CN1878539A

CN1878539A - Taste masked pharmaceutical compositions comprising bitter drug and pH sensitive polymer

Info

Publication number: CN1878539A
Application number: CNA200380110830XA
Authority: CN
Inventors: 莫汉·戈帕里克希纳·库尔卡尼; 阿尼奥帕·拉梅什·曼乔治
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2003-12-15
Filing date: 2003-12-15
Publication date: 2006-12-13
Anticipated expiration: 2023-12-15
Also published as: AU2003292509B2; JP2007518670A; AU2003292509A1; EP1694302A1; AU2003292509B9; CN1878539B; CA2549572A1; WO2005055987A1

Abstract

The present invention discloses pharmaceutical compositions comprising of pH sensitive polymers used for taste masking highly bitter drugs. The pH sensitive polymer acts as a reverse enteric coating, which is soluble in the acidic pH range 1.0 to 3.0 normally found in the stomach but is insoluble in the pH range 3.5 to 7 thus inhibiting the release of the bitter drug at the pH of saliva and also at the pH of reconstitution medium in case of liquid orals.

Description

The pharmaceutical composition that contains the taste masking of bitterness medicine and pH sensitive polymer

Invention field

The method that the present invention relates to comprise the taste masking compositions of bitterness medicine and pH sensitive polymer and prepare said composition.The invention still further relates to the preparation method of the taste-masking pharmaceutical compositions that comprises bitterness medicine and pH sensitive polymer.

Background of invention

Though developed many induction systems to be used for different route of administration, for example oral administration, parenteral, nose administration and transdermal administration or the like, but for drug conveying, oral administration route is still the most attractive, because this mode of administration is simple, convenient, Noninvasive and common medicament delivery method.Most of prescription drugss are designed to oral application, because the patient can automedication and without hospitalization.Peroral dosage form can design according to the character of the character of medicine, medication and to the demand of needed any special effect in the induction system.Conventional peroral dosage form comprises: such as the liquid mixture of solution, suspensoid, such as the solid dosage forms of tablet and capsule and liquid-filling capsule or the like.This solid dosage forms also can as controlled release, slow release or extended release, improve according to needed therapeutical effect.Yet, the patient at extreme age, for example child and old people often feel difficulty when swallowing solid oral dosage form.For these patients, drug main will provide with the liquid dosage form such as solution, emulsion and suspension.But these dosage forms are exposed to taste bud with active pharmaceutical ingredient perception ground usually, and when medicine had ill-sorted taste or bitterness, this just became very serious problem.

Because oral administration, the bitterness of medicine is unfavorable factor in many aspects.Taste is the important parameter of control compliance.The disagreeable taste of medicine causes dysphagia or causes that the patient escapes takes medicine, thereby causes low patient's compliance.The conventional taste masking technology such as sweeting agent, aminoacid, flavoring agent is normally unsuccessful in the taste of covering utmost point bitter medicine thing, these utmost point bitter medicine things are quinine, barberin, etoricoxib, antibiotic, for example levofloxacin, ofloxacin, Sparfloxacin, Gatifloxacin, ciprofloxacin, CEFUROXIME AXETIL, Abboticine and clarithromycin for example.Therefore the taste masking technology is considered to important, and develops this technology by many researcheres.

When medicine had ill-sorted taste and bitterness, taste masking was a subject matter.In addition, this problem is not limited only to the liquid oral compositions such as solution, dry syrup and suspension, and also may run into this problem in the process for preparation of chewable tablet or dispersible tablet the time, but wherein these dosage forms make active component perception ground be exposed to taste bud usually.Depend on the kind of dosage form, having made ins all sorts of ways overcomes the disagreeable taste and the bitterness of medicine.

Patent application WO 03/13470 discloses use glycyrrhyzinate ammonium taste masking preparation, be made up of the drying composite of Paroxetine and glycyrrhyzinate, but it can be manufactured to dispersion powder or available mould and makes and can disperse or chewable tablet.Patent application WO03/11227 discloses a kind of taste that is used for the ibuprofen administration and has covered compositions, and it is containing under the ibuprofen chewable tablet form of polymer, carbomer 934, can cause that throat catches.European patent discloses the quality of chewable tablet and acetaminophen active component for No. 1219291 and has covered (texture masked) granule, it is covered the polymer ethyl cellulose by taste, form thin polymer film, and the quality of hydroxypropyl emthylcellulose, Polyethylene Glycol 800 and acesulfame potassium is covered bag by solution bag quilt.

In other one piece of patent application JP 2002363066, medicine or food compositions that a kind of taste is covered are disclosed, it is suitable for making granule, tablet or chewable tablet.The fine particle that taste is covered is by using polymer such as ethyl cellulose, and hydroxypropyl emthylcellulose obtains.European patent EP 1166777 discloses the chewable tablet of being made by the granule of having covered taste.The active component ibuprofen by intestinal polymer HPMCP and not dissolving films form agent cellulose acetate bag quilt, and there is not chewable tablet that throat burns by mixing aspartame, acesulfame potassium, citric acid, granular mannitol, fumaric acid, the bag of Celluloasun Microcrystallisatum and spice is made by granule.

The taste concealing technique also is extended to and can disperses dosage form and rapid the decomposition in the tablet.Patent application WO01/58449 discloses water-dispersible powder and the tablet that needs the Paroxetine that medicine discharges immediately, and the taste masking agent that contains methacrylic acid copolymer.This taste is covered the spray drying method of compositions by Paroxetine and polymer and is obtained.

Patent application WO 02/64119 disclose in the oral cavity, can cover unhappy taste and in digestive tract in the tablet active component by the quick decomposition tablet of fast Absorption.The disclosure file be only limited under neutrality or the alkali condition indissoluble in the water but under acid condition in the water dissolubility high and produce the medicine of unhappy taste.The physicochemical properties of different pharmaceutical molecule are that different and such system is unsuitable for water soluble drug.Patent application WO 01/52848 discloses a kind of taste of Linezolid and has covered oral formulations, it is by the solvent cohesion microencapsulation antibiotic of ethyl cellulose and a kind of Lac arbitrarily sealing coating, and further be made into suspension by granule, decompose effervescent or chewable tablet fast with functional polymer Eudragit L30D bag.The microsome of these preparations can be suspended in the aqueous medium before to child and gerontal patient's oral administration, and these patients are unwilling and/or find that swallow tablet etc. is very difficult.Can prepare quick decomposition tablet, it can be distributed to rapidly in mouth in the granule that taste covers.

In the past attempted various taste concealing methods, and comprised making spent ion exchange resin, medicine can be accepted the complexing of excipient, and lipid and the different polymeric material bag quilt to medicine.In these methods, bag is by the technology that is extensive use during taste is covered.The bag of active component can be used known any technology, as the microcyst method, and hot melt granulation, wurster's coating, spray drying method.

A kind of ion exchange resin that is to use in the taste concealing method.Use various resin anion (R.A.)s such as DuoliteAP143/1083 (cholestyramine resin (cholestyramine resin), American Pharmacopeia), cationic resin such as Amberlite IRP 64 (methacrylate and divinyl benzene crosslinked copolymer) and Dowex (based on polystyrolsulfon acid and divinyl benzene crosslinked).The United States Patent (USP) 6514492 that transfers Schering Plough discloses the taste that makes spent ion exchange resin AMBERLITE.RTM.IRP 69 cover Carbostyril derivative and has eliminated the bitterness of quinolones in the oral liquid with this.

Patent application WO01/70194 discloses and has been suitable for adhering in consumer's mouth and the oral thin film of dissolved quick dissolving.This thin film is made up of ion exchange resin, Amberlite (amberlite) and water-soluble polymer amylopectin as the taste masking agent of bitterness medicine dextromethorphan.This thin film is attached in the oral cavity and dissolve release of active ingredients.Want to use in liquid oral medicine if taste is covered, in preparation, use water-soluble polymer will limit the use of transmission system.In addition, such transmission system may bad being accepted in very important child of compliance and old preparation.United States Patent (USP) the 6th, 001 discloses a kind of Orally administered controlled syrup suspension of the dextromethorphan that is adsorbed on the polystyrene Sulfonate resin that contains No. 392.The pharmaceutical polymer complex is by ethyl cellulose or ethyl cellulose emulsion and plasticizer with as the mixture bag quilt of dispersible polymers in the water of SURELEASE.To the medicine that needs rapid action directly to discharge, the sustained release of active component may not be that delay favourable and that discharge may or have the problem of the medicine of limited absorption window.

Finding to make spent ion exchange resin absorption to contain amino medicine when covering utmost point bitter medicine thing and medicine and will be dispersed in the liquid oral compositions for a long time comes the taste masking adaptability limited.

Complexing is to cover the another kind of method of bitterness medicine taste.United States Patent (USP) 4,808,411 disclose a kind of taste of being made up of the carbomer of 25% to 95% Abboticine and 75% to 5% covers compositions, and its Chinese medicine and carbomer combine with the ionic interaction of carbomer by Abboticine.This synthetic further is coated in the HYDROXY PROPYL METHYLCELLULOSE polymer of functionality and makes preparation good to eat.Abboticine slowly discharges to avoid obviously feeling bitterness in the mouth from synthetic.Clearly, in patent disclosed, realized the slow release rather than the rapid release of bitterness medicine.It is not fully that but complexing is covered for taste individually, and for the palatability functionality macromolecule bag that reaches expectation is also needed, and because drug release should not suffer damage, the selection of chelating agent is important.

Pharmaceutical pack is another kind of method, but use separately proof only medium amara thing or enwrapped granule to be created water formulation before administration or the drug products in non-aqueous media, made effective.

Patent application WO 02/092106 discloses a kind of taste that contains polycarbophil and macrolide antibiotics and has covered compositions.This is combined into thing further by acidproof polymer acrylic resin L10055 ^TMThe bag quilt discharges in intestinal.Bioavailability can will not use casing to change owing to discharging in small intestinal for some drugs, and still the drug limits of narrow absorption window is at the upper area of stomach, and bioavailability may be owing to using casing change.European patent EP 0409254 discloses uses ethyl cellulose and sweller to cover the oral particulate preparation with unpleasant taste, and active component discharges from described composition fast.United States Patent (USP) the 5th, 635, the particulate dispersion that these are wrapped by lipid coating with in non-aqueous media that discloses bitterness medicine ranitidine for No. 200 prepares taste and covers preparation.U.S. Patent application disclose for 2003-028025 number be applicable to medicinal preparation for oral administration shape especially the taste of the Gatifloxacin of pediatric medicament composition cover compositions.One or both of the crystal coprecipitate of Gatifloxacin and stearic acid and palmitic acid are used to cover effectively in the mouth and the bitterness that passes through Gatifloxacin in 14 days circulation aqueous suspensions of capacity.

Patent application WO 02/72111 discloses a kind of taste and has covered medicine Ketek suspension.Used 4 kinds of different coating materials Novata AB, Eudragit E100, glyceryl monostearate and Pulvis Talci M10, and need at least three layers of continuous coatings to cover the taste of Ketek.The granule of described disclosed bag quilt can further be made the dry syrup that can be reassembled as suspension.United States Patent (USP) 4,865,851 disclose the another kind of method of covering high bitterness, the CEFUROXIME AXETIL of the complete lipid coating of usefulness taste masking or the particle form of lipid mixture bag quilt.

Using the taste of lipid to cover fusing point that coating requires lipid wants enough height to avoid dissolving in mouth but can not be too high so that active component dissolves or chemical degradation.It is small that amorphous CEFUROXIME AXETIL with maximum bioavailability has the low melting point about 70 ℃ and the fusing point difference of medicine and lipid.The temperature of mixture atomizing is also than the fusing point height of lipid.Need complicated hot melt granulation technology be used for producing microgranule and do not produce adverse effect based on the microcyst method of lipid drug molecule.

British patent also discloses for No. 2081092 in order to reach taste and has covered the lipid coating of purpose.Yet, find that wax shape coating causes dissolubility variation in intestinal of active component.In addition, this patent disclosure the technology of the polymer mixed by wax and rising property of water overcome this problem.The use of the polymer of the rising property of mentioning in this patent of water makes it not too to be applicable to that the fluid port such as suspension and dry syrup takes medicine.United States Patent (USP) the 5th, 286, No. 489 descriptions are a kind of to mix the porous drug polymeric matrix that forms by the bitterness active component with methylmethacrylate copolymer, and wherein active component was at least 1: 1 the weight ratio of copolymer, and can effectively cover the taste of medicine.Embodiment neither one described in the patent discloses the effect that these polymer Chinese medicines discharge from substrate.Yet can predict the release of medicine from substrate from the instruction of prior art has been hindered.

Patent application WO 00/56266 discloses rising property of use high viscosity water polymer carbomer and has combined with thin film and form the taste that the bitterness medicine is covered in polymethacrylates and passage agent (channelising agent).Rapid release active component in the medium that is added on stomach of rising property of water polymer builder.The taste masking compositions that a kind of two kinds of intestinal polymer mixed that contain methacrylic acid copolymer and O-phthalic acid polymer form is disclosed in another one patent application WO 00/76479.This patent disclosure the use of passage agent, this passage agent contains water-soluble or rising property of the water material that the auxiliary activity component discharges.To discharge active component under the soluble alkaline pH value of polymer be known to disclosed intestinal polymer in this patent.Because the use of intestinal polymer and because the narrow absorption window that medicine has the upper gastro-intestinal tract of being limited in, the release of active component can be delayed.Therefore this system can be limited to use.

People such as M.Cuna are (referring to M.Cuna, M.L.Lorenzo, J.L.Vila-Jato, D.Torres, M.J.Alonso, Acta Technologiae et Legis Medicamenti.volume VII, N.3,1996) microencapsulation of the high bitterness medicine CEFUROXIME AXETIL that is used for taste masking is disclosed, it uses different polymeric material such as cellulose acetate trimellitate, HPMCP-50, HPMCP-55, purpose is taste masking and guarantees to discharge in enteric cavity.

In another publication, people such as Alonso are (referring to M.J.Alonso, M.LLorenzo-Lamosa, M.Cuna, J.L.Vila-Jato and D.Torres, JournalMicroencapsulation, 1997, Volume14, No.5 607-616) has described high bitter medicine thing CEFUROXIME AXETIL encapsulated to form the suspension dosage form at the acrylic acid microsphere of pH sensitivity.The acrylate copolymer that uses is Eudragit E ^TM, Eudragit RL100 ^TM, Eudragit L100-55 ^TMCationic polymer Eudragit E ^TMShow negative interaction with CEFUROXIME AXETIL.Intestinal polymer EudragitL100-55 ^TMGood release action is arranged under alkaline pH value.

Above-mentioned open in, the release of research CEFUROXIME AXETIL in alkaline medium.People such as Dantzig is (referring to Anne H.Danzig in contrast, Dale C.Duckworth, Linda B.Tabas, Biochimica et Biophysica Acta 1191,1994,7-13) show by esterase in the enteric cavity CEFUROXIME AXETIL hydrolysis become cefuroxime, reduce the concentration of CEFUROXIME AXETIL in enteric cavity, cause absorbing reduce and human body in the low bioavailability of CEFUROXIME AXETIL.CEFUROXIME AXETIL has had only the bioavailability of 32-50%, and any reason owing to the preparation aspect all should reduce declined bioavailability of oral administration.

Taste masking preparation should be designed to not so that to sacrifice bioavailability of medicament be cost and should not influence the time that reaches peak value such as the use of the such polymer of casing.In addition, medicine should fully absorb to guarantee the effective treatment concentration in the blood plasma.People such as Vogelman (referring to B.Vogelman, and William A.Craig 108 (5, pt2) 835-40, Journal Pediatric 1986 ﹠amp; B.Vogelman, William A.Craig, S.Ebert, S.Gudmundsson, J.Leggett, J.Infect.Diseases1988,158 (4), 831-47) proof sterilization should be fast and intensive, and bactericidal effect and concentration grow proportionately.Under high drug level, moment finishes completely and almost in sterilization.Absorption and high systemic concentrations are important for producing the desired therapeutic effect rapidly with completely for some drugs.

Because its physicochemical characteristics, in the preparation process, some drugs is challenging, for example, and second generation cephalosporin antibiotic CEFUROXIME AXETIL and from the celecoxib of COX2 inhibitor class.Celecoxib all has relative high dosage demand with cefuroxime, and this has just further strengthened the difficulty of carrying out the dose therapeutically effective administration.When contacting with aqueous medium, CEFUROXIME AXETIL is tending towards gel, and this forces dosage form to form gel in vivo and before is decomposed into granule fast, and discharges medicine quickly.Another problem relevant with CEFUROXIME AXETIL relates to the extreme bitterness of medicine, and this makes CEFUROXIME AXETIL must be mixed with the induction system of bag quilt so that it becomes good to eat.Celecoxib has extremely low water solublity and is difficult for dissolving and disperseing in gastrointestinal tract absorbing rapidly, and in addition, the amorphous form of known celecoxib increases its dissolubility and bioavailability thereof, its trend crystallization when still contacting with aqueous medium.Have the prescription problem and need need not damage bioavailability with the bioactive molecule that overcomes low bioavailability with the administration of quick-release formulation, and the polymer coating that protectiveness is arranged that can the rapid release active component when covering the active component bitterness.

Patent application WO 02/43707 discloses the taste of the CEFUROXIME AXETIL that bilayer film bag quilt is arranged and has covered tablet composition, and wherein the ground floor coating plays bitterness and covers effect, and second layer coating postponed the rupture time of tablet above 40 seconds.Because CEFUROXIME AXETIL has gelation tendencies when contacting with aqueous medium, thus declined bioavailability of oral administration, and cefuroxime discharges rapidly from the nuclear of dosage form to be expected more.

United States Patent (USP) the 5th, 599 discloses liquid formulation No. 556, wherein active component single outer polymer coating and the plasticizer bag quilt that obtains from the prolamin corn protein.With the bitterness medicine Clarith of polyvinylpyrrolidone co-blended by the prolamin bag by to realize that taste is covered and coated granule is dispersed to pH value and is higher than in 6 the suspension medium.It is to degrade rapidly in the arrival stomach that coating is designed to leave in the mouth when compositions.Most liquid oral medicine compositions is preparation (referring to US Pharmacopoeia/NationalFormulary 23/NF18,1995) when pH value is 3.5-5.5.Some drugs may be when higher pH value instability, and some medicinal may be when the pH value of extremely acid instability, and trend time-delay degraded.

United States Patent (USP) the 5th, 489 discloses the chewable tablet that a kind of medicine that wraps quilt is made No. 436, and the low pH value that coating is designed under one's belt can dissolve, but relatively can not be water-soluble during higher pH in mouth.This coating comprises dimethylaminoethyl acrylate methyl ammonia ethyl ester and neutral methacrylate and cellulose ester polymer mixture.Taste mentioned above is covered oral formulations " anti-intestinal " method for coating and has been disclosed together with chewable tablet.

Patent application WO 02/096392 discloses the taste of highly water soluble drugs hydrochloric acid cetrizine and has covered.Use effectively cover cetrizine tablet taste and can common under one's belt acid condition under discharge the polymer of medicine immediately, this polymer is HYDROXY PROPYL METHYLCELLULOSE for example, polyvinylpyrrolidone, ethyl cellulose.

Can find out obviously that from above open file taste is covered and can be realized by many methods.Intestinal polymer such as eudragit L are used to taste and cover, but pH of saliva near 5.8 and these polymer be higher than dissolving in 5.5 o'clock at pH.Therefore medicine might part leach.Cover polymer so need the exploitation taste badly; thereby the pH of saliva in mouth and in the medium of other reconstruct of taking medicine as fluid port bitterness be aggregated thing fully and cover; and can further protect medicine to be in biologically active form; and prevent that moisture from entering dosage form, prevent it to change solvation or polymorphic form into.

Although the use of polymer coating is when contacting with saliva in above-mentioned example, chew the stripping that can effectively delay medicine in the process, when preparation contact with liquid medium for a long time the taste of storage cover liquid component the time it have disadvantageous aspect.In the above-described list of references, there is not one piece of document can satisfy the bitterness of in pharmaceutical composition, covering medicine as suspension, dry syrup, medicine in this dry syrup should can not leach in suspension in 14 days at common recombination stage, and can not satisfy to discharge under one's belt after picked-up and do not influence bioavailability again.Although various technology and the medicated premix of covering bitterness medicine taste well known in the art need find kind otherwise effective technique, additive or its combination at particular agent.

Goal of the invention

The purpose of this invention is to provide oral taste masking compositions, said composition can be carried the active amara of fundamental quantity at once, and has improved palatability by the synthetic pH sensitive polymer of application specific, this pH sensitive polymer dissolves under the acid condition of stomach or expands, and in neutral or nearly neutral medium, do not dissolve or do not expand, it can be applicable to the peroral dosage form of various medicines.The term used herein peroral dosage form means through port with the gastrointestinal of described delivery of composition to individuality, is intended to any pharmaceutical composition to individual administration.Peroral dosage form comprises tablet, for example chewable tablet, dispersible tablet, coated tablet; Liquid such as dry syrup and suspensoid.

The compositions that the purpose of this invention is to provide the taste masking of forming by the pH sensitive polymer, the preparation of drug combination method that the synthetic method of these polymer also is provided and has comprised these polymer.

Another purpose of the present invention is a synthetic polymer, and it can cover the disagreeable taste of described medicine but the dissolution rate and the bioavailability that do not endanger this medicine effectively, and this medicine of rapid release in gastral cavilty also.

Another purpose of the present invention is an exploitation pH sensitive polymer, and it is applicable to the oral liquid of taste masking, for example the solid dosage forms of suspensoid, dry syrup and taste masking, for example chewable tablet, quick dispersible tablet and conventional tablet.

Another purpose of the present invention is to stop described medicine when pH of saliva and leaching from described liquid and solid dosage forms in the reorganization medium.

Another purpose of the present invention is by the whole bag of tricks well known in the art, and for example, microencapsulation, tray dried, fluidized bed processing and spray drying or the like come described amara composition granule is wrapped quilt.

Another purpose of the present invention is that preparation comprises bag by particulate liquid oral dosage form.

Summary of the invention

Therefore, the invention provides and comprise pH sensitive polymer and bitterness medicine, formula is P[A _(x)B _(y)C _(z)]: the taste-masking pharmaceutical compositions of D, wherein P for comprise (A) hydrophobic monomer, (B) alkaline monomer and (C) hydrophilic monomer the pH sensitive polymer and (D) be the bitterness medicine, and (x)=30-95%, (y)=5-70%, (z)=0-60%, all represent with w/w (w/w), and (P): ratio (D) is 30: 1-0.2: 1w/w.

In another embodiment of the present invention, hydrophobic monomer (A) is the acrylic or methacrylic acid esters, it is selected from cyclohexyl acrylate, dodecyl acrylate, 2-EHA, 1-Octyl acrylate, tert-butyl acrylate, phenyl acrylate, butyl acrylate, methyl methacrylate, benzyl methacrylate, cyclohexyl methacrylate, phenyl methacrylate, metering system tert-butyl acrylate, butyl methacrylate, methacrylic acid 2-Octyl Nitrite, propyl methacrylate, is preferably butyl acrylate, methyl methacrylate and butyl methacrylate.

In another embodiment of the present invention, described alkaline monomer (B) is selected from aminoalkyl acrylic acid and methacrylate, it is selected from dimethylaminoethyl acrylate, acrylic acid lignocaine ethyl ester, dimethylaminoethyl methacrylate, diethylaminoethyl methacrylate, methacrylic acid piperidines ethyl ester, methacrylic acid uncle 2-fourth amino ethyl ester and dimethylaminoethyl methacrylate, is preferably dimethylaminoethyl methacrylate and acrylic acid lignocaine ethyl ester.

In another embodiment of the present invention, described alkaline monomer (B) is the thiazolinyl pyridine, it is selected from 2-vinylpyridine, 3-vinylpyridine, 4-vinylpridine and 5-vinyl-2-picoline, 2-vinyl-4-picoline, the different propenyl pyridine of 2-, different propenyl pyridine, is preferably 4-vinylpridine.

In another embodiment of the present invention, described alkaline monomer (B) is selected from vinylquinoline, aminoalkyl vinyl Ether, aminoethyl styrene and allylamine, is preferably allylamine.

In another embodiment of the present invention, described hydrophilic monomer (C) is the acrylic or methacrylic acid esters, and it is selected from hydroxyethyl methylacrylate, Hydroxypropyl methacrylate, hydroxyethyl methacrylate diethyl acetamidomalonate, 2-(Acryloyloxy)ethanol, Hydroxypropyl acrylate, acrylic acid ethoxy ethyl ester, is preferably hydroxyethyl methylacrylate and hydroxyethyl methacrylate diethyl acetamidomalonate.

In another embodiment of the present invention, described medicine comprises macrolide antibiotics, and it is selected from Abboticine, azithromycin and Clarith; Fluoroquinolones, it is selected from ciprofloxacin, enrofloxacin, ofloxacin, Gatifloxacin, levofloxacin and norfloxacin; Cephalosporins, it is selected from cefuroxime, cephalexin, cefadroxil, Cefpodoxime Proxetil (cepfodoximeproxetil) and is selected from ibuprofen and the nonsteroidal anti-inflammatory analgesic drug product of diclofenac sodium, with the cox 2 inhibitor that is selected from etoricoxib and celecoxib, be selected from the antihistaminic of chlorphenamine maleate, be selected from  (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides and other medicine of Linezolid such as dextromethorphan.

In another embodiment of the present invention, the total polymer that is used for covering best the bitter medicine taste is 30 to the ratio of medicine: 1-0.2: 1 weight ratio.Preferred polymer to the ratio of medicine for being 5: 1-0.4: 1 weight ratio.

In another embodiment of the present invention, under one's belt acid pH of described pH sensitive polymer≤3 dissolvings or expand, and o'clock do not dissolve in pH＞3.5 or do not expand.

In another embodiment of the present invention, use described medicine itself or the acceptable salt of its medicine or ester or amide.

In another embodiment of the present invention, described medicine is dispersed in the described polymeric matrix or with it with the form of microgranule and wraps quilt.

In another embodiment of the present invention, the pharmaceutical dosage form that available compositions of the present invention prepares can be such as the oral liquid of dry syrup or suspensoid and chewable tablet or dispersible tablet.

In another embodiment of the present invention, the pharmaceutical composition itself that comprises described microgranule, or its medicine acceptable forms discharge the medicine of minimum from described peroral dosage form when pH of saliva, but in pH≤3 of stomach, the medicine of rapid release fundamental quantity at once.

In preferred embodiments, described microgranule can be formulated as aqueous suspension or recombinate in liquid medium and be used for normal storage period.

In another embodiment, described pharmaceutical composition can be by any technique known, preferably, described bitterness medicine is disperseed or is coated in the pH sensitive polymer substrate to obtain by microencapsulation, spray drying, fluidized bed processing, co-precipitation or in non-solvent by the tray dried method.

In another embodiment, use pH and be 4.5, the reorganization medium that comprises sucrose, fruit salad flavor flavoring agent, citric acid and polyvinylpyrrolidone carries out suspendible to the pharmaceutical polymer substrate of the taste masking that exists with particle form.

The present invention also relates to comprise pH sensitive polymer and bitterness medicine, formula is P[A _(x)B _(y)C _(z)]: the preparation method of the taste-masking pharmaceutical compositions of D, wherein P for comprise (A) hydrophobic monomer, (B) alkaline monomer and (C) hydrophilic monomer the pH sensitive polymer and (D) be the bitterness medicine, and (x)=30-95%, (y)=5-70%, (z)=0-60%, all explain with w/w (w/w), and (P): ratio (D) is 30: 1-0.2: 1w/w.

In another embodiment of the present invention, use described medicine itself or the acceptable salt of its medicine or ester or amide

In another embodiment of the present invention, the total polymer that is used for covering best the bitter medicine taste is 30 to the ratio of medicine: 1-0.2: 1 weight ratio.Preferred polymer is 5 to the ratio of medicine: 1-0.4: 1 weight ratio.

In another embodiment of the present invention, acid pH≤3 dissolving or expand under one's belt of described pH sensitive polymer, and o'clock do not dissolve in pH＞3.5 or do not expand.

Detailed description of the invention

The invention provides oral pharmaceutical composition, it has covered the bitterness of effective ingredient effectively, the disagreeable taste of offending and others.More particularly, the present invention relates to can be used for pH sensitive polymer synthetic of many pharmaceutical compositions, this pH sensitive polymer provides the taste of bitterness active component to cover and basic release at once and absorption, and it is normally suitable in such as the solid of tablet, chewable tablet or dispersible tablet and suspensoid or dry syrup and liquid dosage form.The present invention also relates to prepare this method for compositions.

Because anti-intestinal polymer dissolves in pH≤3 acidity or expands, and as in saliva and maximum 14 days complete storage period seen in the reorganization medium, prevent that this medicine from discharging in pH＞3.5, so compositions of the present invention provides the basic release at once of bitterness reactive compound with the form of taste masking preparation.Synthetic pH sensitive polymer consists essentially of hydrophobic monomer, alkaline monomer and optional hydrophilic monomer.

Key character of the present invention has been to provide the flavor hidden microcapsule of bitterness medicine, it is applicable to oral administration as suspensoid, fast disintegrant, effervescent or chewable tablet, and relate more particularly to such peroral dosage form, by the pH sensitive polymer described microcapsule is carried out the functional membrane bag at the bitterness of this peroral dosage form Chinese medicine and covered.According to the present invention, the flavor hidden microcapsule that is used for covering orally active bitterness medicine taste comprises by emulsifying, solvent evaporation or solvent extraction or the medicament microcapsule in polymer coating substrate by the spray drying technology preparation.More specifically the present invention relates to such as dry syrup, be intended to the liquid oral medicine that taste that department of pediatrics uses is covered.Similarly described preparation is applicable to all, owing to physical factor or preference, prefers the patient of liquid preparation.The reorganization liquid preparation that being also advantageous in that of taste masking compositions of the present invention made from said composition is stable in maximum 14 days in normal therapeutic dose schedule usually.

According to basic feature of the present invention, the taste of bitterness medicine is covered by using the pH sensitive polymer and this bitter medicine is wrapped is finished, wherein this polymer dissolving or expand basically under the acid condition of stomach, and in neutral or nearly neutral pH environment, do not dissolve or do not expand.When being applied to pharmaceutical dosage form, for example, such as the oral liquid of dry syrup or suspensoid with such as the tablet of chewable tablet or dispersible tablet, described pH sensitive polymer discharges described active component in the acid pH environment of stomach, but by preventing that this medicine seepage in pH of saliva or suspension medium or nearly neutral water environment from keeping agreeable to the taste taste.Described pH sensitive polymer synthesizes by coming from hydrophobic monomer and alkaline monomer class and optional hydrophilic monomer on using substantially.

The present invention be on the other hand preparation bag quilt the bitterness medicine suspensoid and in maximum 14 days recombination stages, prevent this medicine seepage in suspension medium, and also guarantee active medicine basic release and do not influence bioavailability in simulated gastric fluid.Therefore pH sensitive polymer of the present invention suppresses described activating agent and discharges in the aqueous medium of pH＞3.5, suppresses the bitterness medicine in saliva, also in the reorganization medium, as leaching in the oral liquid, and in the environment of pH≤3 of stomach this medicine of rapid release.

The present invention also provides the taste of bitterness medicine to cover, and this bitterness medicine for example is a macrolide antibiotics, for example, and Abboticine, azithromycin and Clarith; Fluoroquinolones, for example, ciprofloxacin, enrofloxacin, ofloxacin, Gatifloxacin, levofloxacin and norfloxacin; Cephalosporins, for example, cefuroxime, cephalexin, cefadroxil, Cefpodoxime Proxetil (cepfodoxime proxetil) and such as the nonsteroidal anti-inflammatory analgesic drug product of ibuprofen and diclofenac sodium, reach cox 2 inhibitor such as etoricoxib and celecoxib, antihistaminic such as chlorphenamine maleate,  (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides and other medicine such as Linezolid such as dextromethorphan.Medicine itself or the acceptable salt of its medicine or ester or amide can be used for the present invention.Be preferably used for implementing medicine of the present invention and can be selected from CEFUROXIME AXETIL, ciprofloxacin, celecoxib and Clarith.In the pharmaceutical composition of the present invention, the total polymer that is used for covering best the bitter medicine taste is 30: 1 to 0.2: 1 weight ratios to the ratio of medicine.More preferably polymer is 5 to the ratio of medicine: 1-0.4: 1 weight ratio.

Especially, the present invention includes the exploitation of preparation, said preparation is as the liquid suspension of stable taste masking, it can be ingested, and do not produce the disagreeable taste relevant with described activating agent, during the pH level in being exposed to human stomach, still provide bioavailability at once simultaneously.

As described herein, another feature of the taste masked particle that is obtained is can be randomly and the acceptable mixed with excipients such as flavoring agent, sweeting agent, suspending agent and/or antiseptic of other medicines, and be formulated as dry syrup or be pressed into fast disintegrant, effervescent or chewable tablet.The stabilized aqueous suspension can be prepared from the dry syrup powder, to be used to be unwilling and/or to be difficult to the child and the gerontal patient's of swallow tablet maximum 14 days oral administrations.Rapid disintegration tablet is disintegrate fast in mouth, therefore is applicable to that those are difficult to the patient's of swallow tablet oral administration.The dosage form of this oral administration in the reorganization acidity of medium, discharged 10% at the most in maximum 14 days, and most preferably at the most 5%, but in gastric acid, rapid release 40-60% at least in 15 minutes, and in 1 hour at least 70%.

The particle mean size of described microcapsule is about the 30-1000 micron, most preferably is about 100-500 micron.

The example of medicine spendable bitterness, disagreeable taste includes, but are not limited to macrolide antibiotics, for example, and Abboticine, azithromycin and Clarith; Fluoroquinolones, for example, ciprofloxacin, enrofloxacin, ofloxacin, Gatifloxacin, levofloxacin and norfloxacin; Cephalosporins, for example, cefuroxime, cephalexin, cefadroxil, Cefpodoxime Proxetil (cepfodoxime proxetil) and such as the nonsteroidal anti-inflammatory analgesic drug product of ibuprofen and diclofenac sodium; Reach cox 2 inhibitor such as celecoxib and etoricoxib; Antihistaminic such as chlorphenamine maleate;  (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides and other medicine such as Linezolid such as dextromethorphan.

The various derivants of polymethacrylates and cellulosic polymer have been used for bag by the CEFUROXIME AXETIL medicine in the past.The release characteristic spectrum of this medicine from these materials depends on the polymer type that is used to wrap quilt.Disclosing CEFUROXIME AXETIL among the patent application WO0236126 continues to discharge from the compositions that comprises eudragit L30D, eudragit RL 30D and eudragit RS 30D.CEFUROXIME AXETIL in 0.07N HCl 1 hour and be that release in 6.8 the phosphate buffer discloses as follows at pH:

Time: 60 minutes 120 minutes 180 minutes 240 minutes 360 minutes

Discharge %:34.6 44.3 67.4 83.7 96.1

Alonso discloses CEFUROXIME AXETIL and has discharged from the microgranule that obtains by the polymer coating of using eudragit E, eudragit L100-55 and eudragit RL-100 (referring to M.J.Alonso, M.L Lorenzo-Lamosa, M.Cuna, J.L.Vila-Jato and D.Torres, Journal ofMicroencapsulation, 1997, Volume 14, No.5,607-616).20-30 minute the time, CEFUROXIME AXETIL almost completely discharges from eudragit E microsphere in 0.07N HCl.With compare among the 0.07N HCl, be that CEFUROXIME AXETIL slowly discharges from eudragit E microsphere in 7 the Sorensens buffer at pH.The release data are summarized as follows:

0.07N HCl medium

Time: 10 minutes to 20 minutes

Discharge %: high to 80-100

PH5.8 Sorensens buffer solution medium

Time: 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

Discharge %: maximum 20 30 40 45 50 60

But cationic polymer eudragit E shows and the negative interaction of CEFUROXIME AXETIL that in the presence of eudragit E, CEFUROXIME AXETIL shows significant Degradation.With the microsphere of eudragit L 55 and RL under the condition of pH5.2 2 hours, discharge＜9%, under the condition of pH6.0 30 minutes, significantly discharge 75% amount.

People such as M.Cuna disclose and have used different polymeric materials, for example, cellulose acetate trimellitate, HPMCP-50, HPMCP-55 wrap CEFUROXIME AXETIL and are come taste masking (referring to M.Cuna, M.L.Lorenzo, J.L.Vila Jato, D.Torres, M.J.Alonso, ActaTechnologiae et Legis Medicamenti.volume VII, N.3,1996).The release data are summarized as follows:

(utilizing the microsphere of HPMCP-55) is when pH5.2

Time: 15 minutes to 60 minutes

Discharge %: less than 15%

(utilizing the microsphere of HPMCP-55) is when pH6.0

Time: 15 minutes 30 minutes

Discharge %:50-75 75-100

In above-mentioned disclosing, release to CEFUROXIME AXETIL in alkaline medium is studied, wherein people such as Dantzig (referring to Anne H.Dantzig, Dale C.Duckworth, Linda B.Tabas, Biochimica et Biophysica Acta 1191,1994,7-13) show that esterase is hydrolyzed to cefuroxime with CEFUROXIME AXETIL in the enteral chamber, reduced cefuroxime ester concentration in the inner chamber, and cause absorbing minimizing, make CEFUROXIME AXETIL reduce in the intravital bioavailability of people.

In the presence of aqueous medium, be tending towards gelation such as the drug molecule of CEFUROXIME AXETIL.If described tablet is not moistureproof at lay up period, then causes bad dissolubility and reduce drug bioavailability.Therefore, the liquid oral medicine of CEFUROXIME AXETIL needs protection against the tide between recombination stage.Because enzyme, esterase are hydrolyzed to cefuroxime with it, thereby cefuroxime can not reduce its bioavailability through intestinal absorption, so CEFUROXIME AXETIL has limited absorption region in gastrointestinal tract.CEFUROXIME AXETIL is also relevant with utmost point bitter taste.Therefore, the pharmaceutical composition of CEFUROXIME AXETIL needs taste masking.Therefore, for CEFUROXIME AXETIL, the application of water solublity and enteric coatings is restricted.In a preferred embodiment of the invention, being used for the bitterness medicine of taste masking comprises CEFUROXIME AXETIL, ciprofloxacin and Clarith.One of the present invention is characterised in that described polymer rapid expanding and/or dissolving under condition of acidic pH, rapid delivery of pharmaceuticals from this polymer coating simultaneously, CEFUROXIME AXETIL for example, it has the low bioavailability of 32-50%, does not therefore cause any absorption delay and changes its bioavailability.The release of described medicine from the used polymer of the present invention is disclosed in

Among the embodiment.

Another feature of the present invention is available pH sensitive polymer, by microencapsulation, spray drying, fluidized bed processing, co-precipitation in non-solvent, perhaps by the tray dried method described medicine is wrapped and is obtained compositions of the present invention.This medicine is dispersed in this polymeric matrix.

In another feature, described taste masking compositions produces by described medicine microencapsulation in polymeric matrix.The microencapsulation of bitterness medicine can be by emulsifying, solvent evaporation or solvent extraction and pharmaceutical polymer solution spray drying or medicine be dispersed in the polymer solution and obtain.If described medicine is insoluble in this polymer solution, then under assistance, this medicine is evenly dispersed in this polymer solution such as the dispersant of surfactant.Preferred surfactants is the nonionic surfactant that belongs to SPAN and TWEEN class.Preferred solvent is that described medicine and polymer all are dissolved in this solvent.In a preferred embodiment of the invention, the selected solvent that is used to dissolve this medicine and polymer is alcohol, for example, and methanol, ethanol, isopropyl alcohol, butanols; Chlorinated hydrocabon, for example, dichloromethane, chloroform; Ketone, for example methyl ethyl ketone, methyl iso-butyl ketone (MIBK) and acetone.The preferred solvent that is used to dissolve this medicine and polymer is methanol, acetone and dichloromethane.The solvent that is used to dissolve this medicine and polymer is preferably 1: 1 to 1: 1.5 mixture of acetone or methanol and dichloromethane.

The flavor hidden microcapsule of described bitterness medicine can obtain by the microencapsulation of emulsified solvent evaporation technique.Decentralized photo is the organic solvent that contains this medicine and polymer, and disperse medium is a liquid paraffin.Synthetic pH sensitive polymer is dissolved in (1: 1 to 1: 1.5 mixture of acetone, methanol, dichloromethane or methanol and dichloromethane) in the organic solvent.Described medicine is added generation solution or uniform dispersion in this polymer solution.This organic facies adding is comprised in the light liquid paraffin of span 85 (0.1 to 1% w/w (w/w)).The constant mechanical agitation speed of 1000rpm and room temperature continue 3-4 hour.Evaporating solvent, and the microsphere that isolated by filtration obtained, with petroleum ether and 27 ℃ the time maximum 24 hours of vacuum drying.

The flavor hidden microcapsule of described bitterness medicine also can obtain by the microencapsulation of emulsified solvent extractive technique.Decentralized photo is the organic solvent that contains this medicine and polymer, and disperse medium is a liquid paraffin.Synthetic pH sensitive polymer is dissolved in (1: 1 to 1: 1.5 mixture of acetone, methanol, dichloromethane or methanol and dichloromethane) in the organic solvent.Described medicine is added generation solution or uniform dispersion in this polymer solution.This organic facies adding is comprised in the light liquid paraffin of span 85 (0.1 to 1% w/w (w/w)).The constant mechanical agitation speed of 500rpm and 25 ℃ continue 30 minutes, and add 40ml hexane or cyclohexane extraction with 5ml/ minute speed, add 40ml hexane or cyclohexane extraction subsequently more fast.Continue to stir again 10-15 minute, this microgranule of isolated by filtration then, with petroleum ether or normal hexane washing and 27 ℃ the time maximum 24 hours of vacuum drying.

Perhaps, described taste masking microgranule can obtain by spray drying.With the drug-polymer solution in the organic solvent or dispersion spray drying to obtain the taste masking microgranule.Dry gas can be such as the noble gas of nitrogen, argon and carbon dioxide or air.The preferred gas of the present invention is air.The gas access temperature of spray dryer depends on used solvent, but can be 35 to 150 ℃, is preferably 40 to 60 ℃.Gas outlet temperature depends on solvent equally, but can be 25 to 50 ℃, is preferably 25 to 40 ℃.With this polymer dissolution in 1: 1 mixture of methanol or methanol and dichloromethane, and with medicine or dissolving or be dispersed in this polymer solution.With gained mixture spray drying to obtain the taste masking microgranule.

Resulting taste masking particle and granule can with such as natural or artificial perfume, citric acid and tartaric flavoring agent, sweeting agent and other medicines such as sucrose, glucide and aspartame (aspartame) can be accepted mixed with excipients to be mixed with conventional intact tablet, chewable tablet or dispersible tablet, dry syrup, suspension, wafer or any other suitable peroral dosage form.

The present invention is oriented to the taste of liquid oral compositions more and covers, and this liquid oral compositions is applicable to that gerontal patient or those are difficult to swallow the patient of solid dosage forms.This taste-masking pharmaceutical compositions prepares by in liquid-carrier the drug particles of described polymer coating being recombinated, and this liquid-carrier comprises sucrose, flavoring agent and citric acid and such as the suspending agent of cellulose derivative or polyvinylpyrrolidone or xanthan gum or the like.The pharmaceutical composition of taste masking of the present invention can be that 4.5 reorganization medium prepares with the pH that comprises sucrose, fruit salad flavor flavoring agent, citric acid and polyvinylpyrrolidone.

Among the embodiment 1-12 provided below exemplary taste-masking pharmaceutical compositions is carried out mensuration with the drug release of time correlation.In the time of 37 ± 0.5 ℃, in the 0.07N of 900ml hydrochloric acid, the USP II type instrument of using the 100rpm rotation discharges from described taste masked particle CEFUROXIME AXETIL to be tested.In the time of 15,30,45,60 and 90 minutes, take out sample.Each amount of taking out is replaced to keep sink conditions (sink conditions) with fresh medium.

In the time of 37 ± 0.5 ℃, in the 0.1N of 900ml hydrochloride buffer, the USP II type instrument of using the 100rpm rotation discharges from described taste masked particle ciprofloxacin to be measured.In the time of 15,30,45 and 60 minutes, take out sample.Each amount of taking out is replaced to keep sink conditions with fresh medium.

In the time of 37 ± 0.5 ℃, in the pH of 900ml was 2.8 acetate buffer solution, the USP II type instrument of using the 100rpm rotation discharges from described taste masked particle Clarith to be measured.In the time of 15,30,45 and 60 minutes, take out sample.Each amount of taking out is replaced to keep sink conditions with fresh medium.

By 37 ± 0.5 ℃ the time, use the USP II type instrument of 100rpm rotation, to be placed 30 minutes in the 0.1N of 100ml HCl by the compositions that celecoxib and polymer are formed, the 0.1N NaOH solution that adds 900ml subsequently comes celecoxib discharged from taste masked particle to be measured.In the time of 15,30,45 and 60 minutes, from 0.1N NaOH solution, take out sample.Each amount of taking out is replaced to keep sink conditions with fresh medium.

The hereinafter with reference exemplary embodiment is described taste masking compositions and characteristic thereof, should not be interpreted as limitation of the scope of the invention by any way.

Embodiment 1

Can obtain flavor hidden microcapsule by the emulsified solvent evaporation technique.The 3.50g ciprofloxacin is dispersed in the polymer solution, and this polymer solution comprises the 900mg polymer in 45ml methanol and dichloromethane (1: the 1) mixture.The set of monomers of this polymer becomes the methyl methacrylate of 60% weight ratio, the hydroxyethyl methylacrylate of 25% weight ratio and the vinylpyridine of 15% weight ratio.Add nonionic surfactant Span 85 to promote that ciprofloxacin disperses in this polymer solution with 0.5% w/w (w/w).Under mechanical agitation, the ciprofloxacin decentralized photo is added dropwise in the light liquid paraffin bath.Continue constant mechanical agitation speed 3-4 hour of 1000rpm under the room temperature.Evaporating solvent, and the microsphere that is obtained separates by filtering, with petroleum ether and 27 ℃ the time vacuum drying 24 hours.Drug release pattern to prepared compositions is studied, and the results are shown in Table 1.Result in the table 1 shows that this medicine discharges at once.

Table-1
Table-1		Time (minute)	Discharge %
15	86.58	Time (minute)	Discharge %
15	86.58	30	91.57
45	96.85	30	91.57

Embodiment 2

Obtain the flavor hidden microcapsule of described bitterness medicine by the microencapsulation of emulsified solvent evaporation technique.The 2.35g ciprofloxacin is dispersed in the polymer solution, and this polymer solution comprises the 7.0g polymer in 40ml methanol and dichloromethane (1: the 1) mixture.The set of monomers of this polymer becomes the methyl methacrylate of 60% weight ratio, the hydroxyethyl methylacrylate of 25% weight ratio and the vinylpyridine of 15% weight ratio.Application class is similar to the microencapsulation that the method described in the embodiment 1 is finished ciprofloxacin and this pH sensitive polymer.Drug release pattern to prepared compositions is studied, and the results are shown in Table 2.

Table 2
Table 2		Time (minute)	Discharge %
15	61.45	Time (minute)	Discharge %
15	61.45	30	68.30
45	74.56	30	68.30
45	74.56	60	81.42

Embodiment 3

Microencapsulation by the emulsified solvent evaporation technique obtains flavor hidden microcapsule.The 2.0g Clarith is dissolved in the polymer solution, and this polymer solution comprises the 4.0g polymer in 40ml methanol and dichloromethane (1: the 1) mixture.The set of monomers of this polymer becomes the methyl methacrylate of 60% weight ratio, the hydroxyethyl methylacrylate of 25% weight ratio and the vinylpyridine of 15% weight ratio.The method that application class is similar to embodiment 1 is finished the microencapsulation of Clarith and pH sensitive polymer.Drug release pattern to prepared compositions is studied, and the results are shown in Table 3.

Table 3
Table 3		Time (minute)	Discharge %
15	48.20	Time (minute)	Discharge %
15	48.20	30	65.51
45	72.80	30	65.51
45	72.80	60	82.59

Embodiment 4

Microencapsulation by the emulsified solvent evaporation technique obtains flavor hidden microcapsule.The 2.0g Clarith is dissolved in the polymer solution, and this polymer solution comprises the 1.2g polymer in 30ml methanol and dichloromethane (1: the 1) mixture.The set of monomers of this polymer becomes the methyl methacrylate of 60% weight ratio, the hydroxyethyl methylacrylate of 25% weight ratio and the vinylpyridine of 15% weight ratio.The method that application class is similar to embodiment 1 is finished the microencapsulation of Clarith and pH sensitive polymer.Drug release pattern to prepared compositions is studied, and the results are shown in Table 4.

Table 4
Table 4		Time (minute)	Discharge %
15	53.97	Time (minute)	Discharge %
15	53.97	30	69.40
45	76.32	30	69.40
45	76.32	60	85.59

Embodiment 5

Obtain the flavor hidden microcapsule of cephalosporins CEFUROXIME AXETIL by the microencapsulation of emulsified solvent evaporation technique.The 2.0g CEFUROXIME AXETIL is dissolved in the polymer solution, and this polymer solution comprises the 6.0g polymer in 40ml methanol and dichloromethane (1: the 1) mixture.The set of monomers of this polymer becomes the methyl methacrylate of 43% weight ratio, the hydroxyethyl methylacrylate of 42% weight ratio and the vinylpyridine of 15% weight ratio.The method that application class is similar to embodiment 1 is finished the microencapsulation of CEFUROXIME AXETIL and pH sensitive polymer.Drug release pattern to prepared compositions is studied, and the results are shown in Table 5.

Table 5
Table 5		Time (minute)	Discharge %
15	95.2	Time (minute)	Discharge %
15	95.2	30	97.2

The taste-masking pharmaceutical compositions microcapsule of preparation is 4.5 by using pH among the embodiment 5, comprise the reorganization medium of sucrose, 2% fruit salad flavor flavoring agent qs., citric acid qs. and the polyvinylpyrrolidone of 85% weight/volume, be prepared into and contain the microgranule that is equivalent to 4 dose drugs.The drug release of 7 days lay up period is shown in the table 6.

Table 6

Natural law	Discharge %
Natural law	Discharge %	2	0.26
3	0.31	2	0.26
3	0.31	4	0.38
5	0.50	4	0.38
5	0.50	6	0.60
7	0.68	6	0.60

Embodiment 6

Obtain the flavor hidden microcapsule of CEFUROXIME AXETIL by the microencapsulation of emulsified solvent evaporation technique.The 2.0g CEFUROXIME AXETIL is dissolved in the polymer solution, and this polymer solution comprises the 6.0g polymer in 40ml methanol and dichloromethane (1: the 1) mixture.The set of monomers of this polymer becomes the methyl methacrylate of 60% weight ratio, the hydroxyethyl methylacrylate of 25% weight ratio and the vinylpyridine of 15% weight ratio.Application class is similar to the microencapsulation that method described in the embodiment 1 is finished CEFUROXIME AXETIL and pH sensitive polymer.Drug release pattern to prepared compositions is studied, and the results are shown in Table 7.

Table 7
Table 7		Time (minute)	Discharge %
15	78.72	Time (minute)	Discharge %
15	78.72	30	80.52
45	88.2	30	80.52
45	88.2	60	95.12

The taste-masking pharmaceutical compositions microcapsule of preparation is 4.5 by using pH among the embodiment 6, comprise the reorganization medium of sucrose, 2% fruit salad flavor flavoring agent qs., citric acid qs. and the polyvinylpyrrolidone of 85% weight/volume, be prepared into and contain the microgranule that is equivalent to 4 dose drugs.The drug release of 7 days lay up period is shown in the table 8.

Table 8

Natural law	Discharge %
Natural law	Discharge %	2	0.25
3	0.27	2	0.25
3	0.27	4	0.38
5	0.45	4	0.38
5	0.45	6	0.57
7	0.64	6	0.57

Embodiment 7

Obtain the flavor hidden microcapsule of bitterness medicine cephalosporins CEFUROXIME AXETIL by the microencapsulation of emulsified solvent evaporation technique.The 2.0g CEFUROXIME AXETIL is dissolved in the polymer solution, and this polymer solution comprises the 6.0g polymer in 40ml methanol and dichloromethane (1: the 1) mixture.The set of monomers of this polymer becomes the methyl methacrylate of 70% weight ratio and the vinylpyridine of 30% weight ratio.Application class is similar to the microencapsulation that method described in the embodiment 1 is finished CEFUROXIME AXETIL and pH sensitive polymer.Drug release pattern to prepared compositions is studied, and the results are shown in Table 9.

Table 9

Time (minute)	Discharge %
Time (minute)	Discharge %	15	92.7
30	96.2	15	92.7
30	96.2	45	97.3

The taste-masking pharmaceutical compositions microcapsule of preparation is 4.5 by using pH among the embodiment 7, comprise the reorganization medium of sucrose, 2% fruit salad flavor flavoring agent qs., citric acid qs. and the polyvinylpyrrolidone of 85% weight/volume, be prepared into and contain the microgranule that is equivalent to 4 dose drugs.The drug release of 7 days lay up period is shown in the table 10.

Table 10

Natural law	Discharge %
Natural law	Discharge %	2	0.76
3	1.32	2	0.76
3	1.32	4	1.71
5	1.73	4	1.71
5	1.73	6	2.10
7	2.14	6	2.10

Embodiment 8

Obtain the flavor hidden microcapsule of bitterness medicine cephalosporins CEFUROXIME AXETIL by the microencapsulation of emulsified solvent evaporation technique.The 2.0g CEFUROXIME AXETIL is dissolved in the polymer solution, and this polymer solution comprises the 6.0g polymer in 40ml methanol and dichloromethane (1: the 1) mixture.The set of monomers of this polymer becomes the methyl methacrylate of 35% weight ratio, the hydroxyethyl methylacrylate of 35% weight ratio and the vinylpyridine of 30% weight ratio.Application class is similar to the microencapsulation that method described in the embodiment 1 is finished CEFUROXIME AXETIL and pH sensitive polymer.Drug release pattern to prepared compositions is studied, and the results are shown in Table 11.

Table 11
Table 11		Time (minute)	Discharge %
15	91.85	Time (minute)	Discharge %
15	91.85	30	95.38

45

97.53

Embodiment 9

With the CEFUROXIME AXETIL in the organic solvent-polymer solution spray drying to obtain the taste masking microgranule.The set of monomers of this polymer becomes the methyl methacrylate of 60% polymer weight ratio, the hydroxyethyl methylacrylate of 25% polymer weight ratio and the 4-vinylpridine of 15% polymer weight ratio.Dry gas is an air.The intake air temperature of spray dryer is 40 ℃ to 70 ℃.Outlet air temperature is 25 ℃ to 60 ℃.This polymer dissolution of 2.4g weight in 1: 1 mixture of methanol and dichloromethane, and is added the CEFUROXIME AXETIL of 4.8g weight in this polymer solution.Range of atomized flow is 1kg to 2kg.Feed rate is 20 to 85rpm.Gained solution spray drying is to obtain the taste masking microgranule.Drug release pattern to prepared compositions is studied, and the results are shown in Table 12.

Table 12
Table 12		Time (minute)	Discharge %
15	53.47	Time (minute)	Discharge %
15	53.47	30	69.97
45	84.47	30	69.97
45	84.47	60	91.72
90	93.18	60	91.72

The taste-masking pharmaceutical compositions microcapsule of preparation is 4.5 by using pH among the embodiment 9, comprise the reorganization medium of sucrose, 2% fruit salad flavor flavoring agent qs., citric acid qs. and the polyvinylpyrrolidone of 85% weight/volume, be prepared into and contain the microgranule that is equivalent to 5 dose drugs.The drug release of 7 days lay up period is shown in the table 13.

Table 13

Natural law	Discharge %
Natural law	Discharge %	2	0.96
3	1.43	2	0.96
3	1.43	4	1.92
5	2.57	4	1.92
5	2.57	6	2.88

7

3.44

Embodiment 10

With the CEFUROXIME AXETIL in the organic solvent-polymer solution spray drying to obtain the taste masking microgranule.The set of monomers of this polymer becomes the methyl methacrylate of 60% polymer weight ratio, the hydroxyethyl methylacrylate of 25% polymer weight ratio and the 4-vinylpridine of 15% polymer weight ratio.Used solvent is 1: 1 mixture of methanol and dichloromethane.Dry gas is an air.The intake air temperature of spray dryer is 40 ℃ to 70 ℃.Outlet air temperature is 25 ℃ to 60 ℃.This polymer dissolution of 2.4g weight in 1: 1 mixture of methanol and dichloromethane, and is added the CEFUROXIME AXETIL of 4.8g weight in this polymer solution.Range of atomized flow is 1kg to 2kg.Feed rate is 20 to 85rpm.Gained solution spray drying is to obtain the taste masking microgranule.Drug release pattern to prepared compositions is studied, and the results are shown in Table 14.

Table 14
Table 14		Time (minute)	Discharge %
15	72.58	Time (minute)	Discharge %
15	72.58	30	85.41
45	89.48	30	85.41
45	89.48	60	93.8
90	94.58	60	93.8

The taste-masking pharmaceutical compositions microcapsule of preparation is 4.5 by using pH among the embodiment 10, comprise the reorganization medium of sucrose, 2% fruit salad flavor flavoring agent qs., citric acid qs. and the polyvinylpyrrolidone of 85% weight/volume, be prepared into the microgranule that contains the medicine that is equivalent to 5 dosage.The drug release of 7 days lay up period is shown in the table 15.

Table 15

Natural law	Discharge %
Natural law	Discharge %	2	0.85
3	1.36	2	0.85
3	1.36	4	2.26
5	3.0	4	2.26
5	3.0	6	3.44

7

3.84

Embodiment 11

With the celecoxib in the organic solvent-polymer solution spray drying to obtain the taste masking microgranule.The set of monomers of this polymer becomes the methyl methacrylate of 60% polymer weight ratio, the hydroxyethyl methylacrylate of 25% polymer weight ratio and the 4-vinylpridine of 15% polymer weight ratio.Used solvent is methanol and dichloromethane (1.5: a 1) mixture.Dry gas is an air.The intake air temperature of spray dryer is 40 ℃ to 70 ℃.Outlet air temperature is 25 ℃ to 60 ℃.This polymer dissolution of 1.5g weight in the mixture (1.5: 1) of methanol and dichloromethane, and is added the celecoxib of 2.0g weight in this polymer solution.Range of atomized flow is 1kg to 2kg.Feed rate is 20 to 85rpm.Gained solution spray drying is to obtain the taste masking microgranule.Drug release pattern to prepared compositions is studied, and the results are shown in Table 16.

Table 16
Table 16		Time (minute)	Discharge %
15	86.8	Time (minute)	Discharge %
15	86.8	30	94.0

Embodiment 12

With the celecoxib in the organic solvent-polymer solution spray drying to obtain the taste masking microgranule.The set of monomers of this polymer becomes the methyl methacrylate of 60% polymer weight ratio, the hydroxyethyl methylacrylate of 25% polymer weight ratio and the 4-vinylpridine of 15% polymer weight ratio.Used solvent is methanol and dichloromethane (1.5: a 1) mixture.Dry gas is an air.The intake air temperature of spray dryer is 40 ℃ to 70 ℃.Outlet air temperature is 25 ℃ to 60 ℃.This polymer dissolution of 0.750g weight in the mixture (1.5: 1) of methanol and dichloromethane, and is added the celecoxib of 2.0g weight in this polymer solution.Range of atomized flow is 1kg to 2kg.Feed rate is 20 to 85rpm.Gained solution spray drying is to obtain the taste masking microgranule.Drug release pattern to prepared compositions is studied, and the results are shown in Table 17.

Table 17
Table 17		Time (minute)	Discharge %
15	73.45	Time (minute)	Discharge %

30

93.74

Claims

1. comprise pH sensitive polymer and bitterness medicine, and formula is P[A _(x)B _(y)C _(z)]: the taste-masking pharmaceutical compositions of D, wherein P for comprise (A) hydrophobic monomer, (B) alkaline monomer and (C) hydrophilic monomer the pH sensitive polymer and (D) be the bitterness medicine, and (x)=30-95%, (y)=5-70%, (z)=0-60%, all with w/w (w/w) expression, and (P): ratio (D) be 30: 1 to 0.2: 1w/w.

2. compositions as claimed in claim 1, wherein said hydrophobic monomer (A) is the acrylic or methacrylic acid esters, described acrylic or methacrylic acid esters is selected from cyclohexyl acrylate, dodecyl acrylate, 2-EHA, 1-Octyl acrylate, tert-butyl acrylate, phenyl acrylate, butyl acrylate, methyl methacrylate, benzyl methacrylate, cyclohexyl methacrylate, phenyl methacrylate, the metering system tert-butyl acrylate, butyl methacrylate, methacrylic acid 2-Octyl Nitrite, propyl methacrylate is preferably butyl acrylate, methyl methacrylate and butyl methacrylate.

3. compositions as claimed in claim 1, wherein said alkaline monomer (B) is selected from aminoalkyl acrylic acid and methacrylate, and described aminoalkyl acrylic acid and methacrylate are selected from dimethylaminoethyl methacrylate, dimethylaminoethyl acrylate, diethylaminoethyl methacrylate, acrylic acid lignocaine ethyl ester, methacrylic acid piperidines ethyl ester, methacrylic acid uncle 2-fourth amino ethyl ester.

4. compositions as claimed in claim 3, wherein said alkaline monomer (B) is selected from dimethylaminoethyl methacrylate and acrylic acid lignocaine ethyl ester.

5. compositions as claimed in claim 1, wherein said alkaline monomer (B) is the thiazolinyl pyridine, and described thiazolinyl pyridine is selected from 2-vinylpyridine, 3-vinylpyridine, 4-vinylpridine and 5-vinyl-2-picoline, 2-vinyl-4-picoline, the different propenyl pyridine of 2-and different propenyl pyridine.

6. compositions as claimed in claim 5, wherein said alkaline monomer (B) is a 4-vinylpridine.

7. compositions as claimed in claim 1, wherein said alkaline monomer (B) is selected from vinylquinoline, aminoalkyl vinyl Ether, aminoethyl styrene and allylamine.

8. compositions as claimed in claim 7, wherein said alkaline monomer (B) is an allylamine.

9. compositions as claimed in claim 1, wherein said hydrophilic monomer (C) is the acrylic or methacrylic acid esters, and described acrylic or methacrylic acid esters is selected from hydroxyethyl methylacrylate, Hydroxypropyl methacrylate, hydroxyethyl methacrylate diethyl acetamidomalonate, 2-(Acryloyloxy)ethanol, Hydroxypropyl acrylate, acrylic acid ethoxy ethyl ester.

10. compositions as claimed in claim 1, wherein said hydrophilic monomer (C) is selected from hydroxyethyl methylacrylate and hydroxyethyl methacrylate diethyl acetamidomalonate.

11. compositions as claimed in claim 1, wherein said medicine comprises macrolide antibiotics, and described macrolide antibiotics is selected from Abboticine, azithromycin and Clarith; Fluoroquinolones, described fluoroquinolones is selected from ciprofloxacin, enrofloxacin, ofloxacin, Gatifloxacin, levofloxacin and norfloxacin; Cephalosporins, described cephalosporins is selected from cefuroxime, cephalexin, cefadroxil, Cefpodoxime Proxetil; Be selected from the nonsteroidal anti-inflammatory analgesic drug product of ibuprofen and diclofenac sodium; With the cox 2 inhibitor that is selected from etoricoxib and celecoxib; Be selected from the antihistaminic of chlorphenamine maleate; Be selected from the oxazolidine ketone of Linezolid; With other medicine such as dextromethorphan.

12. compositions as claimed in claim 1 is wherein used described medicine itself or the acceptable salt of its medicine or ester or amide.

13. compositions as claimed in claim 1, wherein said total polymer is 30: 1 to 0.2: 1 weight ratios to the ratio of medicine.

14. compositions as claimed in claim 1, wherein said total polymer is 5: 1 to 0.4: 1 weight ratios to the ratio of medicine.

15. compositions as claimed in claim 1, wherein said medicine are dispersed in the described polymeric matrix or with described polymeric matrix with the form of microgranule and wrap quilt.

16. the dissolving or expand in the acidity of pH≤3 under one's belt of compositions as claimed in claim 1, wherein said pH sensitive polymer, and o'clock do not dissolve in Ph＞3.5 or do not expand.

17. compositions as claimed in claim 1, wherein the pharmaceutical dosage form of available preparation of compositions of the present invention is selected from and comprises dry syrup or suspensoid and chew or dispersible tablet.

18. compositions as claimed in claim 1, wherein comprise described pharmaceutical composition and comprise described microgranule itself, or medicine can accept dosage form, when pH of saliva, from described peroral dosage form, discharge the medicine of minimum, but in pH≤3 of stomach, the described medicine of rapid release fundamental quantity at once.

19. compositions as claimed in claim 1, wherein said microgranule are formulated as aqueous suspension or recombinate in aqueous medium in normal storage period.

20. compositions as claimed in claim 1, wherein said pharmaceutical composition is by any technique known, preferably, described bitterness medicine is disperseed or is coated in the described pH sensitive polymer substrate to obtain by microencapsulation, spray drying, fluidized bed processing, co-precipitation or in non-solvent by the tray dried method.

21. it is 4.5 that compositions as claimed in claim 1, the flavor-hidden pharmaceutical polymeric matrix of wherein said particle form are used pH, the reorganization medium that comprises sucrose, fruit salad flavor flavoring agent, citric acid and polyvinylpyrrolidone carries out suspendible.

22. comprise pH sensitive polymer and bitterness medicine, and formula is P[A _(x)B _(y)C _(z)]: the preparation method of the taste-masking pharmaceutical compositions of D, wherein P for comprise (A) hydrophobic monomer, (B) alkaline monomer and (C) hydrophilic monomer the pH sensitive polymer and (D) be the bitterness medicine, and (x)=30-95%, (y)=5-70%, (z)=0-60%, all represent with w/w (w/w), and (P): ratio (D) be 30: 1 to 0.2: 1w/w, described method comprises that the described medicine with particulate form disperses or is coated in the substrate by described polymer formation.

23. method as claimed in claim 22, wherein said hydrophobic monomer (A) is the acrylic or methacrylic acid esters, described acrylic or methacrylic acid esters is selected from cyclohexyl acrylate, dodecyl acrylate, 2-EHA, 1-Octyl acrylate, tert-butyl acrylate, phenyl acrylate, butyl acrylate, methyl methacrylate, benzyl methacrylate, cyclohexyl methacrylate, phenyl methacrylate, the metering system tert-butyl acrylate, butyl methacrylate, methacrylic acid 2-Octyl Nitrite, propyl methacrylate is preferably butyl acrylate, methyl methacrylate and butyl methacrylate.

24. method as claimed in claim 22, wherein said alkaline monomer (B) is selected from aminoalkyl acrylic acid and methacrylate, described aminoalkyl acrylic acid and methacrylate are selected from dimethylaminoethyl methacrylate, dimethylaminoethyl acrylate, diethylaminoethyl methacrylate, acrylic acid lignocaine ethyl ester, methacrylic acid piperidines ethyl ester, methacrylic acid uncle 2-fourth amino ethyl ester, are preferably dimethylaminoethyl methacrylate and acrylic acid lignocaine ethyl ester.

25. method as claimed in claim 22, wherein said alkaline monomer (B) is the thiazolinyl pyridine, described thiazolinyl pyridine is selected from 2-vinylpyridine, 3-vinylpyridine, 4-vinylpridine and 5-vinyl-2-picoline, 2-vinyl-4-picoline, the different propenyl pyridine of 2-and different propenyl pyridine, is preferably 4-vinylpridine.

26. method as claimed in claim 22, wherein said alkaline monomer (B) is selected from vinylquinoline, aminoalkyl vinyl Ether, aminoethyl styrene and allylamine, is preferably allylamine.

27. method as claimed in claim 22, wherein in another embodiment of the present invention, described hydrophilic monomer (C) is the acrylic or methacrylic acid esters, described acrylic or methacrylic acid esters is selected from hydroxyethyl methylacrylate, Hydroxypropyl methacrylate, hydroxyethyl methacrylate diethyl acetamidomalonate, 2-(Acryloyloxy)ethanol, Hydroxypropyl acrylate, acrylic acid ethoxy ethyl ester, is preferably hydroxyethyl methylacrylate and hydroxyethyl methacrylate diethyl acetamidomalonate.

28. method as claimed in claim 22, wherein said medicine comprises macrolide antibiotics, and described macrolide antibiotics is selected from Abboticine, azithromycin and Clarith; Fluoroquinolones, described fluoroquinolones is selected from ciprofloxacin, enrofloxacin, ofloxacin, Gatifloxacin, levofloxacin and norfloxacin; Cephalosporins, described cephalosporins is selected from cefuroxime, cephalexin, cefadroxil, Cefpodoxime Proxetil; Be selected from the nonsteroidal anti-inflammatory analgesic drug product of ibuprofen and diclofenac sodium; With the cox 2 inhibitor that is selected from etoricoxib and celecoxib; Be selected from the antihistaminic of chlorphenamine maleate; Be selected from the oxazolidine ketone of Linezolid; With other medicine such as dextromethorphan.

29. method as claimed in claim 22 is wherein used described medicine itself or the acceptable salt of its medicine or ester or amide.

30. method as claimed in claim 22, wherein said total polymer is 30: 1 to 0.2: 1 weight ratios to the ratio of medicine.

31. method as claimed in claim 30, wherein said total polymer is 5: 1 to 0.4: 1 weight ratios to the ratio of medicine.

32. the dissolving or expand in the acidity of pH≤3 under one's belt of method as claimed in claim 22, wherein said pH sensitive polymer, and o'clock do not dissolve in Ph＞3.5 or do not expand.

33. method as claimed in claim 22, wherein said compositions obtains by the microencapsulation of emulsified solvent extraction method.Described method comprises described pH sensitive polymer is dissolved in the organic solvent, described organic solvent is selected from acetone, methanol, 1: 1 to 1: 1.5 mixture of dichloromethane and methanol and dichloromethane, described medicine is added in the described polymer solution to obtain solution or uniform dispersion, the amount that this organic facies is added with 0.1 to 1%w/w contains in the light liquid paraffin of span 85, speed with about 500rpm mechanically continues to stir described mixture and continue about 30 minutes under about 25 ℃ temperature, add 40ml hexane or cyclohexane extraction with 5ml/ minute speed, add another 40ml hexane or cyclohexane extraction subsequently fast, continue again to stir 10-15 minute, the described microgranule of isolated by filtration then, with petroleum ether or normal hexane washing and 27 ℃ the time maximum 24 hours of vacuum drying.

34. method as claimed in claim 22, the drug microparticles of wherein said polymer coating obtains by spray drying, described method comprises sprays described drug-polymer solution in the organic solvent or dispersion to obtain the microgranule that described taste is covered, in the presence of dry gas, with the microgranule drying of being sprayed, described dry gas is selected from nitrogen, argon, carbon dioxide and air.

35. method as claimed in claim 34, the gas access temperature of wherein said spray dryer depends on used solvent, and is 35 to 150 ℃.

36. method as claimed in claim 35, wherein said gas access temperature are 40 to 60 ℃.

37. method as claimed in claim 34, wherein said gas outlet temperature depends on used solvent, and is 25 to 50 ℃.

38. method as claimed in claim 37, wherein said gas outlet temperature are 25 to 40 ℃.

39. method as claimed in claim 34, wherein said polymer dissolution are in (1: 1) of methanol or methanol and dichloromethane mixture, and described medicine or dissolving or be dispersed in the described polymer solution.

40. method as claimed in claim 22, the taste of wherein said medicine are covered microgranule and flavoring agent, citric acid and tartaric acid, the sweeting agent that is selected from sucrose, glucide and aspartame and the acceptable mixed with excipients of other medicines to be formulated as conventional tablet, chewable tablet or dispersible tablet, dry syrup, suspensoid, effervescent or any other suitable peroral dosage form.