swallow tablets. Alternatively, fast disintegrating tablets can be formulated to rapidly disperse into flavor masked granules in the mouth.

  Various methods of flavor masking have been tried earlier and include the use of ion exchange resins, complex of bitter drugs with pharmaceutically acceptable excipients, and coating of drugs with lipids and various polymeric materials. . Of these, coating is the most widely used technique for flavor masking. The coating of the active ingredient can be carried out by any technique known in the art, for example microencapsulation, hot melt granulation, fluidized bed coating, spray drying.

  One approach as flavor masking is the use of ion exchange resins. Various anions such as Duolite AP143 / 1083® (Cholestyramine resin USP), cations such as Amberlite IRP 64® (a copolymer of methacrylic acid crosslinked with divinyl benzene) Resin and Dowex (based on polystyrene sulfonic acid cross-linked with divinyl benzene) are used. US Pat. No. 6,514,492 discloses an ion exchange resin for flavor masking of quinolone derivatives, AMBERLITE. RTM. Disclose the use of IRP 69®, resulting in the removal of the extreme bitter taste of quinolone in oral liquid dosage forms.

  International Patent Publication No. WO 01/70194 discloses fast-dissolving oral consumption films that are adapted to adhere and dissolve in the consumer's mouth. The film is composed of a bitter drug, an ion exchange resin / amberlite as a dextromethorphan flavor masking agent, and a water-soluble polymer pullulan. The film adheres to the oral cavity and dissolves to deliver the active ingredient. The use of the water soluble polymer in the formulation will limit the use of such a delivery system if the flavor masking is desired for a liquid oral formulation. Moreover, such delivery systems would probably not be acceptable for child and elderly formulations where patient consent is important.

  US Pat. No. 6,001,392 discloses a controlled release syrup suspension for oral administration containing dextromethorphan that is absorbed upon contact with a polystyrene sulfonate ion exchange resin. The drug polymer composite is coated with a mixture of ethyl cellulose with a plasticizer or ethyl cellulose latex and a water dispersible polymer such as SURELEASE®. As a drug that requires immediate release for immediate action, controlled release of the active ingredient is not preferred, and delays in release may also be a concern for drugs with limited absorption regions .

  The use of ion exchange resins to absorb drugs containing amino groups for flavor masking has found limited applicability in masking the flavor of very bitter drugs and where the drug is , Dispersed in a liquid oral composition.

  Complexes are yet another method of flavor masking for bitter drugs. US Pat. No. 4,808,411 discloses a flavor masked composition comprising 75-95% erythromycin and 5-75% carbomer, where the drug and carbomer are They are joined together by ionic interactions between erythromycin and carbomers. The complex is further coated with a functional polymer, hydroxy propyl methyl cellulose phthalate, to make the formulation tasty. Erythromycin is slowly released from the complex to avoid significant perception of mouth bitterness. It is clear that the premature release of the bitter drug and the sustained release is critical as disclosed in the present invention. However, compounding alone is not enough to mask the flavor. The proper selection of the complexing agent is important because coating with a functional polymer is necessary to obtain the desired taste, and drug release should not be compromised.

  Drug coating is another method, but only for moderate bitter drugs or when the coated particles are formulated as a liquid formulation prior to administration or in a non-aqueous solvent. You may find that it is only effective for the product.

  International Patent Publication No. WO 02/092106 discloses a flavor masked composition comprising polycarbophil and a macrolide antibiotic, clarithromycin. The complex is further coated with an acid resistant polymer, Eudragit L100 55®, releasing the drug into the intestine. For some drugs, the bioavailability will not be altered by the use of enteric coatings when the drug is released into the small intestine, but it has a narrow absorption region that is limited to the upper gastric region. The use of enteric coatings of drugs with can change the bioavailability. European Patent Publication No. EP 0409254 discloses an oral particulate formulation having an unpleasant taste masked using ethyl cellulose, and an aqueous swelling agent when the active ingredient is rapidly released from the formulation.

  US Pat. No. 5,635,200 discloses drugs that are bitter by lipid coating, flavor masked formulations of ranitidine, and dispersion of these coated particles in a non-aqueous solvent. US Patent Application Publication No. 2003-028025 discloses a flavor masked composition of gatifloxacin suitable for use in oral dosage forms, particularly for pediatric preparations. Crystalline coprecipitation with gatifloxacin and / or stearic acid and / or palmitic acid affects the bitter taste of gatifloxacin throughout the 14-day dosing cycle in the mouth and in aqueous suspension Used for masking.

  International Patent Publication No. WO 02/72111 discloses a taste-masked pharmaceutical suspension of telithromycin. Four different coating agents, Novata AB, Eudragit E100, glycerol monostearate, and talc M10 are used, and at least 3 consecutive layers of coating are absolutely necessary to taste mask the tethromycin . The coated granules as disclosed can be further formulated as a dry syrup and reconstituted as a suspension. US Pat. No. 4,865,851 flavor masks the very bitter l-acetoxy ester of cefuroxime in particulate form coated with an essential coating of lipid or mixture of lipids that helps to mask the flavor Yet another method for disclosing is disclosed.

  The flavor masking coating using lipids should have a melting point of the lipids that is high enough to prevent melting in the mouth and not so high that the active ingredient itself dissolves or chemically degrades. Need. The substantially amorphous form of cefuroxime axetil with maximum bioavailability has a low melting point of about 70 ° C., and the difference in melting point of the lipid and drug is negligible and the mixture is a mist. The temperature to be converted is also higher than the melting point of the lipid. Lipid-based microencapsulation requires very sophisticated hot melt granulation methods to produce microparticles without adversely affecting the drug.

  British Patent No. 2081092 also discloses a lipid coating for flavor masking. However, the wax coating has been found to result in less dissolution of the active ingredient in the gastrointestinal tract. Furthermore, the patent discloses a technique to overcome this problem by mixing the wax with a water swellable polymer.

  U.S. Pat.No. 5,286,489 is a porous drug polymer matrix that is effective in masking the taste of the drug with a bitter active ingredient and a methyl methacrylate ester copolymer, Disclosed are such matrices formed by mixing in an active ingredient: copolymer weight ratio of at least 1: 1. None of the patented examples disclose the effect of these polymers on releasing the drug from the matrix. It is observed that the drug release is delayed from the matrix described in the specification.

  International Patent Publication No. WO 00/56266 discloses the combination of film-forming polymethacrylates and channeling agents with high density swellable polymer carbomers for taste masking of bitter drugs. The addition of the water swellable polymer helps in the rapid release of the active ingredient in the stomach media.

  International Patent Publication No. WO 00/76479 discloses a flavor masking composition using a mixture of two enteric polymers comprising a methacrylic acid copolymer and a phthalate polymer. The application discloses the use of a channeling agent comprising a water soluble or water swellable material to assist in the release of the active ingredient. Enteric polymers as disclosed in the patent are known to release the active ingredient at an alkaline pH at which the polymer dissolves. The release of the active ingredient is delayed by the use of enteric polymers and in the case of drugs with a narrow absorption area limited to the upper gastrointestinal tract; therefore, such a system will be of limited use.

  Putting the very bitter drug cefuroxime axetil into microcapsules for flavor masking is Cuna et al (disclosed by M. Cuna, ML Lorenzo, JL Vila-Jato, D. Torres, MJ Alonso, Acta Technology et Legis Medicamenti. Volume VII, N. 3, 1996). Use different polymeric materials, such as cellulose acetate trimellitate, HPMCP-50, HPMCP-55, with the final goal of masking the flavor, and ensure its release into the intestinal cavity.

  Still other publications Alonso et al (MJ Alonso, ML Lorenzo-Lamosa, M. Cuna, JL Vila-Jato and D. Torres, Journal of Microencapsulation, 1997, Volume 14). No. 5,607-616) describes the encapsulation of cefuroxime axetil, a very bitter drug, in a pH sensitive acrylic microsphere to prepare a suspension dosage form. The acrylic polymers used were eudragit E®, eudragit RL 100®, eudragit L100-55®. The cationic polymer eudragit E® exhibits a negative interaction with cefuroxime axetil. The enteric polymer eudragit L100-55® exhibits beneficial release in alkaline pH.

  In the above disclosure, the release of cefuroxime axetil has been studied in basic media. On the other hand, Danzig et al (Anne H. Dantzig, Dale C. Duckworth, Linda B. Tabas, Biochimica et Biophysica Acta 1191, 1994, 7-13) is in cefuroxime axetil in estrus, It has been shown to be degraded to cefuroxime, reducing cefuroxime axetil in the intestinal lumen and resulting in reduced absorption leading to low bioavailability of cefuroxime axetil in humans. Cefuroxime axetil already has a low bioavailability of 32-50%, so further reduction of bioavailability due to the dosage form should be minimized.

  The flavor masking formulation should be designed so that the bioavailability of the drug is not compromised, and the use of polymers such as enteric coatings should not affect peak times. In addition, the drug should be absorbed in minutes to ensure an effective therapeutic concentration in plasma. Vogleman et al (B. Vogleman, William A. Craig Journal of Pediatric 1986, 108 (5, pt2) 835-40, & B. Vogleman, William A. Craig, S. Ebert, S. Ebert, S. Ebert, S. Ebert, S. Ebert, S. Ebert, S. Ebert, S. Ebert, S. Ebert, S. Ebert. of Infectious Diseases 1988, 158 (4), 831-47) establishes that sterilization is performed quickly, thoroughly and increases in proportion to the concentration. Under high concentrations of the drug, the sterilization is complete and almost instantaneous. Fast and complete absorption and high systemic concentrations of the drug are important to elicit the desired therapeutic effect.

  There are drugs that pose challenges between formulations due to their physicochemical properties, such as cefuroxime axetil, second generation cephalosporin antibiotics, and celecoxib, from the class of COX2 inhibitors. Both celecoxib and cefuroxime require relatively high doses that further increase the difficulty in administering therapeutically effective doses. Cefuroxime axetil shows a tendency to gel on contact with aqueous media, indicating that the dosage form breaks down into quick particles and releases the drug at an earlier stage before gelling occurs in vivo. I need. Another problem with cefuroxime axetil involves formulating cefuroxime axetil in a coated delivery system to make it tasty with respect to the extreme bitterness of the drug. Celecoxib has extremely low water solubility and is not easily dissolved and is not dispersed due to rapid absorption in the gastrointestinal tract, and may also increase its dissolution and its bioavailability. Known amorphous forms of celecoxib tend to crystallize in contact with aqueous media. Etoroxib, another molecule from the COX2 inhibitor family, is also associated with extreme bitterness. Such active molecules that raise formulation issues and need to be administered as a quick release formulation to overcome low bioavailability are those that are active ingredients without compromising the bioavailability It is necessary to have a protective polymer coating that rapidly releases and masks the bitter taste of the active ingredient.

  International Patent Publication No. WO 02/43707 describes a tablet-shaped cefuroxime axetil oral medication in which cefuroxime axetil is contained in the tablet core and coated with hydroxypropyl methyl cellulose and a shellac double layer film coat A composition is disclosed. The first coat described serves to mask the bitter taste of cefuroxime axetil, and the second coat serves to delay the burst time of the tablet for more than 40 seconds. Since cefuroxime axetil is associated with a tendency to gel in contact with aqueous media and consequently reduce bioavailability, rapid release of cefuroxime from the center of the dosage form is further desired. .

  US Pat. No. 5,599,556 discloses a solution where the active ingredient is coated with a single outer polymer coating derived from prolamin cereal protein and plasticizer. The bitter drug, clarithromycin, mixed with polyvinyl pyrrolidine, is coated with prolamin to achieve flavor masking, and the coated particulate material is dispersed in a suspending solvent of pH greater than 6. . The coating is designed to disintegrate quickly once the composition leaves the mouth and reaches the stomach. The majority of pharmaceutical liquid oral compositions are formulated at pH 3.5 to 5.5 (US Pharmacopeia / National Formula 23 / NF 18, 1995). Some drugs will not be stable at high pH, and some drugs will not be stable within extremely acidic pH and will tend to degrade over long-term exposure.

  U.S. Pat. No. 5,489,436 describes a coating from a coated drug when the coating is designed to be soluble at low pH in the stomach, but relatively insoluble at high pH in the mouth. A manufactured chewable tablet is disclosed. The coating comprises a polymer blend of dimethylaminoethyl methacrylate and neutral methacrylic acid ester and cellulose ester. A method of “reverse enteric” coating of the above-described flavor masking oral formulation is disclosed with chewable tablets.

  International Patent Publication No. WO 02/096392 discloses flavor masking for the highly water soluble drug cetridine hydrochloride. Polymers such as hydroxypropyl methyl cellulose, polyvinyl pyrrolidine, and ethyl cellulose mask the flavor of cetridine in the tablet mold and immediately undermine the drug under the general acidic conditions in the stomach. Used to release.

  As is apparent from the above disclosure, flavor masking can be accomplished in a variety of ways. A number of natural or synthetic polymers, resins, and waxes alone or in combination are used for flavor masking. Enteric polymers such as Eudragit L are used as flavor masking, but the pH of saliva is around 5.8 and these polymers are solubilized above pH 5.5 and are therefore drug drugs There is a possibility of partial leaching. There is a need for the development of a flavor masking polymer, since the bitter taste is completely masked by the polymer at the pH of the saliva in the mouth and the pH in the reconstitution solvent as in the case of the liquid oral drug. And in addition, the drug in the biologically active form is removed from the moisture in the dosage form and without affecting the absorption and bioavailability of the drug in the stomach. It has been found to be able to protect against rapid release.

  The use of a polymer coat as mentioned in the examples above can be effective to inhibit dissolution of the drug during the swallowing process while in contact with saliva, while in contact with an aqueous medium. It is disadvantageous in producing flavor masked liquid dosage forms over the desired long shelf life. The drug should not be leached into the suspending medium for up to 14 days, the normal reconstitution period, and further released into the gastric cavity immediately after ingestion without affecting the bioavailability There is no description in the above references that satisfactorily masks the bitter taste of the drug in a pharmaceutical composition such as a suspension or dry syrup, which should be done. The need to clarify effective techniques, additives for specific substances, or combinations thereof, regardless of the numerous techniques and pharmaceutical additives used in the field to mask the flavor of bitter drug Remains.

Objects of the invention The main object of the invention is an oral flavor which has an improved taste by the use of specially synthesized pH-sensitive polymers and can deliver a substantial amount of the bitter active ingredient immediately. Providing a mask composition, wherein the pH sensitive polymer is soluble or swellable under acidic conditions of the stomach and insoluble or non-swellable in a neutral or near neutral medium; And can be applied to various pharmaceutical oral dosage forms. The term “oral dosage form” as used herein is a pharmaceutical composition intended to be administered to an individual by delivering the composition to the digestive tract of the individual via the mouth. Means. Oral dosage forms include tablets such as chewable tablets, dispersible tablets, coated tablets, liquids such as dry syrups and suspensions.

  It is an object of the present invention to provide a flavor masking composition comprising pH sensitive polymers and a method for producing a pharmaceutical composition comprising these polymers.

  Another object of the invention is to synthesize a polymer, which effectively masks the unpleasant taste of the drug, but impairs the dissolution rate and bioavailability of the drug. And further rapidly release the drug into the stomach cavity.

  Another object of the present invention is pH sensitive, suitable for taste masking suspensions, liquid oral drugs such as dry syrups, and solid dosage forms such as chewable tablets, fast dispersible tablets, and conventional tablets. Is to develop polymers.

  Another object of the present invention is to prevent leaching of the drug from the liquid and solid dosage forms at saliva pH and in the reconstitution medium.

  Another object of the present invention is also to assist in coating the bitter drug particles by various methods used in the art, such as microencapsulation, tray drying, fluidized bed method, and For example, spray drying.

  Yet another object of the present invention is to formulate a liquid oral dosage form containing the coated particles.

SUMMARY OF THE INVENTION Therefore, the present invention is a flavor masked pharmaceutical composition with enhanced bioavailability, comprising a pH sensitive polymer and a bitter drug and having the formula P [A _{( x)} B _(y) C _(z) ]: D, {where P is a pH sensitive polymer, (A) is a hydrophobic monomer, (B) is a basic monomer, ( C) is a hydrophilic monomer, and (D) is a bitter drug, where X is in the range of 30-95%, Y is in the range of 5-70%, and Z is 0- All the above percentages are given in terms of weight and the ratio of (P) :( D) ranges from 30: 1 to 0.2: 1. }, The pharmaceutical composition is provided.

  In one embodiment of the present invention, the hydrophobic monomer (A) comprises cyclohexyl acrylate, dodecyl acrylate, 2 ethyl hexyl acrylate, octyl acrylate, tertiary butyl acrylate, phenyl acrylate, butyl acrylate, methyl Methacrylate, benzyl methacrylate, cyclohexyl methacrylate, phenyl methacrylate, tert-butyl methacrylate, butyl methacrylate, 2-ethylhexyl methacrylate, propyl methacrylate, preferably butyl acrylate, methyl methacrylate, and butyl methacrylate Acrylic acid or methacrylic acid ester selected from the group consisting of

  In another embodiment of the present invention, the basic monomer (B) is dimethyl amino ethyl methacrylate, dimethyl amino ethyl acrylate, diethyl amino ethyl methacrylate, diethyl amino ethyl acrylate, piperidine Amino methacrylate acrylic acid and methacrylic acid selected from the group consisting of ethyl methacrylate, 2 tert-butyl amino ethyl methacrylate, preferably dimethyl amino ethyl methacrylate, and diethyl amino ethyl acrylate Selected from the group consisting of esters.

  In still another embodiment of the present invention, the basic monomer (B) is 2-vinyl pyridine, 3-vinyl pyridine, 4-vinyl pyridine, and 5-vinyl 2-picoline, 2-vinyl 4-picoline. An alkenyl pyridine selected from the group consisting of 2-isopropenyl pyridine, isopropenyl pyridine, preferably 4-vinyl pyridine.

  In yet another embodiment of the present invention, the basic monomer (B) is selected from vinyl quinoline, aminoalkyl vinyl ether, amino ethyl styrene, and allyl amine, preferably allyl amine.

  In still another embodiment of the present invention, the hydrophilic monomer (C) in the present invention is hydroxy ethyl methacrylate, hydroxy propyl methacrylate, hydroxy ethyl ethyl methacrylate, hydroxy ethyl acrylate, hydroxy propyl. Acrylic acid or methacrylic acid ester selected from the group consisting of acrylate, hydroxyethyl ethyl acrylate, preferably hydroxy ethyl methacrylate, and hydroxyethyl ethyl methacrylate.

  In still another embodiment of the present invention, the drug is a macrolide antibiotic selected from the group consisting of erythromycin, azithromycin, and clarithromycin, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, Non-steroidal group selected from the group consisting of cephalosporin, ibuprofen, and diclofenac sodium selected from the group consisting of fluoroquinolone, cefuroxime, cephalexin, cefadroxyl, cefpodoxime proxetyl selected from the group consisting of levofloxacin and norfloxacin An anti-his selected from the group consisting of chlorpheniramine maleate, a COX2 inhibitor selected from the group consisting of drugs and anti-inflammatory and analgesic drugs, and etoroxib and celecoxib Including Min agents, oxazolidinone selected from the group consisting of linezolid, and other drugs such as dextromethorphan.

  In yet another embodiment of the invention, the total polymer: drug ratio for optimal flavor masking of bitter drugs ranges from 30: 1 to 0.2: 1 on a weight basis. Further preferred polymer: drug ratios are in the range of 5: 1 to 0.4: 1 on a weight basis.

  In another embodiment of the invention, the pH sensitive polymer dissolves or swells at the acidic pH ≦ 3 found in the stomach and is insoluble or non-swellable within the pH> 3.5 range. It remains.

  In another embodiment of the invention, the drug itself, or a pharmaceutically acceptable salt or ester or amide thereof is used.

  In another embodiment of the invention, the drug is in particulate form dispersed within or coated with the polymer matrix.

  In another aspect of the invention, the pharmaceutical dosage form that can be manufactured using the composition of the invention is a liquid oral drug, for example, a dry syrup or suspension, and a chewable or dispersible tablet. .

  In another aspect of the invention, the pharmaceutical composition comprising the microparticles alone or in a pharmaceutically acceptable dosage form releases a minimal amount of drug from the oral dosage form at saliva pH. However, at the pH ≦ 3 found in the stomach, it releases a substantial amount of the drug immediately.

  In a preferred embodiment, the microparticles are formulated as an aqueous suspension or reconstituted in a liquid medium over a normal shelf life.

  In another embodiment of the invention, the pharmaceutical composition is a pH sensitive polymer by any known technique, preferably by microencapsulation, spray drying, fluidized bed method, non-solvent coprecipitation or tray drying method. Obtained by dispersing or coating the bitter drug in the matrix.

  In another aspect of the invention, the flavor masked drug polymer matrix in particulate form comprises the reconstitution medium at pH 4.5 comprising sucrose, a number of fruit flavors, citric acid, and polyvinyl pyrrolidone. Use to be suspended.

The present invention is a method for producing a flavor-masked pharmaceutical composition, the pharmaceutical composition comprising a pH sensitive polymer and a bitter drug, and the formula P [A _(x) B _(y) C _(z) ]: D, {where P is a pH sensitive polymer, (A) is a hydrophobic monomer, (B) is a basic monomer, and (C) is hydrophilic. Monomer, and (D) is a bitter drug, where (X) is 30-95%, (Y) is 5-70%, and (Z) is 0-60% Where all the above percentages are given in terms of weight, and the ratio of (P) :( D) ranges from 30: 1 to 0.2: 1. Wherein the method also relates to the method of manufacture comprising dispersing or coating the drug in particulate form in a matrix formed by the polymer.

  In an embodiment of the present invention, the hydrophobic monomer (A) includes cyclohexyl acrylate, dodecyl acrylate, 2 ethyl hexyl acrylate, octyl acrylate, tertiary butyl acrylate, phenyl acrylate, butyl acrylate, methyl From methacrylate, benzyl methacrylate, cyclohexyl methacrylate, phenyl methacrylate, tert-butyl methacrylate, butyl methacrylate, 2-ethyl hexyl methacrylate, propyl methacrylate, preferably butyl acrylate, methyl methacrylate, and butyl methacrylate An acrylic or methacrylic acid ester selected from the group consisting of

  In another embodiment of the present invention, the basic monomer (B) is dimethyl amino ethyl methacrylate, dimethyl amino ethyl acrylate, diethyl amino ethyl methacrylate, diethyl amino ethyl acrylate, piperidine An amino alkyl acrylic acid selected from the group consisting of ethyl methacrylate, 2-tert-butyl amino ethyl methacrylate, preferably dimethyl amino ethyl methacrylate, and diethyl amino ethyl acrylate, and Selected from the group consisting of methacrylic acid esters.

  In still another embodiment of the present invention, the basic monomer (B) is 2-vinyl pyridine, 3-vinyl pyridine, 4-vinyl pyridine, and 5-vinyl 2-picoline, 2-vinyl 4-picoline. An alkenyl pyridine selected from the group consisting of 2-isopropenyl pyridine, isopropenyl pyridine, preferably 4-vinyl pyridine.

  In yet another embodiment of the invention, the basic monomer (B) is selected from vinyl quinoline, amino alkyl vinyl ether, amino ethyl styrene, and allyl amine, preferably allyl amine. .

  In another embodiment of the present invention, the hydrophilic monomer (C) comprises hydroxy ethyl methacrylate, hydroxy propyl methacrylate, hydroxy ethyl ethyl methacrylate, hydroxy ethyl acrylate, hydroxy propyl acrylate, hydroxy An acrylic or methacrylic acid ester selected from the group consisting of ethyl ethyl acrylate, preferably hydroxy ethyl methacrylate, and hydroxy ethyl ethyl methacrylate.

  In one embodiment of the present invention, the drug is a macrolide antibiotic selected from the group consisting of erythromycin, azithromycin, and clarithromycin, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin, And a non-steroidal drug selected from the group consisting of cephalosporin, ibuprofen, and diclofenac sodium selected from the group consisting of fluoroquinolone, cefuroxime, cephalexin, cefadroxyl, and cefpodoxime proxetil selected from the group consisting of norfloxacin An anti-inflammatory agent and an analgesic, and an antihista selected from the group consisting of chlorpheniramine maleate, a COX2 inhibitor selected from the group consisting of etoroxib and celecoxib Including emissions agents, oxazolidinone selected from the group consisting of linezolid, and other drugs such as dextromethorphan.

  In another embodiment of the invention, the drug itself or a pharmaceutically acceptable salt or ester or amide thereof is used.

  In other embodiments of the invention, the ratio of the total polymer to drug for optimal flavor masking of bitter drugs is in the range of 30: 1 to 0.2: 1 on a weight basis. More preferably, the ratio of total polymer to drug is from 5: 1 to 0.4: 1 on a weight basis.

  In another embodiment of the present invention, the pH sensitive polymer dissolves or swells in the acidic pH ≦ 3 state found in the stomach and is insoluble or non-swelled within the range of pH> 3.5. Remains.

  In another embodiment of the invention, the drug is in the form of microparticles dispersed in or coated with the polymer matrix.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an oral pharmaceutical composition that effectively masks the bitter, unpleasant and other unpleasant flavors of the active ingredient. That is, the present invention relates to the synthesis of pH sensitive polymers that can be used in various pharmaceutical compositions that provide flavor masking and substantial immediate release and absorption of the bitter active ingredient, and the polymer comprises: It is generally desirable for chewable or dispersible tablets and solid and liquid dosage forms such as suspensions or dry syrups. It also relates to a method for producing such a composition.

  The composition of the present invention is in the form of a flavor masked formulation that provides a substantially immediate release of the bitter active ingredient, wherein the immediate release is the reverse enteric polymer in an acidic pH ≦ 3 state. Due to the hindrance of the release of the drug in the range of pH> 3.5 seen in saliva and in the reconstitution medium over the entire storage period of up to 14 days. The pH sensitive polymer is synthesized essentially comprising a hydrophobic monomer, a basic monomer, and optionally a hydrophilic monomer.

  An important feature of the present invention is to provide flavor masked microparticles of a bitter drug that are suitable for oral administration such as suspensions, fast dispersible, foamed or chewable tablets. More specifically, it relates to an oral dosage form in which the bitter taste of the drug is masked by a functional membrane coating on the microparticles with a pH sensitive polymer. For flavor masking of orally effective bitter drugs related to the present invention, a flavor masked particulate composition was produced by an emulsification method, solvent evaporation method or solvent extraction method or by the spray drying method. Microcapsules of the drug in a polymer coating matrix. More specifically, the present invention relates to a flavor-masked liquid oral form such as the dry syrup for administration to children. Furthermore, it is useful for formulations for all patients who would prefer liquid formulations as a result of physical challenges or preferences. The flavor masked composition of the present invention is further advantageous in that a reconstituted liquid formulation comprising the composition is stable over the normal pharmaceutical dosage regimen, typically up to 14 days. .

  For the basic features of the present invention, flavor masking of a bitter drug is obtained by using a pH sensitive polymer coating for the bitter drug, where the polymer is under acidic conditions in the stomach. It is essentially solubilized or swellable and remains insoluble or non-swellable at neutral or near neutral pH. The pH-sensitive polymer releases the active ingredient at the acidic pH of the stomach when applied to liquid oral drugs such as dry syrups or suspensions, and pharmaceutical dosage forms such as chewable or dispersible tablets. However, it maintains a savory flavor by preventing leaching of the drug at the pH of saliva or suspending media or in an aqueous environment near neutrality. The pH sensitive polymer is synthesized by using essentially hydrophobic monomers, and basic monomers, and optionally monomers from the class of hydrophilic monomers.

  Other aspects of the invention include formulating the coated bitter drug in the form of a suspension, preventing leaching of the drug in the suspension medium during reconstitution for up to 14 days, and It also ensures substantial release of the active drug in the simulated gastric juice without compromising on bioavailability. The pH-sensitive polymer of the present invention provides the activity in aqueous media at pH> 3.5 in order to inhibit the leaching of bitter drugs in saliva and in the reconstitution medium in the case of liquid oral drugs. It inhibits the release of the ingredients and releases the drug rapidly within the pH ≦ 3 range found in the stomach.

  The present invention provides flavor masking for bitter drugs, where the bitter drugs are, for example, macrolide antibiotics such as erythromycin, azithromycin, and clarithromycin, ciprofloxacin, enrofloxy. Non-steroidal drugs and anti-inflammatory and analgesic drugs such as saquinone, ofloxacin, gatifloxacin, levofloxacin, fluoroquinolones such as cefuroxime, cephalexin, cefadroxyl, cephalosporins such as cefpodoxime proxetil, ibuprofen, diclofenac sodium And COX2 inhibitors such as etoroxixib and celecoxib, antihistamines such as chlorpheniramine maleate, oxazolidinones such as linezolid, and dextromethol Which is another of the drugs, such as § down. The drug itself or a pharmaceutically acceptable salt or ester or amide can be used in the present invention. The drugs preferred for the practice of the present invention may be selected from a wide range including cefuroxime axetil, ciprofloxacin, celecoxib, and clarithromycin. For the pharmaceutical compositions described herein, the ratio of total polymer to drug for optimal masking of bitter drugs is in the range of 30: 1 to 0.2: 1 on a weight basis. . More preferably, the polymer to drug ratio is from 5: 1 to 0.4: 1 on a weight basis.

  In particular, the present invention provides a rapid bioavailability for exposure to pH levels found in the human stomach, while being able to be ingested without forming an unpleasant flavor for the active ingredient. Development of formulations useful as stable flavor masking liquid suspensions.

  In other features, the flavor masked particles obtained as described in the present invention may optionally be other pharmaceutically acceptable such as flavoring agents, sweeteners, suspending agents, and / or preservatives. Mixed with excipients and formulated as a dry syrup or hardened into rapidly degradable, foamed or chewable tablets. A stable aqueous suspension may consist of the dry syrup powder for oral administration for up to 14 days for pediatric or elderly patients, wherein the patient is a pediatric or elderly patient Those who are unwilling to swallow the tablet and / or find it difficult to swallow. Rapidly dispersible tablets are suitable for oral administration to patients who disperse rapidly in the mouth and are therefore difficult to swallow. Such dosage forms for oral administration should release less than 10%, most preferably less than 5%, at a pH of the reconstitution medium for up to 14 days, but at the pH found in the stomach Should release 40-60% within at least 15 minutes and 70% rapidly within at least 1 hour.

  The average particle size of the microcapsules will range from about 30 to 1000 microns, most preferably from about 100 to 500 microns.

  Examples of bitter, unpleasant flavor drugs that can be used are macrolide antibiotics such as erythromycin, azithromycin, and clarithromycin, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin, And non-steroidal and anti-inflammatory and analgesic drugs such as ibuprofen, diclofenac sodium, and COX2 such as celecoxib, and celecoxib, and fluoroquinolones such as norfloxacin, cefuroxime, cephalexin, cefadroxyl, cefpodoxime proxetil Inhibitors include, but are not limited to, antihistamines such as chlorpheniramine maleate, oxazolidinones such as linezolid, and other drugs such as dextromethorphan.

  Polymethacrylate and various derivatives of cellulose polymers are used prior to coating the antibiotic cefuroxime axetil. The statistical release data of the drug from these materials depends on the type of polymer used for the coating. International Patent No. WO 0236126 discloses sustained release of cefuroxime axetil from a composition comprising eudragit L30D, eudragit RL30D, and eudragit RS30D. The 1 hour release of cefuroxime axetil in 0.07N HCl and pH 6.8 phosphate buffer is disclosed below.

Time: 60 minutes 120 minutes 180 minutes 240 minutes 360 minutes Release%: 34.6 44.3 67.4 83.7 96.1

  Alonso discloses sustained release of cefuroxime axetil from microparticles obtained using polymer coatings of Eudragit E, Eudragit L100-55, and Eudragit RL-100 (MJ Alonso, ML Lorenzo- Lamosa, M. Cuna, JL Vila-Jato and D. Torres, Journal of Microencapsulation, 1997, Volume 14, No. 5, 607-616). The release of the cefuroxime axetil was almost complete from eudragit E microspheres in 0.07N HCl within 20-30 minutes. Release from eudragit E microspheres in pH 7 Sorensens buffer was found to be slow compared to 0.07 N HCl. The release data is briefly shown below.

0.07N HCl medium Time: 10-20 minutes Release%: Up to 80-100

Sorensens buffer medium at pH 5.8 Time: 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes Release%: up to 20 30 40 45 50 60

  However, the cationic polymer eudragit E showed a negative interaction with cefuroxime axetil, which showed considerable degradation in the presence of Eudragit E. The microspheres using eudragit L55 and RL showed a significant amount of release <2% within 2 hours at pH 5.2 and 75% within 30 minutes at pH 6.0.

  M.M. Cuna et al has described a coating of cefuroxime axetil (M. Cuna, ML Lorenzo, J. Co.) for taste masking using different polymeric materials such as cellulose acetate trimellitate, HPMCP-50, HPMCP-55. L. Vila Jato, D. Torres, M. J. Alonso, Acta Technology et Legis Medicamenti. Volume VII, N. 3, 1996). Release data is briefly shown below.

(Microsphere with HPMCP-55) at pH 5.2
Time: 15 to 60 minutes Release%: Less than 25% at maximum

pH 6.0 (microspheres with HPMCP-55)
Time: 15 minutes 30 minutes Release%: 50-75 75-100

  For the above disclosure, the release of cefuroxime axetil was tested in basic medium, while Dantzig et al (Anne H. Dantiz, Dale C. Duckworth, Linda B. Tabas, Biochimica et Biophysica Acta 1191, 1994, 1994). 13) showed that cefuroxime axetil was hydrolyzed by esterase to cefuroxime in the intestinal lumen, where the esterase reduced and reduced the concentration of the cefuroxime axetil in the lumen Lead to low bioavailability of human cefuroxime axetil.

  Drug molecules such as cefuroxime axetil tend to gel in the presence of a liquid medium. If the tablets are not protected from wetting during storage, they become sparingly soluble and low bioavailability. Therefore, the liquid oral formulation of cefuroxime axetil needs to protect the drug from an aqueous environment during reconstitution. Cefuroxime axetil has a limited absorption region in the gastrointestinal tract where the enzyme esterase hydrolyzes it to cefuroxime and cannot be absorbed beyond that tube, so its bioavailability is Reduce. Cefuroxime axetil is also associated with a very bitter flavor. The pharmaceutical composition of cefuroxime axetil is therefore required to be flavor masked. Water soluble and enteric coating polymers for cefuroxime axetil are therefore of limited use.

  In a preferred embodiment of the invention, the bitter drug used for flavor masking includes cefuroxime axetil, ciprofloxacin hydrochloride, and clarithromycin. One feature of the present invention is the rapid swelling of the polymer at acidic pH and / or rapid release from the polymer coating of a drug such as cefuroxime axetil with a low bioavailability of 32-50%. Or it must be lysed and therefore must not lag in absorption and change bioavailability. The release of the drug from the polymer used in the present invention is disclosed in the examples.

  In another aspect of the invention, the pharmaceutical composition can be obtained by coating the drug by use of a pH sensitive polymer, the obtaining method comprising: microencapsulation method, spray drying method, fluidized bed method, non-solvent Either by coprecipitation or by tray drying. The drug is dispersed in the polymer matrix.

  In yet another aspect, the flavor masking composition is made by microencapsulation of the drug in the polymer matrix. Microencapsulation of the bitter drug can be obtained by emulsification, solvent evaporation or solvent extraction, and spray drying of the drug polymer solution or dispersion of the drug in the polymer solution. If the drug does not dissolve in the polymer solution, then it is uniformly dispersed in the polymer solution with the aid of a dispersing agent such as a surfactant. The preferred surfactants are nonionic surfactants belonging to the SPAN and TWEEN classes. In a preferred embodiment of the present invention, the solvent selected for solubilization of the drug and polymer is an alcohol such as methanol, ethanol, isopropanol, butanol, a chlorinated hydrocarbon such as dichloromethane or chloroform, methyl ethyl. • Ketones such as ketones, methyl iso-butyl ketone, and acetone. Preferably, the solvent used to dissolve the drug and polymer is methanol, acetone, and dichloromethane. A preferred solvent for dissolving the drug and polymer is acetone or a mixture of methanol and dichloromethane in a ratio of 1: 1 to 1: 1.5.

  Flavor masked microcapsules of the bitter drug can be obtained by microencapsulation by an emulsion solvent evaporation method. The dispersed phase is an organic solvent containing the drug and a polymer, and the dispersion medium is liquid paraffin. The pH sensitive polymer to be synthesized is dissolved in an organic solvent (acetone, methanol, dichloromethane, or a mixture of methanol and dichloromethane in a ratio of 1: 1 to 1: 1.5). The drug is added to the polymer solution and becomes a solution or uniform dispersion. The organic phase is then added into light liquid paraffin-containing span 85 (0.1-1% (w / w)). It is maintained for 3-4 hours at a constant mechanical stirring ratio of 1000 rpm and at room temperature. The solvent is evaporated and the resulting microspheres are separated by filtration, washed with petroleum ether or with n-hexane and dried under vacuum for up to 24 hours.

  The flavor-masked microcapsules of the bitter drug can be further obtained by an emulsifying solvent extraction method. The dispersed phase is an organic solvent containing the drug and polymer, and the dispersion medium is liquid paraffin. The synthesized pH-sensitive polymer is dissolved in the organic solvent (acetone, methanol, dichloromethane, or a mixture of methanol and dichloromethane in a ratio of 1: 1 to 1: 1.5). The drug is added to the polymer solution and becomes a solution or uniform dispersion. The organic phase is then added into light liquid paraffin-containing span 85 (0.1-1% (w / w)). Maintained for 30 minutes at a constant mechanical stirring ratio of 500 rpm and 25 ° C., and 40 ml of n-hexane or cyclohexane was added at a rate of 5 ml / min, after which another 40 ml of n-hexane or cyclohexane was added. Added quickly. Stirring is maintained for an additional 10-15 minutes, then the microparticles are separated by filtration, washed with petroleum ether or n-hexane, and dried at 27 ° C. under vacuum for up to 24 hours.

  Alternatively, the flavor masked microparticles can be obtained by spray drying. The drug-polymer solution or dispersion in the organic solvent is spray dried to obtain the flavor masked microparticles. The dry gas can be an inert gas, such as nitrogen, argon, and carbon dioxide or air. A preferred gas in the present invention is air. The gas inlet temperature for the spray dryer depends on the choice of solvent used, but can range from 35 to 150 ° C, preferably from 40 to 60 ° C. The gas exhaust temperature likewise depends on the solvent, but can range from 25 to 50 ° C., preferably from 25 to 40 ° C. The polymer is dissolved in methanol or a 1: 1 mixture of methanol and dichloromethane, and the drug is either dissolved or dispersed in the polymer solution. The resulting mixture is spray dried to obtain the flavor masked microparticles.

  Flavor masked microparticles and granules obtained include natural or artificial flavors such as fragrance additives, citric acid and sweeteners such as tartaric acid, sucrose, saccharin, and aspartame, and other pharmaceutically acceptable excipients. It is mixed with the agent and manufactured as any conventional, chewable or dispersible tablet, dry syrup, suspension, sachet or other suitable oral dosage form.

  The present invention is directed to flavor masking of the liquid oral composition suitable for pediatric patients or those who have difficulty swallowing solid dosage forms. The flavor masked pharmaceutical composition comprises the polymer-coated drug in a liquid medium containing sucrose, flavor, and citric acid, and in a suspension such as a cellulose derivative or polyvinyl pyrrolidone or xanthan gum. Manufactured by reconstitution of particles. The flavor masked composition of the present invention is made by using a pH 4.5 reconstitution medium comprising sucrose, a number of fruit flavors, citric acid, and polyvinyl pyrrolidone.

  Flavor masked pharmaceutical compositions as illustrated in Examples 1-12 below were tested for drug release over time. Release of cefuroxime axetil from the flavor masked microparticles was measured in 900 ml of 0.07 N hydrochloric acid at 37 ± 0.5 ° C. using an instrument rotating at 100 rpm, USP type II. The sample was collected at 15, 30, 45, 60, and 90 minutes. The amount recovered at each time was replaced with fresh solvent to maintain sink conditions.

  Release of ciprofloxacin hydrochloride from the flavor masked particles was measured in 900 ml of 0.1N hydrochloric acid buffer at 37 ± 0.5 ° C. using an instrument rotating at 100 rpm, USP type II. The sample was collected at 15, 30, 45, and 60 minutes. The amount recovered at each time was replaced with fresh solvent to maintain sink conditions.

  Release of clarithromycin from the flavor masked particles was measured in 900 ml of pH 2.8 acetate buffer at 37 ± 0.5 ° C. using an instrument rotating at 100 rpm, USP type II. The sample was collected at 15, 30, 45, and 60 minutes. The amount recovered at each time was replaced with fresh solvent to maintain sink conditions.

  Celecoxib release from the flavor-masked particles was celecoxib for 30 minutes in 100 ml of 0.1 N HCl at 37 ± 0.5 ° C. using an instrument rotating at 100 rpm, USP type II, and Measurements were made by placing the composition containing the polymer and then adding 900 ml of 0.1 N NaOH solution. Samples were collected from 0.1 N NaOH at 15, 30, 45, and 60 minutes. The amount recovered at each time was replaced with fresh solvent to maintain sink conditions.

  A flavor masking composition, and its application, is shown below in connection with an illustrative example, which in no way should be construed as limiting the scope of the invention in any way .

Example 1
Flavor masked microparticles were obtained by the emulsion solvent evaporation method. 3. 50 g of ciprofloxacin was dispersed in a polymer solution containing 900 mg of polymer in 45 ml of a mixture of methanol and dichloromethane (1: 1). The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight vinyl pyridine. Span 85, a nonionic surfactant, was added at 0.5% (w / w) to promote the dispersion of ciprofloxacin in the polymer solution. The ciprofloxacin dispersion was added dropwise to a light liquid paraffin bath with mechanical stirring. Maintained at a constant mechanical agitation ratio of 1000 rpm and room temperature for 3-4 hours. The solvent was evaporated and the resulting microparticles were separated by filtration, washed with petroleum ether and dried at 27 ° C. under vacuum for 24 hours. The drug release pattern of the manufactured composition was tested and the results are shown in Table 1. The results in Table 1 indicate the immediate release of the drug.

Example 2
Fine bites of the bitter-tasting drug masked were obtained by microencapsulation by an emulsion solvent evaporation method. 2.35 g of ciprofloxacin was dispersed in a polymer solution containing 7.0 g of polymer in 40 ml of a mixture of methanol and dichloromethane (1: 1). The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight vinyl pyridine. Microencapsulation of ciprofloxacin with the pH sensitive polymer was obtained using a method similar to that mentioned in Example 1. The drug release pattern of the composition produced was tested and the results are shown in Table 2.

Example 3
Flavor masked microcapsules were obtained by microencapsulation by emulsion solvent evaporation. 2.0 g of clarithromycin was dissolved in a polymer solution containing 4.0 g of polymer in 40 ml of a mixture of methanol and dichloromethane (1: 1). The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight vinyl pyridine. Microencapsulation of clarithromycin with a pH sensitive polymer was obtained using a method similar to that of Example 1. The drug release pattern of the composition produced was tested and the results are shown in Table 3.

Example 4
Flavor masked microcapsules were obtained by microencapsulation by emulsion solvent evaporation. 2.0 g of clarithromycin was dissolved in a polymer solution containing 1.2 g of polymer in 30 ml of a mixture of methanol and dichloromethane (1: 1). The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight vinyl pyridine. Microencapsulation of clarithromycin with a pH sensitive polymer was obtained using a method similar to that of Example 1. The drug release pattern of the composition produced was tested and the results are shown in Table 4.

Example 5
Flavor masked microcapsules of cefuroxime axetil, a cephalosporin antibiotic, were obtained by microencapsulation by emulsion solvent evaporation. 2.0 g of cefuroxime axetil was dissolved in a polymer solution containing 6.0 g of polymer in 40 ml of a mixture of methanol and dichloromethane (1: 1). The polymer has a monomer composition of 43 wt% methyl methacrylate, 42 wt% hydroxyethyl methacrylate, and 15 wt% vinyl pyridine. Microencapsulation of cefuroxime axetil with pH sensitive polymer was obtained using a method similar to that of Example 1. The drug release pattern of the composition produced was tested and the results are shown in Table 5.

  The fine-flavored masked pharmaceutical composition produced in Example 5 is composed of 85% (w / v) sucrose, an appropriate amount of flavoring with various fruit flavors, an appropriate amount of citric acid, and polyvinyl pyrrolidone. By using a reconstitution medium having a pH of 4.5 containing 2%, it is produced as microparticles having a drug corresponding to 4 doses. The drug release during the 7 day storage period is shown in Table 6.

Example 6
Cefuroxime axetil flavor masked microcapsules were obtained by microencapsulation by an emulsion solvent evaporation method. 2.0 g of cefuroxime axetil was dissolved in a polymer solution containing 6.0 g of polymer in 40 ml of a mixture of methanol and dichloromethane (1: 1). The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight vinyl pyridine. Microencapsulation of cefuroxime axetil with a pH sensitive polymer was obtained using a method similar to that described in Example 1. The drug release pattern of the composition produced was tested and the results are shown in Table 7.

  The fine-grained flavor masked pharmaceutical composition prepared in Example 6 comprises 85% (w / v) sucrose, an appropriate amount of flavoring with various fruit flavors, an appropriate amount of citric acid, and polyvinyl pyrrolidone. By using a reconstitution medium having a pH of 4.5 containing 2%, it is produced as microparticles having a drug corresponding to 4 doses. The drug release during the 7 day storage period is shown in Table 8.

Example 7
Flavor masked microcapsules of cefuroxime axetil, which is a bitter cephalosporin antibiotic, were obtained by microencapsulation by an emulsion solvent evaporation method. 2.0 g of cefuroxime axetil was dissolved in a polymer solution containing 6.0 g of polymer in 40 ml of a mixture of methanol and dichloromethane (1: 1). The polymer has a monomer composition of 70% by weight methyl methacrylate and 30% by weight vinyl pyridine. Microencapsulation of cefuroxime axetil with the pH sensitive polymer was obtained using a method similar to that described in Example 1. The drug release pattern of the composition produced was tested and the results are shown in Table 9.

  The fine-grain flavor masked pharmaceutical composition prepared in Example 7 comprises 85% (w / v) sucrose, an appropriate amount of flavoring with various fruit flavors, an appropriate amount of citric acid, and polyvinyl pyrrolidone. By using a reconstitution medium having a pH of 4.5 containing 2%, it is produced as microparticles having a drug corresponding to 4 doses. The drug release during the 7 day storage period is shown in Table 10.

Example 8
A flavor-masked microcapsule of cefuroxime axetil, a bitter cephalosporin antibiotic, was obtained by microencapsulation by an emulsion solvent evaporation method. 2.0 g of cefuroxime axetil was dissolved in a polymer solution containing 6.0 g of polymer in 40 ml of a mixture of methanol and dichloromethane (1: 1). The polymer has a monomer composition of 35% by weight methyl methacrylate, 35% by weight hydroxyethyl methacrylate, and 30% by weight vinyl pyridine. Microencapsulation of cefuroxime axetil with a pH sensitive polymer was obtained using a method similar to that described in Example 1. The drug release pattern of the composition produced was tested and the results are shown in Table 11.

Example 9
The cefuroxime axetyl-polymer solution in the organic solvent was spray dried to obtain flavor masked microparticles. The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight 4 vinyl pyridine. The dry gas was air. The air intake temperature of the spray dryer was in the range of 40 to 70 ° C. The exhaust temperature was in the range of 25-60 ° C. 2.4 g of the polymer was dissolved in a mixture of methanol and dichloromethane (1: 1), and 4.8 g of cefuroxime axetyl was added to the polymer solution. The atomization was in the range of 1-2 kg. The said feed rate was made into the range of 20-85 rpm. The obtained solution was spray-dried to obtain fine particles masked with the flavor. The drug release pattern of the manufactured composition was tested and the results are shown in Table 12.

  The fine-grained flavor masked pharmaceutical composition prepared in Example 9 is composed of 85% (w / v) sucrose, an appropriate amount of flavoring with a variety of fruit flavors, an appropriate amount of citric acid, and polyvinyl pyrrolidone. By using a reconstitution medium having a pH of 4.5 containing 2%, it is produced as fine particles having a drug corresponding to 5 doses. The drug release during the 7 day storage period is shown in Table 13.

Example 10
The cefuroxime axetyl-polymer solution in the organic solvent was spray dried to obtain flavor masked microparticles. The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight 4 vinyl pyridine. The solvent used was a mixture of methanol and dichloromethane (1: 1). The dry gas was air. The air intake temperature of the spray dryer was in the range of 40 to 70 ° C. The exhaust temperature was in the range of 25-60 ° C. 2.4 g of the polymer was dissolved in a mixture of methanol and dichloromethane (1: 1), and 4.8 g of cefuroxime axetyl was added to the polymer solution. The atomization was in the range of 1-2 kg. The said feed rate was made into the range of 20-85 rpm. The obtained solution was spray-dried to obtain fine particles masked with the flavor. The drug release pattern of the composition produced was tested and the results are shown in Table 14.

  The fine-grain flavor masked pharmaceutical composition prepared in Example 10 comprises 85% (w / v) sucrose, an appropriate amount of flavoring with various fruit flavors, an appropriate amount of citric acid, and polyvinyl pyrrolidone. By using a reconstitution medium having a pH of 4.5 containing 2%, it is produced as fine particles having a drug corresponding to 5 doses. The drug release during the 7 day storage period is shown in Table 15.

Example 11
The celecoxib-polymer solution in the organic solvent was spray dried to obtain flavor masked microparticles. The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight 4 vinyl pyridine. The solvent used was a mixture of methanol and dichloromethane (1.5: 1). The dry gas was air. The air intake temperature of the spray dryer was in the range of 40 to 70 ° C. The exhaust temperature was in the range of 25-60 ° C. 1.5 g of the polymer was dissolved in a mixture of methanol and dichloromethane (1.5: 1) and 2.0 g of celecoxib was added into the polymer solution. The atomization was in the range of 1-2 kg. The said feed rate was made into the range of 20-85 rpm. The obtained solution was spray-dried to obtain fine particles masked with the flavor. The drug release pattern of the composition produced was tested and the results are shown in Table 16.

Example 12
The celecoxib-polymer solution in the organic solvent was spray dried to obtain flavor masked microparticles. The polymer has a monomer composition of 60% by weight methyl methacrylate, 25% by weight hydroxyethyl methacrylate, and 15% by weight 4 vinyl pyridine. The solvent used was a mixture of methanol and dichloromethane (1.5: 1). The dry gas was air. The air intake temperature of the spray dryer was in the range of 40 to 70 ° C. The exhaust temperature was in the range of 25-60 ° C. 0.750 g of the polymer was dissolved in a mixture of methanol and dichloromethane (1.5: 1) and 2.0 g of celecoxib was added into the polymer solution. The atomization was in the range of 1-2 kg. The said feed rate was made into the range of 20-85 rpm. The obtained solution was spray-dried to obtain fine particles masked with the flavor. The drug release pattern of the composition produced was tested and the results are shown in Table 17.

Claims (40)

A flavor masked pharmaceutical composition comprising a pH sensitive polymer and a bitter drug and having the formula P [A _(x) B _(y) C _(z) ]: D, wherein { , P is a pH sensitive polymer, (A) is a hydrophobic monomer, (B) is a basic monomer, (C) is a hydrophilic monomer, and (D) is a bitter drug (X) is 30 to 95%, (Y) is 5 to 70%, and (Z) is in the range of 0 to 60%, where all the above percentages are expressed in terms of w / w. And the ratio of (P) :( D) ranges from 30: 1 to 0.2: 1 (w / w). }. The pharmaceutical composition comprising   The hydrophobic monomer (A) is cyclohexyl acrylate, dodecyl acrylate, 2 ethyl hexyl acrylate, octyl acrylate, tertiary butyl acrylate, phenyl acrylate, butyl acrylate, methyl methacrylate, benzyl methacrylate, Cyclohexyl methacrylate, phenyl methacrylate, tert-butyl methacrylate, butyl methacrylate, 2 ethyl hexyl methacrylate, propyl methacrylate, preferably selected from the group consisting of butyl acrylate, methyl methacrylate, and butyl methacrylate The composition of claim 1 comprising an acrylic or methacrylic ester.   The basic monomer (B) is dimethyl amino ethyl methacrylate, dimethyl amino ethyl acrylate, diethyl amino ethyl methacrylate, diethyl amino ethyl acrylate, piperidine ethyl methacrylate, 2 tert-butyl. The composition according to claim 1, selected from the group consisting of amino-alkyl-acrylic acid and methacrylic acid ester selected from the group consisting of amino-ethyl methacrylate.   4. The composition according to claim 3, wherein the basic monomer (B) is selected from dimethyl amino ethyl methacrylate and diethyl amino ethyl acrylate.   The basic monomer (B) is 2-vinyl pyridine, 3-vinyl pyridine, 4-vinyl pyridine, 5-vinyl 2-picoline, 2-vinyl 4-picoline, 2 isopropenyl pyridine, and iso The composition of claim 1 comprising alkenyl pyridine selected from the group consisting of propenyl pyridine.   The composition according to claim 5, wherein the basic monomer (B) comprises 4-vinyl pyridine.   The composition according to claim 1, wherein the basic monomer (B) is selected from vinyl quinoline, aminoalkyl vinyl ether, amino ethyl styrene, and allyl amine.   The composition according to claim 7, wherein the basic monomer (B) comprises allyl amine.   The hydrophilic monomer (C) is composed of hydroxy ethyl methacrylate, hydroxy propyl methacrylate, hydroxy ethyl ethyl methacrylate, hydroxy ethyl acrylate, hydroxy propyl acrylate, hydroxy ethyl ethyl acrylate. The composition of claim 1 which is an acrylic or methacrylic ester selected from the group.   The composition according to claim 1, wherein the hydrophilic monomer (C) is selected from hydroxy ethyl methacrylate and hydroxy ethyl ethyl methacrylate.   The drug is selected from the group consisting of a macrolide antibiotic, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin, and norfloxacin selected from the group consisting of erythromycin, azithromycin, and clarithromycin Non-steroidal and anti-inflammatory and analgesic drugs selected from the group consisting of cephalosporin, ibuprofen, and diclofenac sodium selected from the group consisting of fluoroquinolone, cefuroxime, cephalexin, cefadroxyl, and cefpodoxime proxetil A COX2 inhibitor selected from the group consisting of ethoroxib and celecoxib, an antihistamine selected from the group consisting of chlorpheniramine maleate, and linezolid Including more oxazolidinone selected, and other drugs such as dextromethorphan composition of claim 1.   The composition according to claim 1, wherein the drug itself or a pharmaceutically acceptable salt or ester or amide thereof is used.   The composition of claim 1, wherein the ratio of total polymer to drug is in the range of 30: 1 to 0.2: 1 on a weight basis.   The composition of claim 1, wherein the ratio of total polymer to drug is in the range of 5: 1 to 0.4: 1 on a weight basis.   The composition of claim 1, wherein the drug is in the form of microparticles dispersed in or coated with the polymer matrix.   The pH-sensitive polymer dissolves or swells in the acidic pH ≦ 3 state found in the stomach and remains insoluble or non-swelled in the range of pH> 3.5. A composition according to 1.   The composition according to claim 1, wherein the pharmaceutical dosage form that can be produced using the composition of the present invention is selected from liquid oral drugs including dry syrups or suspensions and chewable or dispersible tablets.   The pharmaceutical composition comprising only the microparticles or comprising the microparticles in a pharmaceutically acceptable dosage form, which releases a minimal amount of drug from the oral dosage form at saliva pH, but in the stomach 2. The composition of claim 1, wherein the composition rapidly releases a substantial amount of the drug immediately at a pH ≦ 3 found in   The composition of claim 1, wherein the microparticles are formulated as an aqueous suspension or reconstituted in a liquid medium over a normal shelf life.   Said bitter taste in a matrix of pH sensitive polymer by any of the known techniques, preferably by microencapsulation, spray drying, fluidized bed method, co-precipitation in non-solvent or by tray drying method The composition according to claim 1, obtained by dispersing or coating a certain drug.   The particulate masked taste masked drug polymer matrix is suspended using the reconstitution medium at pH 4.5 comprising sucrose, a number of fruit flavors, citric acid, and polyvinyl pyrrolidone. 2. The composition according to 1. A method for producing a flavor masked pharmaceutical composition comprising a pH sensitive polymer and a bitter drug, and said formula P [A _(x) B _(y) C _(z) ]: D wherein {wherein P is the pH sensitive polymer, (A) is a hydrophobic monomer, (B) is a basic monomer, and (C) is a hydrophilic monomer. And (D) is a bitter drug, where (X) is 30-95%, (Y) is 5-70%, and (Z) is 0-60% Where all the above percentages are given in terms of weight, and the ratio of (P) :( D) ranges from 30: 1 to 0.2: 1. Where the method comprises:
Dispersing the drug in the form of fine particles in a matrix formed by the polymer, or
Coating.   The hydrophobic monomer (A) is cyclohexyl acrylate, dodecyl acrylate, 2 ethyl hexyl acrylate, octyl acrylate, tertiary butyl acrylate, phenyl acrylate, butyl acrylate, methyl methacrylate, benzyl methacrylate, Selected from the group consisting of cyclohexyl methacrylate, phenyl methacrylate, tert-butyl methacrylate, butyl methacrylate, 2-ethyl hexyl methacrylate, propyl methacrylate, preferably butyl acrylate, methyl methacrylate, and butyl methacrylate 23. A method according to claim 22 which is an acrylic or methacrylic ester.   The basic monomer (B) is dimethyl amino ethyl methacrylate, dimethyl amino ethyl acrylate, diethyl amino ethyl methacrylate, diethyl amino ethyl acrylate, piperidine ethyl methacrylate, 2-tert. -Selected from the group consisting of amino-alkyl-acrylic acid and methacrylic acid ester selected from the group consisting of butyl-amino-ethyl-methacrylate, preferably dimethyl-amino-ethyl-methacrylate, and diethyl-amino-ethyl-acrylate 23. The method of claim 22, wherein:   The basic monomer (B) is 2-vinyl pyridine, 3-vinyl pyridine, 4-vinyl pyridine, 5-vinyl 2-picoline, 2-vinyl 4-picoline, 2 isopropenyl pyridine, iso 23. A process according to claim 22 which is an alkenyl pyridine selected from the group consisting of propenyl pyridine, preferably 4-vinyl pyridine.   23. A process according to claim 22, wherein the basic monomer (B) is selected from vinyl quinoline, amino alkyl vinyl ether, amino ethyl styrene, and allyl amine, preferably allyl amine. .   In another embodiment of the present invention, the hydrophilic monomer (C) is hydroxy ethyl methacrylate, hydroxy propyl methacrylate, hydroxy ethyl ethyl methacrylate, hydroxy ethyl acrylate, hydroxy propyl acrylate, hydroxy 23. A process according to claim 22, wherein the process is an acrylic or methacrylic acid ester selected from the group consisting of ethyl ethyl acrylate, preferably hydroxy ethyl methacrylate, and hydroxy ethyl ethyl methacrylate.   The drug is selected from the group consisting of a macrolide antibiotic, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin, and norfloxacin selected from the group consisting of erythromycin, azithromycin, and clarithromycin Non-steroidal and anti-inflammatory and analgesic drugs selected from the group consisting of cephalosporin, ibuprofen, and diclofenac sodium selected from the group consisting of fluoroquinolone, cefuroxime, cephalexin, cefadroxyl, and cefpodoxime proxetil A COX2 inhibitor selected from the group consisting of ethoroxib and celecoxib, an antihistamine selected from the group consisting of chlorpheniramine maleate, and linezolid Including more oxazolidinone selected, and other drugs such as dextromethorphan, The method of claim 22.   23. The method of claim 22, wherein the drug itself, or a pharmaceutically acceptable salt or ester or amide thereof is used.   23. The method of claim 22, wherein the total polymer to drug ratio is in the range of 30: 1 to 0.2: 1 on a weight basis.   24. The method of claim 22, wherein the total polymer to drug ratio is in the range of 5: 1 to 0.4: 1 on a weight basis.   23. The pH-sensitive polymer dissolves or swells in the acidic pH ≦ 3 state found in the stomach and remains insoluble or non-swelled within a pH> 3.5 range. The method described in 1. The composition is an emulsified solvent extraction method comprising the following steps:
Dissolving the pH sensitive polymer in an organic solvent selected from acetone, methanol, dichloromethane, and a mixture of methanol and dichloromethane in a ratio of 1: 1 to 1: 1.5;
Adding the drug to the polymer solution to obtain a solution or uniform dispersion;
Adding this organic phase to light liquid paraffin-containing span 85 in an amount of 0.1-1% (w / w);
Mechanically stirring the mixture at a rate of about 500 rpm and at about 25 ° C. for about 30 minutes;
Add 40 ml of n-hexane or cyclohexane at a rate of 5 ml / min; then quickly add another 40 ml of n-hexane or cyclohexane;
Maintaining stirring for 10-15 minutes; and then separating the microparticles by filtration; and washing the separated microparticles with petroleum ether or n-hexane; and under vacuum for up to 24 hours under vacuum Drying at 27 ° C .;
23. The method of claim 22, wherein the method is manufactured by microencapsulation using the method comprising: Drug microparticles coated with the polymer are obtained by spray drying, where the spray drying comprises the following steps:
Spraying the drug-polymer solution or dispersion in an organic solvent to obtain the flavor masked microparticles;
Subjecting the sprayed microparticles to drying in the presence of a drying gas selected from the group consisting of nitrogen, argon, carbon dioxide, and air;
23. The method of claim 22, comprising:   35. The method of claim 34, wherein the gas inlet temperature for the spray dryer depends on the solvent used and is in the range of 35-150C.   36. The method of claim 35, wherein the gas inlet temperature is in the range of 40-60 ° C.   35. The method of claim 34, wherein the gas exhaust temperature depends on the solvent and is in the range of 25-50C.   38. The method of claim 37, wherein the gas exhaust temperature is in the range of 25-40C.   The polymer is dissolved in methanol or a mixture of methanol and dichloromethane (1: 1) and the drug is either dissolved or dispersed in the polymer solution. 34. The method according to 34.   A flavor masked particulate of the drug is mixed with a flavoring agent, citric acid and a sweetener selected from tartaric acid, sucrose, saccharin, and aspartame, and other pharmaceutically acceptable excipients, 23. The method of claim 22, formulated as a chewable or dispersible tablet, dry syrup, suspension, sachet or other suitable oral dosage form.