CN102000344B - Medicament coating composition with masked taste - Google Patents

Abstract

The invention discloses a medicament coating composition with improved comprehensive performance and masked taste hardly detected by a user. The medicament coating composition comprises: an outer coating, and a medicament core, wherein the outer coating contains a polymer which is not dissolved or hardly dissolved in water under any pH value, a polymer which is dissolved in an acidic medium but is not dissolved or hardly dissolved in a neutral or alkaline pH medium and a particulate matter which does not contain unpleasant odor, is not dissolved or hardly dissolved in water but can be dissolved in acidic medium and alkaline medium, and the medicament core is coated by the coating and contains unpleasant odor. The coating composition can stimulate the medicament to be released in the stomach and stimulate the medicament which is unreleased or incompletely released to enter the intestines to be released in the intestines so that the coating composition conveys the medicament contents tothe body system for more complete circulation and has higher medicament bioavailability.

Description

A kind of medication coat compositions of taste masking

Technical field

The present invention relates to the difficult medication coat compositions of being discovered by the user of a kind of abnormal flavour.Particularly, the present invention relates to a kind of difficult medication coat compositions of being discovered by the user of abnormal flavour of improved combination properties, this coating composition can promote medicine release under one's belt, can promote again not discharge under one's belt or discharge the release of medicine in intestinal that just enters intestinal fully, it is more complete that the compositions that makes coating is delivered to the body circulation with ingredient, and the bioavailability of medicine is higher.

Technical background

A lot of active component, for example antibiotic, have strong unpleasant taste, as the bitterness of sense of taste aspect, pungent, astringent taste etc., the stink of olfactory sensation aspect.The many-sided adverse effect of the normal generation of this offending abnormal flavour, for example, the undesirable taste of medicine can make and be difficult to swallow, or makes patient avoid Drug therapy, causes thus patient's low conformability.When medicament was mixed with the tablet of swallowed whole or capsule, the taste of active component was not problem usually, do not contact with mouth because capsule can prevent active component, and tablet can be wrapped by to prevent that tablet active component within the short time in the mouth from contacting with mouth.But, the method for this taste-masking can not be applied to be fit to child, old people and many other patients before administration or the dosage form of decomposing in the administration process, for example chewable tablet and liquid preparation.And child, old people and many other patients have any problem when taking undecomposed Tablet and Capsula.Therefore, the unpleasant taste of the activating agent in the preparation of sheltering these before administration or in the administration process and needing to decompose makes it to possess good palatability or edibility and advises for guaranteeing that patient abides by that to take be vital.

A kind of possible method of sheltering the active component unpleasant taste commonly used is coating.It will contain the coated taste masked clothing of moulded products of the active component of unpleasant taste, and coating has stoped the release of active component, thereby has stoped the generation of unpleasant taste.

For example, US Patent No. 5489436 discloses the chewable tablet of coating taste masking, and the coating that wherein contains the granule of medicine is " anti-enteric coating " type, is designed to can dissolve under the low pH value in stomach but have water to indissolubility under higher in the mouth pH value.This coating contains the polymer blend of dimethylaminoethyl acrylate methyl amino-ethyl ester and natural methacrylate and cellulose esters.Gratifying in the granule taste masking effect of this coating, still, cellulosic polymer under all pH value permeability and dissolubility but very low, cause discharging very slowly of active substance; Dimethylaminoethyl acrylate methyl amino-ethyl ester and natural methacrylate polymers are gastric solubilities, dissolubility pH is dependent, its dissolubility is subject to the strong effect of PH values, perhaps it can only hang down under pH value and could dissolve, can not dissolve under neutral and alkaline pH condition, in other words, this preparation holdup time under one's belt not in long enough and/or stomach pH value enough not low, the polymer of this class gastric solubility just can fully not dissolve, and preparation leaves stomach and enters the release very slowly that will cause active substance in intestinal at this moment.This preparation time under one's belt and the impact of the factors such as the function (as gastric emptying etc.) that is subjected to stomach of the pH value in stomach and food.The factors such as pH value in the function of stomach (as gastric emptying etc.) and stomach are subjected to the impact of the physiologic factors such as people's body constitution, disease, age, sex, position, and individual variation is large.Multiple studies show that, food is to affect preparation time and the very important influence factor of the pH value in stomach under one's belt, as when having an appointment 200ml or more (non-lipid) fluid in stomach, preparation time and the pH value in stomach under one's belt will be subject to significant impact, the preparation time under one's belt will significantly reduce, and the pH value in stomach will significantly rise.In addition, Dosage Form Factors also affects the key factor in this medicine-releasing system gastric emptying time etc. as state (solid or liquid), size and the density of medicine-releasing system.If be subject to the impact of above-mentioned unfavorable factor, said preparation all discharges position (being stomach) at medicine and can not be detained the sufficiently long time under enough low pH value environment, the polymer of gastric solubility is without abundant dissolving, medicine just can not all discharge, in case and said preparation (medicine-releasing system) leaves after drug main wants the off-position, the release of medicine and absorption just may be not exclusively, and therefore the bioavailability of medicine reduces.Similar this technology also has US6551617B1.

For another example, in order to strengthen in stomach the dissolution velocity of above-mentioned gastric solubility coating in acid environment (polyvinyl acetate and dimethylaminoethyl methacrylate and neutral methacrylate), US Patent No. 6663893B2 (perhaps referring to EP1276470B1) and US6551617B1, added alkaline modifier in aforementioned coating composition, with the release of enhanced activity composition.It is triethanolamine (TEA), basic amino acid, Talcum, ammonia soap., meglumine (meglumine), trimethylamine, calcium silicates, Magnesiumaluminumsilicate, conventional food basifier or its mixture that is used for food industry that these two patents disclose suitable alkaline modifier example.Basic amino acid for example can be, L-arginine, L-Histidine, (Semen Maydis) alcohol soluble protein (prolamine, zein) or its mixture.

But US6663893B2 and US6551617B1 also have many significant deficiency:

Water miscible alkaline modifier such as triethanolamine (TEA), basic amino acid such as L-arginine and L-Histidine, meglumine, trimethylamine etc. are because of its larger water solublity, easily dissolve in the oral cavity, therefore it easily makes coating produce micropore in the oral cavity, easily make medicine stripping from micropore, thereby produce the follow-up offending abnormal flavour of people that allows, especially this coating composition holdup time in the oral cavity longer, as greater than 40 seconds or longer.in addition, although the material that these polarity are very large has strengthened in the stomach dissolution velocity of coating in acid environment, but the polymer phase capacitive in they and coating is very poor, both two interphase interfaces can occur during blend can be very high, the problem that mutual bonding force is very poor, (when adopting non-water-soluble matchmaker, also can cause and disperse inequality), water miscible alkaline modifier (or claiming porogen) also will become the stress concentration point in coating, become the weak link in coating, coating machine intensity or mechanical performance are significantly reduced, as intensity, toughness, the declines such as elasticity, coating is broken.These drawbacks have not only limited their additions in coating, but also have a strong impact on the formulation products performance (referring to document: US06974591 background technology part; " polymer chemistry and physics ", Wang Zijie chief editor, China Light Industry Press publishes, 1992 04 month the 1st edition, the 345th page; " surface and interface of high polymer ", Wu Renjie chief editor, Science Press (Beijing), the 104th～110 page; The modification of inorganic filler, Jiangxi chemical industry, calendar year 2001, the 4th phase, the 17th～18 page).

Although Talcum, calcium silicates, Magnesiumaluminumsilicate and zein etc. have certain hydrophobicity, and be relative with the compatibility of polymer better, yet calcium silicates, Magnesiumaluminumsilicate have stronger adsorptivity, easily adsorb medicine, the slow medicine stripping under one's belt of resistance makes drug absorption slack-off; And, calcium silicates, Magnesiumaluminumsilicate form gel in water under the effects such as acid or water, and gel also can hinder slow gastric solubleness coating and medicine stripping under one's belt, make drug absorption slack-off, these factors all will affect the bioavailability of medicine (referring to the relevant clause part of document works: The Merck Index, 13 ^thEdtion; " pharmaceutical necessities complete works of ", Luo Mingsheng, Gao Tianhui chief editor, Sichuan science tech publishing house, March in 1993 the 1st edition; " the pharmaceutic adjuvant handbook, (original work the 4th edition), the volumes such as sieve R.C., Zheng Jun democracy is translated, Chemical Industry Press, January in 2005 the 1st edition).

Alcohol soluble protein refers to water insoluble, also be insoluble to water-free alcohols, but can be dissolved in the albumen in the alcohol solution of volume fraction 60%～95%, alcohol soluble protein only is dissolved in the aqueous solution that contains the surfactants such as SDS (sodium lauryl sulphate) except alcohol solution usually.And (seed) albumen that is dissolved in acid or alkali is listed in glutelin (referring to document: Tanaka Y, et al.Isolation and characterization of protein bodies in the rice endosperm, [J] .Agric Biol Chem, 1980,44:1633～1639; Rice Prolamines extraction conditions and total content distribute, Jiang Donghua etc., Zhejiang Agriculture journal, 19 (3): 174～178,2007; The dissolution characteristics of high-lysine component research in hordein, Dong Niu etc., Botany Gazette, 1989,31 (9): 689～695; Wheat gliadin and glutelin progress, Dong Chaohua etc., the biological journal of mountain farming, 22 (2): 164～168,2003), as water insoluble in zein, diluted acid and diluted alkaline only could dissolve in strong basicity (pH11.5 or higher) solution, and easily produce precipitation (referring to document: chemical industry dictionary, http://www.chemyq.com/xz/xz7/63938pkqbn.htm in low concentration salt solution; Zein extraction process and Study on Functional, Zhang Zhong, Qi Aiyun, grain and feed industries, 09 phase in 2004; " the pharmaceutic adjuvant handbook, (original work the 4th edition), the volumes such as sieve R.C., Zheng Jun democracy is translated, Chemical Industry Press, January in 2005 the 1st edition, the 801st page).Because alcohol soluble protein or zein do not dissolve in diluted acid, can not generate solable matter with the diluted acid effect, therefore, alcohol soluble protein or zein are difficult to performance in the effect of accelerating medicine stripping under one's belt.Equally, Talcum is also so, because of its all dissolving hardly in diluted acid, diluted alkaline, can not generate water-soluble material with the acid effect.

Ammonia soap. has preferably water solublity and certain hydrophobicity (containing hydrophobic group oleic acid base) is arranged, but, it does not produce water miscible salt under the acid effect under one's belt, and only produce water-fast fluid oil (dripping), and this oil (dripping) is attached to the clothing film because of more difficult the redissolution in intestinal or stomach, therefore it also is difficult to the stripping under one's belt of further acceleration medicine; In addition, the ammonia soap. chemical property is stable not, and smell is produced in easily oxidation.

Can not generate the alkali compounds of water-soluble material due to above-mentioned and sour effect, can not form micropore in coating, and they under one's belt with gastric solubleness polymer competition hydrion, therefore, they have suppressed the stripping of gastric solubleness polymer on the contrary, the medicine stripping under one's belt of to a certain degree having slowed down.

Prior defective is, water-insoluble alkaline modifier such as Talcum, calcium silicates, Magnesiumaluminumsilicate and zein that US Patent No. 6663893B2 (perhaps referring to EP1276470B1) and US6551617B1 mention, insoluble in alkali, they can not promote the release of medicine in the intestinal of alkalescence, said preparation (medicine-releasing system) release under one's belt not exclusively just leaves after drug main will discharge the position, the release of remaining medicine and be absorbed in and also will be difficult in intestinal carry out fully reduces the bioavailability of medicine.

In addition, some alkaline modifier that US Patent No. 6663893B2 (perhaps referring to EP1276470B1) and US6551617B1 mention have offending abnormal flavour, (Adeps Sus domestica sample stink is arranged, the stink of becoming sour is more arranged after oxidation as L-arginine (mildly bitter flavor), L-Histidine (bitter in the mouth), ammonia soap.; And ammonia stink), meglumine (being with salty and bitter flavor), triethanolamine (the ammonia stink is arranged), trimethylamine (have the smelly and fish of ammonia wake up foul smell flavor).

Special needs to be pointed out is, above-mentioned anti-" enteric coating " technology of having used two kinds of different polymer often has many micropores in these clothing films.When these two kinds different polymer phase capacitives were better, these micropores can slowly heal in storage voluntarily, and the permeability of clothing film is slowly descended, and the bioavailability of medicine is reduced.

Therefore, need in reality above-mentioned technology is overcome its defective on the basis of inheriting its advantage.

Goal of the invention

The purpose of invention is to provide a kind of difficult medication coat compositions of being discovered by the user of abnormal flavour of improved combination properties.

Particularly, one of purpose of invention is to provide a kind of difficult medication coat compositions of being discovered by the user of abnormal flavour of improved combination properties, this coating composition can promote medicine release under one's belt, can promote again not discharge under one's belt or discharge the release of medicine in intestinal that just enters intestinal fully, it is more complete that the compositions that makes coating is delivered to the body circulation with ingredient, and the bioavailability of medicine is higher.

Two of the purpose of invention is to provide a kind of difficult medication coat compositions of being discovered by the user of abnormal flavour of improved combination properties, this coating composition can strengthen the effect of the offending abnormal flavour of covering medicine largely, is perceived the time of the offending abnormal flavour of medicine after the prolong drug coating composition is taken in the oral cavity.

Three of the purpose of invention is to provide a kind of difficult medication coat compositions of being discovered by the user of abnormal flavour of improved combination properties, and the mechanical performance of the coating of this coating composition is enhanced largely.

Other goals of the invention are seen the detailed description of following description.

Summary of the invention

The present invention relates to a kind of in the administration process offending abnormal flavour be difficult for the medication coat compositions discovered by the user, it is characterized in that this coating composition comprises:

A), the coating covered outward, this coating contains:

1), a kind of pharmaceutically acceptable all being insoluble under any pH value or water-fast polymer almost,

2), a kind ofly pharmaceutically acceptablely be dissolved in acid medium but be insoluble to or be dissolved in hardly polymer in neutrality or alkaline pH medium, and

3), a kind of pharmaceutically acceptable without offending abnormal flavour be insoluble to or water-soluble but can be dissolved in the particulate matter of acid medium and alkaline medium hardly, wherein, above-mentioned all be insoluble under any pH value or almost water-fast polymer and above-mentioned be dissolved in acid medium but be insoluble to or the polymer phase that is dissolved in hardly in neutrality or alkaline pH medium perhaps fully compatible;

B), contained a kind of core core that the medicine of offending abnormal flavour is arranged by what above-mentioned coating coated.

Term used herein " offending abnormal flavour " refer to for the user in mouth during buccal aspect the sense of taste, olfactory sensation especially sense of taste aspect feel any offending taste, comprise hardship, puckery, Earthy Taste, metallic taste, salty, strong acid, strong alkali, strong salt, do, pungent (sharp), strongly cool, hot, burning, pungent, wooden flavor, cigarette, peppery, stink and/or the offending aftertaste of any people of allowing.

Term " active component ", " bioactive ingredients ", " medical active component ", " active matter ", " activating agent " that the present invention uses reaches " bioactive substance ", " medicine " etc. and refers to that any material has detectable biological effect and comprises any physiological, diagnosis, preventative or pharmacological effect when it bestows live body.This term is intended to include but not limited to material any pharmacy, therapeutic, preventative, the threpsology.

Term used herein " is dissolved in acid medium or alkaline medium " and refers to generate water miscible product with dilute hydrochloric acid or diluted alkaline effect, does not generate the meaning of the product of water-fast on-gaseous.

Term used herein " is dissolved in " dissolubility that refers in the material solvent (temperature 25 ℃ time) and is not less than 33mg/ml, preferably is not less than 50mg/ml, more preferably is not less than 100mg/ml, is not less than best 500mg/ml.

Term used herein " is insoluble to or is dissolved in hardly " and referring to that the dissolubility of material in solvent (temperature 25 ℃ time) is not more than 30mg/ml, preferably is not more than 15mg/ml, more preferably is not more than 10mg/ml, is not more than best 1mg/ml.

" pharmaceutically acceptable " that the present invention relates to refers to can be mixed with each other in preparation and mutually can not reduce preparation stability and/or effect without illeffects and be applicable to the part or the meaning of whole body administration.

The term that the present invention uses " comprises " and reaches " containing " and refer to include but not limited to or can also comprise other one-tenth similar implication of grading except this thing.

The term " a kind of " that the present invention uses refers to be at least a kind of, can be a kind of for only having, also can be two kinds or multiple.

The term " simulated gastric fluid " that the present invention uses refers to contain or do not contain the hydrochloric acid solution of 1% pepsic pH value 1.2.

The term " simulated intestinal fluid " that the present invention uses refers to contain or do not contain the phosphate buffer of the pH value 7.8 of 1% pancreatin.

Detailed description of the invention

The below introduces the present invention in detail, the main component in the paper coating.

Wish not exclusively to be limited by following principle.The compatibility between polymer performance for fully incompatible, (part) compatible reach fully compatible.Two kinds have the polymer phase of certain compatibility mixed, at first mutually moistening at the interface, and then biphase macromolecular chain segment phase counterdiffusion by warm-up movement, the result of diffusion makes two kinds of polymer produce obvious Concentraton gradient on the both sides, interface.This zone with obvious Concentraton gradient has consisted of two alternate boundary layers.The thickness of boundary layer depends mainly on the compatibility of two kinds of polymer.Increase along with the compatibility, diffusion improves, and boundary is more and more fuzzyyer, and interfacial layer thickness is increasing, so that final boundary disappears fully, become homogeneous blend, reach fully compatible (compatibility of polymer alloy and increase-volume, University Of Qingdao's journal, May nineteen ninety-five, the 10th volume, l phase, the 91st page).Just because of this mutual scattering and permeating, the polymer that certain compatibility is arranged after mixing mutually, can slowly heal in storage or can quickly-healing at higher than the temperature of the glass transition point of polymer, result can make two kinds of compatible polymer that to a certain degree fusion occurs between mutually, gap between reducing or eliminating both, thereby can make the micropore that forms in the coating process dwindle or eliminate, and form coating or the coating of more complete densification.The coating of more complete densification or coating are conducive to stop the medicine that offending abnormal flavour is arranged from the coating composition stripping, prevent or delay to produce the follow-up offending abnormal flavour of people that allows, strengthen the effect of the offending abnormal flavour of covering medicine, extend the time of being perceived the offending abnormal flavour of medicine after coating composition is taken in the oral cavity.In addition, the coating of more complete densification or clothing film can improve its mechanical performance, break under the effect of external force or cracked probability to reduce it, thereby improve its taste masking performance.This low permeability and high-mechanical property be conducive to prevent or the coating composition that delays quickly disintegrated core core at intraoral disintegration.

Can only form fully independently interface between two kinds of complete incompatible polymers, scattering and permeating heals voluntarily as in storage mutually, can not be in the gap of merging higher than the temperature healing of the glass transition point of polymer between eliminating both, the micropore healing that forms in the coating process is eliminated, thereby in coating or coating, micropore is many especially, permeability is large especially, after coating composition is taken, the medicine of offending abnormal flavour is arranged easily from the coating composition stripping, the user may be perceived the offending abnormal flavour of medicine in the oral cavity.Two kinds of non-constants of coating machine performance that complete incompatible polymer consists of, coating composition easily breaks under external force, thereby makes medicine prominent releasing in the oral cavity of offending abnormal flavour.Particularly for the coating composition of the core core with fast disintegration property, because reaching too low mechanical performance, its too high permeability may make it at intraorally rapidly disintegrating.

For these reasons, the present invention adopts both (part) perhaps fully compatible all being insoluble to or water-fast polymer and be dissolved in acid medium but be insoluble to or be dissolved in hardly polymer in neutrality or alkaline pH medium almost mutually under any pH value.

The compatibility between polymer and polymer can be used " similar compatibility " principle and estimated or predict, as polarity or nonpolar similarity.Also can with can characterize polymers the solubility parameter of size of intermolecular cohesion be used for estimating the compatibility between polymer and polymer.Generally, especially for nonpolar amorphous polymer blend, when the difference of the solubility parameters of two polymer less than 0.5 or the difference of the solubility parameters of polymer and organic solvent less than 1.5 the time, both just can with the arbitrary proportion mixing, both have the good compatibility.When having very strong polarity and can form hydrogen bond for the co-mixing system that contains crystalline polymer or polymer molecule, can adopt two dimension or three solubility parameters to judge that the compatibility of system is (referring to Shaw M.T., J ApplPolym Sci, 1974,18:449).

1), the cosolvent method the following easier method of exemplary application of the present invention proves or predicts the compatibility between polymer and polymer:, two kinds of macromolecules are dissolved into respectively in the same solvent, then mix mutually, judge the polymer-polymer miscibility size according to two solution mixing situations.2), microscopic method, but with the phase contrast microscope method particularly its mixed phase of electron microscope method direct observation hold degree.3), the solution viscosity method, the viscosity of solution can disclose the compatibility of polymer blend solution, and is to the percentage composition of polymer mapping, as linear in its relation with viscosity under different polymer concentrations, shows to reach the fully compatible of molecular level between polymer; Being tied to form non-linearly as its pass, is that part is compatible; When being complete incompatible co-mixing system, the S-type curve of its relation.4), by the use of thermal means and dynamic mechanical analysis method (surveying vitrification point Tg), three kinds of Tg variation tendencies can appear in special recommendation the method for the present invention, polymer alloy system, suppose that the Tg of two kinds of polymer in Binary Alloy System is respectively Tg ₁And Tg ₂(Tg ₁＜Tg ₂), (1), complete compatible system: a Tg only occurs, Tg ₁＜Tg＜Tg ₂(2), complete incompatible system: two Tg occur, be respectively Tg ₁And Tg ₂(3), the compatible system of part: two Tg occur ₁', Tg ₂', Tg ₁＜Tg ₁'＜Tg ₂'＜Tg ₂

The evaluation of the compatibility between more or more detailed polymer and clothing membrane polymer or Forecasting Methodology can be with reference to pertinent literatures, as, the prediction of the polymer alloy compatibility and sign, Ye Jiajia etc., engineering plastics are used, 2007, the 35th volume, the 12nd phase, the 81st～83 page; Improve the progress of polymer blending material interface compatibility, Dong Meng etc., paint spraying and plating, in October, 2006, the 4th the 5th phase of volume, the 24th～29 page; Compatibility Between Polymers prediction and the sign of Polymer Alloy Membrane, Gu Xiaoyu etc., polymer material science and engineering, in January, 2004, the 20th the 1st phase of volume, the 5th～8 page; Polyblend: the compatibility of II. polymer, Rhizoma Zingiberis Recens northern Shandong, macromolecule circular, in JIUYUE, 1993, the 3rd phase, the 178th～184 page; The compatibility of polyblend and Theoretical Calculation thereof, Lv Feijie etc., tropical agriculture science, 02 phase in 1985, the 15th～19 page.

The present invention relates to all be insoluble under any pH value or almost water-fast polymer play skeleton function in coating, in order to strengthen the mechanical performance of coating, make coating can bear larger external force and not break at tabletting, in the process such as chewing.

Suitable all be insoluble under any pH value or almost water-fast polymer can all be insoluble under any pH value or almost water-fast block polymer or copolymer for pharmaceutically acceptable, be generally hydrophobic polymer.Suitable polymer can be selected from but be not limited to all be insoluble under any pH value or almost water-fast cellulose esters, acrylic acid (ester) base polymer, polyvinyl acetate, polyvinyl chloride and compositions thereof.Preferably, select cellulose esters and polyvinyl acetate.More preferably, select cellulose esters.preferred examples of polymer includes but not limited to ethyl cellulose, methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, the disuccinic acid cellulose, polyvinylacetate, methacrylic acid (ester) polymer, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, Merlon, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, vinyl acetate-vinyl chloride copolymer, polrvinyl chloride, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride).

for fear of many drawbacks of with an organic solvent bringing (as with an organic solvent can high producing higher viscosity, higher viscosity often makes the coating process become difficult, easily make sticking limit between particle, easily make drug release become unstable, between making batch, larger difference appears in drug release), preferably adopt the latex in water liquid of being scattered in of above-mentioned polymer, pseudo-latex and emulsion, contain 80～95% polrvinyl chloride as an adoptable example for what US4557925 provided, 0.5 the aqueous dispersion coating solution of the terpolymer of～19% polyvinylacetate and 0.5～10% polyvinyl alcohol, another available example is the aqueous dispersion coating solution that contains 50～100% polrvinyl chloride and 0～50% polyvinylacetate copolymer.

Commercial kind of supplying if any:

Or

(ethyl cellulose (EC)),

RS30D,

RE30D or

RL30D (acrylic resin), acetate fiber rope (CA) CA398-10 latex, Kollicoat SR 30 D or KOLLIDON SR (polyvinyl acetate).

Almost all sites in mouth is neutral environment, and pH value wherein is about 7.Be used in coating composition insoluble in mouth carry out cover ingredient, drug particles or drug particles agglomerate can the undesirable abnormal flavour of masking agents.But this coating must be formulated into fast decoupled under one's belt, so that active constituents of medicine is discharged in vivo.Be dissolved in acid medium but be insoluble to or be dissolved in hardly the requirement that polymer in neutrality or alkaline pH medium can satisfy above-mentioned coating, this base polymer can not dissolve in the oral cavity, the offending abnormal flavour of people do not occur allowing thereby can not make by the stripping in the oral cavity of the medicine of its coating, and this base polymer can be dissolved in acid gastric juice and discharge medicine.Thereby can be dissolved in rapidly in gastric juice and discharge under one's belt active constituents of medicine after guaranteeing to contain the pharmaceutical composition oral administration of making us unhappy abnormal flavour; And, also there is no obvious aftertaste.

Be applicable to of the present inventionly be dissolved in acid medium but be insoluble to or be dissolved in hardly polymer in neutrality or alkaline pH medium, be generally pharmaceutically acceptable at pH6 or more soluble in the water of low value and have a polymer substance of film property, include but not limited to that (a) has the cellulose derivative of list or disubstituted amido, (b) has the polythene derivative of list or disubstituted amido, (c) has the acrylate copolymer of mono-substituted amino, (d) other class chitosan (Chitosan) and their mixture.(a) special example includes but not limited to, benzylamino-methyl cellulose, diethylamino methyl cellulose, piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate and their mixture; (b) special example includes but not limited to vinyl diethylamide-vinyl acetate co-polymer, ethylene benzyl amine-vinyl acetate co-polymer, poly-acetal acetic acid diethylamino vinyl acetate, ethylene piperidyl-acetyl acetal ethylene copolymer, poly-diethylamino methyl styrene and their mixture; (c) special example includes but not limited to the Eudragit E (trade name of Rohm-Pharma, be methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer), polymethylacrylic acid dimethylamino ethyl ester and their mixture; (d) the special example of other classes includes but not limited to chitosan (Chitosan).Wherein, more preferably the gastric solubility polymer is poly-acetal diethylamino vinylacetate or Eudragit E.Most preferably be Eudragit E.

Above-mentioned all be insoluble under any pH value or almost water-fast polymer with above-mentioned be dissolved in acid medium but be insoluble to or be dissolved in hardly (part) between polymer in neutrality or alkaline pH medium mutually perhaps fully compatible example as:

a preferred embodiment is: above-mentioned all be insoluble under any pH value or almost water-fast polymer be selected from and all be insoluble under any pH value or water-fast cellulose esters almost, as ethyl cellulose, methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose and their mixture, above-mentioned be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from the cellulose derivative that (a) has list or disubstituted amido, as the benzylamino-methyl cellulose, diethylamino methyl cellulose, the piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate and their mixture, (b) has the acrylate copolymer of mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture, perhaps (c) chitosan (Chitosan), and their mixture, wherein, the cellulose derivative that list or disubstituted amido arranged is for most preferably.

another preferred embodiment is: above-mentioned all be insoluble under any pH value or almost water-fast polymer be selected from and all be insoluble under any pH value or water-fast acrylic acid (ester) base polymer almost, as methacrylic acid (ester) polymer, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, ethyl acrylate-ethyl acrylate-chlorination trimethyl amino-ethyl Methyl metacrylate 99 polymer and their mixture, above-mentioned be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from the cellulose derivative that (a) has list or disubstituted amido, as the benzylamino-methyl cellulose, diethylamino methyl cellulose, the piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate and their mixture, (b) has the acrylate copolymer of mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture, perhaps (c) has the polythene derivative of list or disubstituted amido, as vinyl diethylamide-vinyl acetate co-polymer, ethylene benzyl amine-vinyl acetate co-polymer, poly-acetal acetic acid diethylamino vinyl acetate, ethylene piperidyl-acetyl acetal ethylene copolymer, poly-diethylamino methyl styrene and their mixture, and their mixture, wherein, acrylate copolymer with mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture are for most preferably.

another preferred embodiment is: above-mentioned all be insoluble under any pH value or almost water-fast polymer be selected from and all be insoluble under any pH value or water-fast polyvinyl acetate almost, as terpolymer, vinyl acetate-vinyl chloride copolymer and their mixture of polyvinylacetate, vinyl chloride-ethylene alcohol-vinylacetate, above-mentioned be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from the acrylate copolymer that (a) has mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture, perhaps (b) has the polythene derivative of list or disubstituted amido, as vinyl diethylamide-vinyl acetate co-polymer, ethylene benzyl amine-vinyl acetate co-polymer, poly-acetal acetic acid diethylamino vinyl acetate, ethylene piperidyl-acetyl acetal ethylene copolymer, poly-diethylamino methyl styrene and their mixture, and their mixture, wherein, polythene derivative with list or disubstituted amido is for most preferably.

another preferred embodiment is: above-mentioned all be insoluble under any pH value or almost water-fast polymer be selected from and all be insoluble under any pH value or water-fast polyvinyl chloride almost, as the terpolymer of vinyl acetate-vinyl chloride copolymer, polrvinyl chloride, vinyl chloride-ethylene alcohol-vinylacetate and their mixture, above-mentioned be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from the acrylate copolymer that (a) has mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture, perhaps (b) has the polythene derivative of list or disubstituted amido, as vinyl diethylamide-vinyl acetate co-polymer, ethylene benzyl amine-vinyl acetate co-polymer, poly-acetal acetic acid diethylamino vinyl acetate, ethylene piperidyl-acetyl acetal ethylene copolymer, poly-diethylamino methyl styrene and composition thereof, with and composition thereof, wherein, polythene derivative with list or disubstituted amido is for most preferably.

The perhaps fully compatible polymer of two kinds of phases in storage slowly healing or at higher than the temperature of the glass transition point of polymer after quickly-healing permeability descend, this may further have influence on the fully dissolving under one's belt of acid soluble polymer, medicine may not discharge or incomplete release, and drug bioavailability may reduce.In order to overcome defects and other purposes, the present invention add in coating or coating without offending abnormal flavour be insoluble to or almost water-fast but can be dissolved in acid medium and can be dissolved in the particulate matter of alkaline medium again.

In the present invention, without offending abnormal flavour be insoluble to or almost water-fast but can be dissolved in acid medium and can be dissolved in the particulate matter of alkaline medium again, can expect to bring into play following effect:

1), can work to discharge promoter, the bioavailability of raising medicine.because being dissolved in acid medium, above-mentioned particulate matter can be dissolved in alkaline medium again, there is no to produce the material that is deposited on coating surface or inside, therefore when it reaches in intestinal from coating after stripping under one's belt, can produce a large amount of micropores, can promote dissolution velocity and the medicine release under one's belt in acid environment under one's belt of gastric solubility coating, can promote again because of gastric solubility coating under one's belt in time dissolving or fully dissolving cause do not discharge under one's belt or discharge fully the release of medicine in intestinal that just enters intestinal, therefore, it can make the compositions of coating that the speed that ingredient is delivered to the body circulation is faster, more complete, improve the bioavailability of medicine.

2), can strengthen the effect of the offending abnormal flavour of covering medicine.Because of described particulate matter without offending abnormal flavour, therefore that it can not produce is new for or extra offending abnormal flavour; Because above-mentioned particulate matter is insoluble to or water-soluble hardly, can not dissolve in the oral cavity, therefore it can prevent or reduce the offending abnormal flavour that stripping produces from coating composition in the oral cavity because of medicine; Because above-mentioned particulate matter is insoluble to or water-soluble hardly, has certain hydrophobicity, compare without hydrophobic water soluble compound with polarity is large, required time of this particulate matter stripping from coating is relatively longer, the speed of stripping is relatively slower, therefore this particulate matter can extend the time of being perceived the offending abnormal flavour of medicine after the medication coat compositions is taken in the oral cavity relatively.

3), stabilizer function.The subenvironment buffering of coating is neutral pH, has strengthened the globality of coating, improved the storage-stable in drying regime or liquid suspension.

4), can strengthen the mechanical performance of coating.Because described particulate matter is insoluble to or water-soluble hardly, has certain hydrophobicity, the water miscible Compound Phase ratio large with polarity, polymer phase capacitive in this particulate matter and coating increases, both two alternate interface energies reduce during blend, mutual bonding force strengthens, and coating machine intensity or mechanical performance are strengthened.

This paper term used herein " be insoluble to or almost water-fast particulate matter " refers to that the dissolubility (temperature 25 ℃ time) in water is not more than 30mg/ml, preferably be not more than 20mg/ml, more preferably be not more than 10mg/ml, be not more than best 1mg/ml and mean diameter and be generally 0.01～200 μ m, be preferably 0.05～100 μ m, being more preferably 0.1～50 μ m, is the particulate matter of 0.5～25 μ m best.Excessive or too small particle diameter may cause the production repeatability problem that is difficult to predict such as relatively poor.

Suitable of the present invention without offending abnormal flavour be insoluble to or almost water-fast but can be dissolved in particulate matter preferred embodiment that acid medium can be dissolved in again alkaline medium as, but be not limited to this: guanyl is (delicious; Dissolubility is less than 1mg/ml), zinc phosphate is (odorless, tasteless; Dissolubility is less than 1mg/ml), CYSTINE is (odorless, tasteless; Dissolubility is 0.11mg/ml approximately), D-Tyrosine (distinguishes the flavor of sweet; Dissolubility is 0.45mg/ml approximately), potassium hydrogen tartrate (has pleasant sour-sweet flavor; Dissolubility is 6.18mg/ml approximately), D-trp (distinguishes the flavor of sweet by force; Dissolubility is 11.3mg/ml approximately), L-threonine (distinguishes the flavor of little sweet; Dissolubility is 15.9mg/ml approximately), (flavor is weak sweet for D-Thr; Dissolubility is 15.9mg/ml approximately), D-Leu (distinguishes the flavor of sweet by force; Dissolubility is 21.9mg/ml approximately), D-phenylalanine (distinguishes the flavor of sweet by force; Dissolubility is 29.6mg/ml approximately), and their mixture.Above-mentioned example is guanyl, zinc phosphate, CYSTINE, D-Tyrosine, potassium hydrogen tartrate, D-trp and their mixture more preferably, more preferably guanyl, CYSTINE, zinc phosphate, potassium hydrogen tartrate and their mixture, most preferably be guanyl, CYSTINE, zinc phosphate and their mixture.This is because they have lower dissolubility in water, at acid medium and alkaline medium dissolution velocity or better solubility property faster.

Add effective dose in coating of the present invention above-mentioned without offending abnormal flavour be insoluble to or almost water-fast but can be dissolved in acid medium and can be dissolved in the particulate matter of alkaline medium again.According to required dissolving or dissolution rate, effective dose can be different.The consumption of above-mentioned particulate matter be the approximately 1wt% of coating gross dry weight amount to about 70wt%, preferred approximately 5wt% is to about 50wt%, and more preferably from about 10wt% to about 40wt%.The above-mentioned particulate matter of too high amount can affect the integrity of coating, and its mechanical performance is descended.Correspondingly, after adding above-mentioned particulate matter, based on the gross dry weight amount of coating, above-mentioned all be insoluble under any pH value or almost the content of water-fast polymer be approximately 10wt% to about 80wt%, preferred approximately 20wt% is to about 60wt%, and more preferably from about 20wt% is to about 50wt%; Above-mentioned be dissolved in acid medium but be insoluble to or the content that is dissolved in hardly the polymer in neutrality or alkaline pH medium is that approximately 10wt% is to about 70wt%, preferred approximately 20wt% is to about 50wt%, and more preferably from about 20wt% is to about 40wt%.

The outer coating of covering of coating composition of the present invention can also add other polymer.Such polymer can be for example polyvinylpyrrolidone (PVP), 2-vinylpyridine (V)/styrene (S) copolymer and its mixture.PVP is water-soluble polymer, and PVP meeting Dissolution and dissociation, discharge medicament under one's belt in water.The polymer weight ratio that this 2-vinylpyridine (V)/styrene (S) copolymer preferably has is V is approximately 65/35 or 80/20 with the ratio of S.Their consumptions in coating be approximately 5wt% to about 30wt%, preferred 10wt% to 25wt%, this is based on the gross dry weight amount of coating.

The outer coating of covering of coating composition of the present invention can also contain a certain amount of super-disintegrant, to accelerate the coating disintegrate.The consumption of super-disintegrant in core material be approximately 0.5wt% to about 30wt%, preferred 1wt% to 20wt%, preferred 2wt% to 15wt%, this is based on the gross dry weight amount of coating.

Can also add the universal additive material in the coating composition that the present invention relates to.The addition of universal additive material in the drug coating layer and application are that the professional is familiar with.General additive comprises but is not limited to antitack agent (separating medium), stabilizing agent, pigment, defoamer, antioxidant, short penetrating agent, polishing material etc.They are used as processing aid, and should guarantee safe and reproducible preparation method and long time stored stability or give pharmaceutical dosage form additional advantageous feature.

Being described in detail as follows of the universal additive material of commonly using in coating.

Plasticizer

For improving the quality of coating, can add in coating prescription plasticizer with the glass transition temperature (Tg) that reduces polymer to suitable scope, and the film forming ability of raising coating material, pliability and the intensity of enhancing coating are improved coating to the coherent condition of substrate.Suitable glass transition temperature (Tg) scope is generally 0～70 ℃, is preferably 10～50 ℃, and be best is 15～40 ℃ goodly.

One ground of plasticizer for high boiling point, low volatility and can with the liquid substance of the micromolecule (Mr is about 150～800, is preferably 300～500) of Polymers Miscibility or the solid matter of low melting point.The example of accessible plasticizer such as physiology compatible (preferred C6～C30, particularly preferably the aliphatic of C10～C16) or aromatic series one is to tricarboxylic acid and C1～C8 (preferably C2～C6, the lipophilic ester that forms of the aliphatic alcohol of C2～C5) particularly preferably by C6～C40.The example of this plasticizer such as dibutyl phthalate, diethyl phthalate, dibutyl sebacate, ethyl sebacate, citric acid triethyl group ester, acetyl triethyl citrate, glycerol triacetate, tributyl SA ester, Isosorbide Dinitrate, sucrose ester.The example of other accessible plasticizers such as glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini.

The consumption of plasticizer is according to the character of desired coating, as glass transition temperature, mechanical performance etc., the kind of plasticizer, the kind of film former (being film forming polymer), consumption etc. and decide, usually consumption is 5～50% (weight ratios), preferred 10～40% (weight ratios), 10～30% (weight ratios) particularly preferably, this is based on the gross dry weight amount of coating ingredients.

Antitack agent (separating medium)

Antitack agent (separating medium) is generally useful hydrophobic material, and one adds in the injection suspension.They stop the gathering of core between film forming stage.The preferred Talcum that uses, magnesium stearate or calcium stearate, the silicic acid of porphyrize, Kaolin or HLB value are 3～8 nonionic emulsifier.The common consumption of antitack agent in coating of the present invention is 0.5～100% (weight ratio) of amount of polymers.In particularly advantageous embodiment, separating medium adds as final coating with conc forms.Undertaken by spraying coated with powder type or by the suspension of 5～30% solid contents.

Stabilizing agent

Stabilizing agent is preferably emulsifying agent or surfactant, and certain interface active agent is namely arranged, and aqueous dispersion is played Stabilization.suitable stabilizing agent example is if any diethanolamine, monoethanolamine, triethanolamine, fatty acid, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), nonoxynolum, octoxinol, oleic acid, poloxamer, polyoxyethylene 50 stearate, polyethylene glycol fatty acid class (Polyoxyl fatty acid), polyethylene glycol alkyl ether (Polyoxyl hydrocarbon ether), polysorbate (Tween), sorbitan ester (Span), fatty acid salt, polyvidone, sodium lauryl sulfate, cetyl stearyl sodium sulfate, sucrose stearate fat, Spheron MD 30/70 and composition thereof.The content of stabilizing agent is 1～15% (weight ratio), preferred 5～10% (weight ratios), and this is based on the wet weight of aqueous dispersion coating solution component.

Pigment

Seldom add with the solubility pigment form.One disperses aluminium oxide or iron oxide pigment to add.Titanium dioxide is as Chinese white.The addition of pigment is 5～60% (weight ratios) of polymeric blends amount in clothing layer of the present invention.Yet because the pigment binding ability is high, addition also can be as high as 100% (weight ratio) of polymeric blends amount.

Defoamer

One ground of defoamer is dimethicone.

In coating, the material of all uses must be pharmaceutically acceptable in principle, is nontoxic, in medicine, patient is safe from danger.

One is approximately 1 to approximately 50 microns the thickness of the coating that coats on core material, preferred approximately 2 to 30 microns, and more preferably from about 4 to 15 microns.This coating preferably accounts for approximately 2 to approximately 50% of whole preparation (coating+ coat before core material) weight, and preferred approximately 5 to approximately 30%.

The below elaborates with regard to coating core core.

The core core that can be used for coating of the present invention includes but not limited to sheet, granule, the ball of rule or irregular form.Preferred core core is granule, ball.Preferred core core is granule.The size of granule or ball is generally 0.01～2.5mm, and the size of sheet is usually at 2.5～30mm.

Be used for core slug particle of the present invention and be preferably spherically, and average particulate diameter is 80～1200 microns, more preferably 100～800 microns, and more preferably 150～400 microns.This core core preferably has 0.85～1.0 sphericity, and more preferably 0.9～1.0.In the present invention, the advantage of spherical nuclei slug particle used is, can improve the coating efficiency in coating process subsequently.

The core core that is used for coating can contain other pharmacy auxiliary agent that is up to 95% medicine and is up to 99.9% (weight ratio) usually.

Other pharmacy auxiliary agent comprises the bases such as filler, binding agent, disintegrating agent, short disintegrating agent, lubricant (comprising fluidizer, antitack agent).Can also comprise the pharmacy auxiliary agents such as solubilizing agent, suspending agent, sweeting agent, aromatic, pigment, absorbent and surfactant (as playing the effects such as moistening, dispersion, solubilising, emulsifying).The ratio of each component of core core can be determined according to the kind of the kind of active component used, polymer used, drug release curve of expection etc.One is got on very well, and the gained coated drugs with said components proportioning can obtain good drug release curve and taste-masking effect.

In the coating composition that the present invention relates to, the core core is approximately 50～approximately 98% of this dosage form gross weight, preferred approximately 70～approximately 95%.

Be applicable to the medicine with joyful taste not of the present invention and compositions such as analgesic, nonsteroidal anti-inflammatory, hydryllin, antitussive, expectorant, bronchodilator, anti-infective, CNS active drug, cardiovascular drug, antineoplastic agent, pravastatin, Bendectin, vitamin, mineral and replenish machine and manure bate, mineral salt, trace element, Chinese herbal medicine extract etc.

Be specially adapted to the example with medicine of joyful taste not of the present invention as follows, but be not limited to this:

Analgesic is such as aspirin, have acetyl phenalgin phenol, acetyl aminophenol, phenacetin, sodium salicylate, codeine, oxycodone and the dihydrocodeinone of caffeine;

The antipyretic-antalgic agent is as Salicylate, Phenylbutazone, indomethacin, Phenacetin, mefenamic acid etc.;

NSAID (non-steroidal anti-inflammatory drug), such as aspirin, ibuprofen, diclofenac, aceclofenac, flufenamic acid, fenoprofen, flurbiprofen, ketoprofen, naproxen and alkaline metal salt thereof, nimesulide, piroxicam and salt thereof, piroxicam, tenidap, diflunisal, Tolmetin sodium, indomethacin, celecoxib, rofecoxib, the U.S. China fir alcohol of left-handed acetyl, tiaprofenic acid (thiapropheaic acid) and mesalazine (the amino hydrate of 5-);

The CoX-2 inhibitor is as etoricoxib and celecoxib;

H2-picks up anti-dose, such as ticlopidine, cimetidine, ranitidine, famotidine, nizatidine, ebrotidine, the miaow fen replaces Buddhist nun fixed (etinidine), niperitone, sulphur to replace fourth (pisatidine) and roxatidine for fourth (sulfotidine), tuvatidine, zaltidine (zaltidine), lupitidine, Buddhist nun's sweet smell for fourth (nifentidine), Pi Sha for fourth, roxatidine, dust;

anti-allergic agent is such as codeine and its hydrochlorate, codeine and phosphate thereof, ebastine, clemastine and fumarate thereof, A Zha is for fourth (azatidine) and maleate thereof, hydroxyzine and embonate thereof and hydrochlorate thereof, chlorphenamine and maleate thereof and tannate, broncovaleas sulfate, pseudo-epinephrine and sulfate and hydrochlorate, brompheniramine and maleate thereof, loratadine, Desloratadine, decarburization ethyoxyl-loratadine (descarboethoxyloratadine), phyenlephrinium and tannate thereof and hydrochlorate, Methscopolamine and nitrate thereof, proformiphen and hydrochlorate thereof, bromine Pfennig Lamine (bromopheniramine) and maleate thereof, terfenadine, acrivastine, A Simi tells, meclizine, cetirizine and hydrochlorate thereof, phenindamine and tartrate thereof, tripelennamine and hydrochlorate thereof, Cyproheptadine and hydrochlorate thereof, promethazine and hydrochlorate thereof, pyrilamine and hydrochlorate thereof and tannate,

antihistaminic medicine such as brompheniramine maleate, chlorphenamine maleate, carbinoxamine maleate, the Fumaric acid clemastine, mizolastine, dexbrompheniramine maleate, hydrochloric acid diphenyl hydramine (diphenylhydramine hydrochloride), azatadine maleate, Diphenhydramine citrate, diphenylpyraline hydrochloride, doxylamine succinate, promethazine hydrochloride, Pyrilamine, the citric acid tripelennamine, triprolidine hydrochloride, acrivastine, brompheniramine, dexchlorpheniramine, fexofenadine, terfenadine, astemizole and nabumetone,

Antiemetics (Antiemitic), such as meclizine and its hydrochloride, and hydroxyzine hydrochloride and pamoate, and diphenhydramine hydrochloride; prochlorperazine and butadiene ene two acid, benzene and quinoline amine hydrochloride, granisetron and its hydrochloride, dronabinol, nabilone, metoclopramide, bismuth subsalicylate, and promethazine hydrochloride, metoclopramide and its halides / hydrates, chlorpromazine, trimethobenzamide and its hydrochloride, thiethylperazine and maleic acid, scopolamine, perphenazine, ondansetron and the hydrochloride salt;

Diarrhea and intestinal anti-inflammatory agent, for example loperamide, 5-aminosalicylic acid, olsalazine, sulfasalazine, budesonide;

Cathartic is as bisacodyl, sodium picosulfate;

Spasmolytic, for example bromination octyl group;

Gastric mucosa protectant is as rebamipide;

Proton pump inhibitor is such as omeprazole, pantoprazole, lansoprazole, terbinafine;

Diarrhea is as loperamide etc.;

Dopamine receptor is picked up anti-dose, as domperidone;

Diuretic, for example Hydrochlorothiazide;

Oral antidiabetic, for example glipizide, metformin, phenformin, gliclazide, glibenclamide, metformin, miglitol, repaglinide;

Antitussive such as benzonatate, caramiphen edisylate, menthol, dextromethorphan hydrobromide, Clofedanol, codeine phosphate etc.;

Bronchodilator is such as breathing heavily peaceful smooth ingot (bentolin), salbutamol, pirbuterol hydrochloride, orciprenaline, albuterol, procaterol and theophylline;

Drug resistance is picked up in selectivity β-2, for example albuterol, terbutaline, ephedrine, orciprenaline sulfate;

Decongestant, example hydrochloric acid pseudoephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine sulfate etc.;

Expectorant is as guaifenesin, hippo, potassium iodide, terpini hydras, Bisolvon, ambroxol etc.;

Flu and cough product are such as dextro-methorphan and its hydration Bromide and guaifenesin and its hydrochlorate;

The 5HT inhibitor is such as sldenafil;

Macrolide antibiotics is such as carat miramycin, Roxithromycin, azithromycin, clarithromycin, Azithromycin, erythromycin;

Ketolide antibiotics is such as Ketek, Beta-alanine, Quetiapine;

Quinolone antibiotic is as lomefloxacin, norfloxacin, enoxacin, ciprofloxacin, Grepafloxacin, enrofloxacin, ofloxacin, Sparfloxacin, trovafloxacin (Trovafloxacin), Gatifloxacin, levofloxacin and norfloxacin;

Cephalosporins, for example CEFUROXIME AXETIL, cefaclor, cephalexin, cefcapene, cefadroxil, cefpodoxime, head are embraced for peace ester, cefteram pivoxil;

Penicillin antibiotics, as floxapenstaphylex, Talampicillin Hydrochloride, Sultamillin Tosilate, Bacampicillin Hydrochloride, amoxicillin, ampicillin, cloxacillin, 2,6-fluorochlorobenzene first isopenicillin;

Sulfa drugs is as bacteresulf;

Tetracycline medication is as tetracycline;

Enzyme inhibitor is as sulbactam sodium;

Antiviral agents is as nevirapine, amiloprilose HCl, acycloguanosine and amantadine

Antifungal agent is as fluconazol;

Other antimicrobials, ora, disinfectant such as berberine, triclosan, cetylpyridinium chloride, domiphen bromide, quaternary ammonium salt, zinc compound, Sanguinarine, fluoride, alexidine, octopamine, EDTA, benzalkonium chloride, cetylpyridinium chloride or iodine sulfur benzene Zhuo, benzydamine, chlorhexidine, and their salt and derivant.

The non-selective CNS inhibitor of whole body is as aliphatic alcohol, barbiturates etc.;

The non-selective CNS analeptic of whole body is as caffeine, nicotine, strychnine, Picrotoxin, pentylenetetrazole etc.;

The medicine of selectively changing CNS function is as phenyl hydantoin, phenobarbital, primidone, carbamazepine, second coloured glaze amine, mesuximide, phensuximide, trimethadione, stable, diazepam, phenacal, ethylphenacemide, acetic acid azoles amine, bromination relax thiazine, gabapentin, phenytoin etc.;

Tranquilizer, sleeping pill, for example chlordiazepoxide, chlorpromazine, oxazepam, medazepam, triazolam, alprazolam, Duo Naxi dissolve, lorazepam;

Anti-Parkinson Cotard medicine is as levodopa, amantadine, pergolide, carbidopa, nicergoline, selegiline etc.;

Narcotic analgesics is as morphine, heroin, hydromorphone, metopon, oxymorphone, Dromoran, codeine, dihydrocodeinone, oxycodone, nalorphine, naloxone, naltrexone etc.;

Psychosis class medicine as, chlorpromazine, promethazine, donepezil, modafinil, Nefazadone, reboxetine, methotrimeprazine, haloperidol, haloperidol, clozapine, Sertraline, Sertindole, reserpine, imipramine, tranylcypromine, clozapine, Ai Ladan (ilaldon) phenelzine, lithium etc.;

The migraine agent is such as two valproic acids and alkaline metal salt, timolol and maleate thereof, propanol and halogen hydrate thereof, Ergotamine and tartrate thereof, caffeine, rizatriptan, eletriptan, the azoles active substance for smooth, sumatriptan and succinate and same treatment class; Dihydroergotamine, its hydride and mesyl compound, not She Gaide (methsergide) and maleate thereof, different U.S. husky Pood's mucus hydrochlorate (isometheptenmucate), dichloralphenazone;

Antuepileptic, for example valproic acid ester, carbamazepine, phenytoin, gabapentin, topiramate;

Antidepressants are such as fluoxetine Hydrochloride, Sertraline, paroxetine, nortriptyline, risperidone, citalopram, olanzapine, buspirone and its salt;

Anticonvulsant, for example carbamazepine and ethosuximide and anti-Parkinson medicament, for example levodopa;

Antihypertensive comprises, as beta-Blocking agent (for example Propranolol, Mei Tuopuluo, bisoprolol, anti-than fluorine Lip river), nifedipine, irbesartan, doxazosin mesylate and Amlodipine Besylate;

Antihypertensive and Coronary Vasodilators, for example Ismo 20 and isosorbide dinitrate, captopril;

Calcium is picked up drug resistance (calcium channel blocker), for example nifedipine, nicardipine, diltiazem, verapamil, Nifedipine and vinpocetine;

ACE inhibitor is as mercaptomethyl propionyl proline, enalapril, lisinopril;

Anti-heart stricture of vagina pain medicine is the same with antihypertensive;

Cardiac glycoside, for example digoxin and digitophyllin;

Anti-arrhythmic is as quinidine;

Cholesterol lowering drug, for example lovastatin, pravastatin;

Antineoplastic agent, for example 5-fluorouracil, flutamide, etoposide and cyclophosphamide;

Antimalarial is as quinine;

Aeroseb-Dex is as prednisone, metacortandralone;

Vitamin is as folic acid, vitamin B1 nitrate, tretinoin element (vitamin A), vitamin C, vitamin E and zinc;

Mineral, for example ferrum, calcium and zinc salt;

Manure bate, for example docusate sodium;

Plant extract, for example Echinacea, bilobalide, Rhizoma Coptidis, Cortex Phellodendri, Semen Plantaginis etc.

Be used for medicine of the present invention and comprise its pharmaceutically available salt form, free acid form, free alkali form, hydrate, optical isomer, various crystal formation and other analog.These drug analogues should consider its with the taste of the compatibility of coating/taste masked polymer, lipotropy filler with it with under one's belt fast the biological usability that is connected of dissolving select.

Said medicine can be embedded in core material or otherwise as be dry mixed or wet granulation and being combined with core material.

The below elaborates with regard to the preparation method of above-mentioned coating composition.

The preparation method of the coating composition that the invention still further relates to comprises following several basic step: 1), the preparation core material; 2), to the core material coating; 3), more preferably, to coating heal (curing) process.

1), preparation core material

The method for preparing core material has no particular limits.Usually preparation method is by direct pressing method with compositions such as active medicinal matter, pharmacy auxiliary agents; do, the pressing method of wet or sintered particles; extrude and rounding subsequently; wet or dry state pelletize or directly make ball (for example on disk) or powder (powder bed) is bonded to the ball (particle) of non-activity material or contains on the granule of active substance, perhaps further in a certain way as make sheet.

2), to the core material coating

At first prepare spray coating liquor.As an embodiment, polymer and other coating additives are dissolved or dispersed in organic solvent, make the organic spray coating liquor that contains polymer.An embodiment, be dissolved or dispersed in coating additive in the aqueous dispersion of polymer for another example, makes the aqueous dispersion spray coating liquor of polymer; If there is no compatibility reaction, can the aqueous dispersion of two or more polymer by certain mixing after, then other coating additives dissolvings or disperse wherein to make the mix moisture prose style free from parallelism spray coating liquor of polymer.

Polymer and the content of other coating additives in organic solution are generally 1～15%, and preferably 2～10%, more preferably 3～8%.Polymer and the content of other coating additives in the aqueous dispersion suspension are generally 2～30%, and preferably 5～20%, more preferably 8～15%.The aqueous dispersion suspension also can contain a certain amount of organic solvent, and its content is often 1～20%, and preferably 1～10%, more preferably 2～5%.

Utilize the solution of above-mentioned gained or suspension by casting, soak the coating processes such as the libation at an ancient wedding ceremony, brushing or spraying to the core material coating.Preferably, adopt spraying method to carry out coating.

In one embodiment, will be less as less than dispersions such as the core material of the need coating of 80 microns such as fine grained, ball or medicine powder, crystal, medicine carrying resins and be suspended in the organic solution or aqueous dispersion that contains polymer mix homogeneously.Adopt spraying method to carry out coating.

In another embodiment, will be larger as making it be suspended in aerial or insert in coating pan or other coating equipment in sugar production lines greater than the core material of the need coating of 80 microns such as sheet, granule, ball, medicine crystal, medicine carrying resin etc., core material is sprayed stated organic solution or the aqueous dispersion that contains polymer, adopt spraying method to carry out.

The coating film forming procedure does not rely on coating process and is undertaken by energy input.This can complete by convection current (heat), radiation (infrared or microwave) or conduction.Thus will be for the solvent of coating as solvent or suspending agent use evaporate, necessary words also applied vacuum are accelerated evaporation.Drying efficiency as higher in needs, the present invention often adopts high efficiency coating equipment in sugar production line (as fluid bed).

The temperature that the coating coating is used should be higher than the minimum film formation temperature (MFT) (minimum film formation temperature refers to the minimum temperature of polymer formation seriality clothing film, and below minimum film formation temperature, polymer particle can not be out of shape and merge and film forming) of polymer.The temperature that the coating coating is used exceeds 10～20 ℃ of minimum film formation temperature usually.If temperature is too low, may make the clothing film crack occur; Excess Temperature is too softening polymer, causes the clothing film coalescence.

During coating, usually core material etc. is preheated to 20～90 ℃, preferably 30～70 ℃, more preferably 30～50 ℃, first apply with low hydrojet speed, after having coated skim clothing film to the core material surface, then improve hydrojet speed to coating and finish.

In order to protect unsettled active component to avoid degraded in healing processing, can use the air in the airtight environment of nitrogen replacement (as airtight casing).

Most suitable or more suitable technological parameter art those skilled in the art is thus determined according to coating material and core material character and experimental result etc.Take fluidized bed coating as falling, the process conditions such as coating temperature, fluidisation air quantity, atomizing pressure and hydrojet speed all can quantitatively be controlled according to practical situation optimization.

The present invention relates to a kind of pharmaceutical preparation, it is characterized in that said preparation comprises the difficult coating composition of being discovered by the user of above-mentioned offending abnormal flavour in the administration process.

the pharmaceutical preparation that the present invention relates to can further be processed as adding some pharmaceutically acceptable excipient (as aromatic for the pastille core material that has applied for preparing by above-mentioned arbitrary mode, sweeting agent, filler) pharmaceutically acceptable any dosage form of making, for example, the conventional liq (or oral liquid) of preparation suspension, masticable tablet, rehydration is the powder of suspension, rapidly-soluble fast solvellae, lozenge, wafer (wafers), chewing gum, the hard-shell capsule of powder/granule/small-sized or micro chip/liquid filler is housed, the soft-shelled gelatin body that has liquid core or fill with powder or granule, can at once discharge or the conventional compressed tablets of delayed release, confection and caked sugar form, aerosol cream, colloid, pouch, perhaps further do not process and directly come into operation, as the tablet of directly taking.The technology of preparing of above-mentioned whole dosage form is all that this area is known.

A preferred embodiment of above-mentioned dosage form is chewable tablet.This chewable tablet can contain other conventional additives except taste masked particle, as filler, comprises that water solublity can suppress carbohydrate such as sucrose, mannitol, sorbitol, maltose alcohol, xylitol, lactose and composition thereof; Conventional dry adhesives comprises cellulose, cellulose derivative, polyvinylpyrrolidone, starch, modified starch and composition thereof, and microcrystalline Cellulose particularly; Sweeting agent is as aspartame, acesulpham k, sucralose and glucide; And lubricant, as magnesium stearate, stearic acid, Talcum and wax.In addition, this chewable tablet can also mix other medicinal adjuvants, comprises as antiseptic, correctives, antioxidant, surfactant and coloring agent.

This chewable tablet can comprise by compacting the mixture preparation of taste masked particle.Some flaking methods are known in the art, for example, comprise with compacting roller bearing technology or landing roller bearing machine, or die casting, water money or extruding technology.Preferably, adopt rotary tablet machine to make by compacting.

The preferred soft chewable tablet of above-mentioned chewable tablet.The hardness of this soft chewable tablet preferably is no more than approximately every square centimeter of (kp/cm of 15 kip ²).More preferably, the hardness of this tablet is approximately 1 to approximately 8, first-selected approximately 2 to about 5kp/cm ²Term used herein " hardness " is to describe the radially breaking strength that detects by conventional medicine hardness detection technique (detecting meter as Schleuruger hardness).

Described thus the present invention in detail, obviously also various changes can have been arranged within the scope of the invention to those skilled in the art, the present invention is not subjected to the described restriction of description.

Embodiment

In order to demonstrate the invention, provide following embodiment.Yet should be appreciated that the present invention is not limited only to these embodiment.

Embodiment 1

cellulose acetate by 40%, (particle diameter is 38～74 μ m for 20% Eudragit E 100 and 40% zinc phosphate granule, or 200～400 order) coating (A) of making is to acetaminophen (APAP) granule (footpath 14～24 orders, described acetaminophen particles is made by dry granulation, it is composed as follows: acetaminophen (APAP) 50%, microcrystalline Cellulose 30%, cross-linking sodium carboxymethyl cellulose 17%, sodium lauryl sulfate 1%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%) implement to apply, after coating procedure finishes, coating accounts for 23.08% (weight ratio) (being granule weightening finish 30%) of whole coated granule.Then drug particles and other compositions that applies mixed in following ratio: coated granule 40.63%, mannitol 49.37%, microcrystalline Cellulose 7.5%, stearic acid 1%, silicon dioxide colloid 0.5%, spice 1%.Then this final mixture is pressed into final sheet and heavily is the tablet of 960mg, and such tablet diameters is 10.5mm, and hardness is 5～10kp approximately, brittleness approximately 0～1%.40% zinc phosphate in coating (A) is changed respectively into 40% triethanolamine, Talcum and Eudragit E 100, and other are constant, prepare respectively reference substance 1,2 and 3 with method.

(1), In Vitro Dissolution test

Be in the simulated gastric fluid of 7.0 pure water and pH1.2 and pH7.8 simulated intestinal fluid, sample and reference substance to be carried out the stripping test at pH.Table 1,2 has shown sample and reference substance in pH is 7.0,1.2 and 7.8 environment, the percent of ingredient stripping within given a period of time.

Table 1 acetaminophen mastication tablet is the percent of stripping in 7.0,1.2 and 7.8 solution at pH

Table 2 acetaminophen mastication tablet is the percent of stripping in 7.0,1.2 and 7.8 solution at pH

Result shows, the characteristic of embodiment example pharmaceuticals In Vitro Dissolution obviously is better than all reference substances: embodiment sample stripping quantity under neutrallty condition is lower, and stripping quantity is all higher under acidity and alkali condition, satisfies clinical taste masking and uses, and is conducive to improve bioavailability; Reference substance 1 stripping quantity under neutrallty condition is all higher, and reference substance 2 and 3 stripping quantity under alkali condition is lower.

(2), bioavailability test

18 health volunteers are (4 of oral two kinds of acetaminophen mastication tablets once, about 600mg, all test specimens were all being placed under 40 ℃ of temperature and relative humidity 75% condition 3 months) and drink 250ml water after, with the blood drug level of Syrups by HPLC acetaminophen.Test result sees Table 3.

Table 3 acetaminophen mastication tablet bioavailability test result ( N=18)

The test result demonstration, after Long-term Storage, the characteristic of the interior stripping of the bioavailability of embodiment sample or body is better than all reference substances, especially reference substance 2 and 3.

(3), sense of taste test

Please 9 special members (testee), 1 sample that makes as stated above or reference substance are placed in respectively their mouthful chew and keep 2 minutes, and measure they when feeling bitterness time and record testee main suit's the sense of taste of test article in the oral cavity.The variations of the time when feeling bitterness, the change of sense of taste and sense of taste power etc. are used for estimating.Acquired results sees Table 4.

The result of the time when table 4 is felt bitterness and the test article sense of taste in the oral cavity

Test result shows, the effect of covering of embodiment sample is better than all reference substances, and the embodiment sample can improve the mouthfeel of pharmaceutical composition very effectively, need not additionally to add odor mask or flavoring agent at pharmaceutical composition.

(4), the measuring mechanical property of filming

The healing processing of sample and the reference substance required minimum pressure of coated particle thing crushing to terminal in mensuration embodiment 3.The results are shown in Table 5.

The table 5 For Measuring Mechanical Properties result of filming

Result shows, the mechanical performance that embodiment films is than the reference substance height of filming, and is particularly high with reference substance 1 and 3.

To sum up acquired results can get, and the combination property of embodiment sample or resultant effect will be got well than reference substance, and overall performance is reinforced.

Embodiment 2

Ethyl cellulose by 24%, 26% diethylamino methyl cellulose, (particle diameter is 23～38 μ m to 49.5% CYSTINE granule, or 400～600 order) and the coating (B) made of glyceryl triacetate 0.5% pipemidic acid granule (footpath 12～20 orders) is implemented to apply, described pipemidic acid granule is made by dry granulation, its component content is composed as follows: pipemidic acid 30%, microcrystalline Cellulose 34%, low-substituted hydroxypropyl cellulose 18%, fructose 8%, lactose 8%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%.After coating procedure finished, coating accounted for 23.08% (weight ratio) (being granule weightening finish 30%) of whole coated granule.Then drug particles and other compositions that applies mixed in following ratio: coated granule 63.73%, mannitol 26.27%, microcrystalline Cellulose 7.5%, stearic acid 1%, silicon dioxide colloid 0.5%, spice 1%.Then this final mixture is pressed into final sheet and heavily is the tablet of 850mg, and such tablet diameters is 13mm, and hardness is 5～10kp approximately, brittleness approximately 0～1%.

The interior coating that hydroxypropyl methylcellulose with 80% and 20% Eudragit NE30D make, the outer layer coating that 24% ethyl cellulose, 75.5% diethylamino methyl cellulose and glyceryl triacetate 0.5% are made is implemented to apply to the pipemidic acid granule, other are constant, prepare reference substance 4 with above-mentioned method.

The interior coating that hydroxypropyl methylcellulose with 80% and 20% Eudragit NE30D make, the outer layer coating that 24% hydroxypropyl methylcellulose, 75.5% diethylamino methyl cellulose and glyceryl triacetate 0.5% are made is implemented to apply to the pipemidic acid granule, other are constant, prepare reference substance 5 with above-mentioned method.

(1), In Vitro Dissolution test

Then in pH is the simulated intestinal fluid solution of the simulated gastric fluid of 7.0 pure water and pH1.2 and pH7.8, sample and reference substance are carried out the In Vitro Dissolution test.Table 6,7 has shown sample and reference substance in pH is 7.0,1.2 and 7.8 environment, the percent of ingredient stripping within given a period of time.

Table 6 pipemidic acid chewable tablet is the percent (%) of stripping in 7.0,1.2 and 7.8 solution at pH

Table 7 pipemidic acid chewable tablet is the percent (%) of stripping in 7.0,1.2 and 7.8 solution at pH

Test result shows, the characteristic of embodiment example pharmaceuticals In Vitro Dissolution obviously is better than all reference substances: embodiment sample stripping quantity under neutrallty condition is lower, and stripping quantity is all higher under acidity and alkali condition, satisfies clinical taste masking and uses, and is conducive to improve bioavailability; Reference substance 4 stripping quantity under alkali condition is all lower, and reference substance 5 stripping quantity under neutrallty condition is higher.

Embodiment 3

KOLLIDONE SR by 38.56%, vinyl diethylamide-vinyl acetate co-polymer of 20.0%, 11.44% EASTMAN 9-45 (monoglyceride of acetoxylation), the coating (A) that 25% hydrogen tartrate k particle (particle diameter is 38～74 μ m, or 200～400 orders) and 5% Talcum are made is implemented to apply to medicine caffeine granule (footpath 40～80 orders).

Embodiment 4

Ethyl cellulose by 22.78%, 22.78% KOLLIDONE SR, 18.0% Eudragit E.100, (particle diameter is 38～74 μ m to 20% zinc phosphate granule, or 200～400 order), the coating (A) made of 11.44% EASTMAN 9-45 (monoglyceride of acetoxylation) and 5% Talcum is implemented to apply to medicine acetyl aminophenol (APAP) granule (footpath 40～80 orders).

Embodiment 5

(particle diameter is 10～18 μ m for 50% polrvinyl chloride-50% polyvinylacetate copolymer by 24%, 26% Eudragit E 100,49.5% CYSTINE granule, or 800～1340 order) and the coating (C) made of glyceryl triacetate 0.5% pipemidic acid granule (footpath 20～40 orders) is implemented to apply, described pipemidic acid granule is made by dry granulation, its component content is composed as follows: pipemidic acid 30%, microcrystalline Cellulose 45%, low-substituted hydroxypropyl cellulose 25%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%.After coating procedure finished, coating accounted for 13.04% (weight ratio) (being granule weightening finish 15%) of whole coated granule.

Embodiment 6

the terpolymer of polyvinylacetate-10% polyvinyl alcohol of 80% polrvinyl chloride-10% by 20%, vinyl diethylamide-vinyl acetate co-polymer of 26%, (particle diameter is 2.6～6.5 μ m to 53.5% guanyl granule, or 2000～5000 order) and the coating (D) made of glyceryl triacetate 0.5% pipemidic acid granule (footpath 16～30 orders) is implemented to apply, described pipemidic acid granule is made by dry granulation, its component content is composed as follows: pipemidic acid 30%, microcrystalline Cellulose 40%, low-substituted hydroxypropyl cellulose 18%, lactose 10%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%.After coating procedure finished, coating accounted for 9.09% (weight ratio) (being granule weightening finish 10%) of whole coated granule.

Embodiment 7

Ethyl cellulose by 20%, 26% Eudragit E 100, (particle diameter is 1.3～2.6 μ m to 53.5% hydrogen tartrate k particle, or 5000～10000 order) and the coating (E) made of glyceryl triacetate 0.5% pipemidic acid granule (footpath 12～20 orders) is implemented to apply, described pipemidic acid granule is made by dry granulation, its component content is composed as follows: pipemidic acid 30%, microcrystalline Cellulose 38%, low-substituted hydroxypropyl cellulose 18%, fructose 6%, lactose 6%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%.After coating procedure finished, coating accounted for 7.41% (weight ratio) (being granule weightening finish 8%) of whole coated granule.

Sample to embodiment 3-7 carries out In Vitro Dissolution test or granule slaking test, the results are shown in Table 8.

Table 8 vitro Drug stripping result

Claims (17)

1. One kind in the administration process offending abnormal flavour be difficult for the medication coat compositions discovered by the user, it is characterized in that this coating composition comprises:

   A), the coating covered outward, this coating contains:

   1), a kind of content is that 10wt% to 80wt% pharmaceutically acceptable all is insoluble under any pH value or water-fast polymer I almost,

   2), a kind of content is that 10wt% to 70wt% pharmaceutically acceptable is dissolved in acid medium but is insoluble to or is dissolved in hardly polymer II in neutrality or alkaline pH medium, and

   3), a kind of content be 1wt% to 70wt% pharmaceutically acceptable without offending abnormal flavour be insoluble to or water-soluble but can be dissolved in the particulate matter of acid medium and alkaline medium hardly, above-mentioned content is all based on the gross dry weight amount of coating,

   Wherein, above-mentioned polymer I is compatible with above-mentioned polymer II,

   Wherein, above-mentioned polymer I is selected from ethyl cellulose, methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate and their mixture, and above-mentioned polymer II is selected from Eudragit E,

   Perhaps, above-mentioned polymer I is selected from polyvinylacetate, vinyl acetate-vinyl chloride copolymer, vinyl chloride-ethylene alcohol-vinyl acetate terpolymer and their mixture, and above-mentioned polymer II is selected from Eudragit E,

   Perhaps, above-mentioned polymer I is selected from polyvinylacetate, vinyl acetate-vinyl chloride copolymer, vinyl chloride-ethylene alcohol-vinyl acetate terpolymer and their mixture, and above-mentioned polymer II is selected from vinyl diethylamide-vinyl acetate co-polymer;

   B), contained a kind of core core that the medicine of offending abnormal flavour is arranged by what above-mentioned coating coated.
2. 2. according to claim 1 coating composition, is characterized in that the described particulate matter that can be dissolved in acid medium and alkaline medium is selected from guanyl, zinc phosphate, CYSTINE, D-Tyrosine, potassium hydrogen tartrate, D-trp, L-threonine, D-Thr, D-Leu, D-phenylalanine and composition thereof.
3. 3. according to claim 1 coating composition, is characterized in that the described particulate matter that can be dissolved in acid medium and alkaline medium is selected from zinc phosphate.
4. 4. according to claim 1 coating composition, is characterized in that the described particulate matter that can be dissolved in acid medium and alkaline medium is selected from guanyl.
5. 5. according to claim 1 coating composition, is characterized in that the described particulate matter that can be dissolved in acid medium and alkaline medium is selected from CYSTINE.
6. 6. according to claim 1 coating composition, is characterized in that the described particulate matter that can be dissolved in acid medium and alkaline medium is selected from potassium hydrogen tartrate.
7. 7. according to claim 1 coating composition, is characterized in that the described mean diameter that can be dissolved in the particulate matter of acid medium and alkaline medium is 0.05～100 μ m.
8. 8. coating composition according to claim 1, is characterized in that described polymer I is selected from ethyl cellulose, cellulose acetate and composition thereof, and described polymer II is selected from Eudragit E.
9. 9. according to claim 1 coating composition, is characterized in that described polymer I is selected from polyvinylacetate, and described polymer II is selected from Eudragit E.
10. 10. the coating composition of any one according to claim 1 to 9, it is characterized in that in coating that described polymer I covers, content is 20wt% to 60wt% outside described, in the coating that described polymer II is covered outside described, content is 20wt% to 50wt%, in the coating that the described particulate matter that can be dissolved in acid medium and alkaline medium covers outside described, content is 5wt% to 50wt%, based on the gross dry weight amount of coating.
11. 11. the coating composition of any one according to claim 1 to 9 is characterized in that described coating does not contain water-soluble material.
12. 12. the coating composition of any one according to claim 1 to 9 is characterized in that described core core is the sheet of rule or irregular form, granule, ball, medicine crystal and/or medicine carrying resin.
13. 13. the coating composition of any one according to claim 1 to 9 is characterized in that described medicine is selected from and has the not analgesic of joyful taste, the antipyretic-antalgic agent, NSAID (non-steroidal anti-inflammatory drug), the CoX-2 inhibitor, anti-allergic agent, the antihistaminic medicine, Bendectin, the intestinal anti-inflammatory agent, cathartic, spasmolytic, gastric mucosa protectant, proton pump inhibitor, diarrhea, dopamine-receptor antagonist, diuretic, oral antidiabetic, antitussive, bronchodilator, selectivity β-2 antagonistic, decongestant, expectorant, macrolide antibiotics, ketolide antibiotics, quinolone antibiotic, cephalosporins, Penicillin antibiotics, sulfa drugs, tetracycline medication, the ACE-inhibitor, antiviral agents, antifungal agent, other antimicrobials, the non-selective CNS inhibitor of whole body, the non-selective CNS analeptic of whole body, the medicine of selectively changing CNS function, tranquilizer, anti-Parkinson Cotard medicine, psychosis class medicine, antuepileptic, antidepressants, anticonvulsant, antihypertensive, anti-Coronary Vasodilators, calcium antagonists, cardiac glycoside, anti-arrhythmic, cholesterol lowering drug, antineoplastic agent, antimalarial, Aeroseb-Dex, vitamin, mineral, manure bate, plant extract.
14. 14. the coating composition of any one according to claim 1 to 9 is characterized in that described medicine is selected from acetyl aminophenol, nimesulide, piroxicam, ticlopidine, brompheniramine maleate, fexofenadine, terfenadine, the carat miramycin, Roxithromycin, azithromycin, clarithromycin, Azithromycin, erythromycin, Ketek, CEFUROXIME AXETIL, cefaclor, cefcapene, cefadroxil, cefpodoxime, cefotiam hexetil, cefteram pivoxil, sulbactam sodium, floxapenstaphylex, Talampicillin Hydrochloride, Sultamillin Tosilate, Bacampicillin Hydrochloride, amoxicillin, ampicillin, cloxacillin, 2,6-fluorochlorobenzene first isopenicillin, fluconazol, Sertraline, donepezil, Ergotamine and tartrate thereof, eletriptan, azoles is for smooth, sumatriptan and succinate thereof, dihydroergotamine, the valproic acid ester, fluoxetine Hydrochloride, paroxetine, risperidone, olanzapine, carbamazepine, levodopa, nifedipine, irbesartan, doxazosin mesylate, mercaptomethyl propionyl proline, enalapril, lisinopril, lovastatin, pravastatin, 5-fluorouracil, flutamide, etoposide, cyclophosphamide, iron salt, calcium salt, zinc salt, the Echinacea plant extract, bilobalide, the Rhizoma Coptidis plant extract, the Cortex Phellodendri plant extract, the Semen Plantaginis plant extract.
15. 15. the coating composition of any one according to claim 1 to 9 is characterized in that described coating accounts for this coating composition gross weight 2～50%, described core core accounts for this coating composition gross weight 50～98%.
16. 16. a pharmaceutical preparation is characterized in that said preparation comprises the coating composition of any one in claim 1 to 15.
17. 17. pharmaceutical preparation according to claim 16, it is characterized in that its dosage form be oral liquid, masticable tablet, rehydration be the powder of suspension, rapidly-soluble fast solvellae, lozenge, wafer, chewing gum, be equipped with powder/granule/small-sized or micro chip/liquid filler hard-shell capsule, can at once discharge or conventional compressed tablets, confection and caked sugar form, aerosol cream, colloid or the pouch of delayed release.