CN101927002A

CN101927002A - Medicament and coating composition

Info

Publication number: CN101927002A
Application number: CN2010102281641A
Authority: CN
Inventors: 钟术光
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-07-16
Filing date: 2010-07-16
Publication date: 2010-12-29
Anticipated expiration: 2030-07-16
Also published as: CN101927002B

Abstract

The invention discloses a medicament and coating composition capable of preventing unpleasant peculiar smell from being perceived by users in an administration process. The composition comprises a core of medicaments with unpleasant peculiar smell, a polymer which covers outside the core and is almost water-insoluble at any pH value, a polymer which is soluble in an acidic medium and is almost insoluble in a neutral or an alkaline pH medium, and a coating which can cover or inhibit the unpleasant peculiar smell and is soluble in the alkaline compound of diluted hydrochloric acid; preferably, the two polymers is compatible or completely compatible; and more preferably, the alkaline compound is almost insoluble. Besides the original advantages, the coating composition also has the advantages of covering or inhibiting the subsequent and/or residual unpleasant peculiar smell of the medicaments and/or unpleasant peculiar smell possibly generated from an additive in the coating, improving medicament release performance, simplifying a formula and a preparation method, reducing production cost, and the like.

Description

A kind of medication coat compositions

Technical field

The present invention relates to a kind of medication coat compositions.More 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.

Technical background

A lot of active component, for example antibiotic has intensive 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 patient's low conformability thus.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 coated with and prevent that tablet active component in 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 in the administration process, decomposing, for example chewable tablet and liquid preparation.And child, old people and many other patients have any problem when taking undecomposed tablet and capsule.Therefore, shelter the unpleasant taste of the activating agent in these preparations that before administration or in the administration process, need to decompose, make it to possess good palatability or edibility and advise 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 a coating.It is coated with the taste masked coating that it will contain the moulded products of active component of unpleasant taste, and coating has stoped the release of active component, thereby has stoped the generation of unpleasant taste.Existing some representational examples of correlation technique are as follows:

United States Patent (USP) 5489436 discloses the chewable tablet of coating taste maskings, and its particulate coating that contains medicine is " anti-enteric coating " type, is designed to can dissolve under the low pH value in the stomach but have water to indissolubility under the higher pH in the mouth.This coating contains the polymer blend of dimethylaminoethyl acrylate methyl amino-ethyl ester and natural methacrylate and cellulose esters.

U.S. Pat 6663893B2 (perhaps referring to EP1276470B1) discloses the pharmaceutical composition of a kind of bag " anti-enteric coating " taste masking.This coating contains polymer and alkaline modifier such as dimethylaminoethyl acrylate methyl amino-ethyl ester, natural methacrylate and cellulose esters.Alkaline modifier in this coating composition can the enhanced activity composition release.

U.S. Pat 6551617B1 provides another kind of coating composition, and it can shelter the boring taste of oral active constituents of medicine.This coating composition has polyvinyl acetate and dimethylaminoethyl methacrylate and neutral methacrylate.Randomly, in this coating composition, can contain alkaline modifier, with the release of enhanced activity composition.

US6663893B2 and US6551617B1 have done certain technological improvement to US5489436.They have all added alkaline modifier at coating composition.1), it is as stabilizing agent expects that this alkalescence modifier brings into play following function in this invention:, the subenvironment buffering of coating is neutral pH, can strengthen the globality of coating, can surmount the coating of alkali-free modifier, can improve the storage-stable in drying regime or the liquid suspension; 2), as the function of plasticizer, this function can reduce the fragility of coating; 3), play release-modifier, can strengthen in the stomach dissolution velocity of coating in the acid environment, it is faster than other system that this function makes that coated medicament is delivered to body circulation speed with ingredient.The alkaline modifier example that these two patent disclosures are suitable is food basifier or its mixture that triethanolamine (TEA), basic amino acid, Talcum, ammonia soap., meglumine (meglumine), trimethylamine, calcium silicates, Magnesiumaluminumsilicate, routine are used for food industry.Basic amino acid for example can be, and L-arginine, L-histidine, (corn) alcohol soluble protein (prolamine, zein) or its mixture.

But US6663893B2 and US6551617B1 have many significant deficiency:

For example, water miscible alkaline modifier such as triethanolamine (TEA), basic amino acid such as L-arginine, meglumine, trimethylamine etc. are because of its bigger water solublity, easily in the oral cavity, dissolve, so 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.In addition, though the material that these polarity are very big has strengthened in the stomach dissolution velocity of coating in the acid environment, but the polymer phase capacitive in they and the coating is very poor, it is very high to occur biphase interface energy during the two blend, 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 the coating, become the weak link in the coating, coating machine intensity or mechanical performance are significantly reduced,, coating is broken as declines such as intensity, toughness, elasticity.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 of high polymer and interface ", Wu Renjie chief editor, Science Press (Beijing), the 104th～110 page; Surface Modification Of Inorganic Fillers, Jiangxi chemical industry, calendar year 2001, the 4th phase, the 17th～18 page).

And for example, though Talcum, calcium silicates, Magnesiumaluminumsilicate and zein etc. have certain hydrophobicity, relative with the compatibility of polymer better, but calcium silicates, Magnesiumaluminumsilicate have stronger adsorptivity, easily the absorption medicine hinders slow medicine stripping under one's belt, makes drug absorption slack-off; And, calcium silicates, Magnesiumaluminumsilicate form gel in water under effects such as acid, and gel has slow releasing function, slow gastric solubleness coating of resistance and medicine stripping under one's belt further, make drug absorption slack-off, these factors all will influence bioavailability of medicament (referring to the relevant clause part of document works: The Merck Index, 13 ^ThEdtion; " pharmaceutical necessities complete works ", 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), volumes such as sieve R.C., Zheng Jun democracy is translated, Chemical Industry Press, January in 2005 the 1st edition).

For another example, alcohol soluble protein is water insoluble, also be insoluble to anhydrous 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 SDS surfactants such as (sodium lauryl sulphates) except that alcohol solution.The albumen (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] .AgricBiol Chem, 1980,44:1633～1639; Oryza sativa L. alcohol soluble protein extraction conditions and total content distribute, Jiang Donghua etc., Zhejiang agricultural journal, 19 (3): 174～178,2007; The dissolution characteristics of high-lysine component research in the 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).For example, zein is water insoluble, diluted acid and diluted alkaline, only in strong basicity (pH 〉=11.5) solution, could dissolve, and in low concentration salt solution, easily produce precipitation (referring to document: chemical industry dictionary, http://www.chemyq.com/xz/xz7/63938pkqbn.htm; Zein extraction process and Study on Functional, Zhang Zhong, Qi Aiyun, grain and feed industry, 2004 09 phases; " the pharmaceutic adjuvant handbook, (original work the 4th edition), 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 quickening medicine stripping under one's belt.Equally, Talcum also is so, because of its all dissolving hardly in diluted acid, diluted alkaline, can not generate water-soluble material with the acid effect.

For another example, ammonia soap. has better water solubility and certain hydrophobicity (containing hydrophobic group oleic acid base) is arranged, but, it does not generate water miscible salt under the acid effect under one's belt, and only produce the water-fast fluid oil (drip) stronger under the room temperature to non-water-soluble coating composition adhesiveness, this oil (dripping) is difficult to be redissolved in intestinal or stomach, easily is adsorbed in the coating, so it also is difficult to the stripping under one's belt of further acceleration medicine; In addition, the ammonia soap. chemical property is stable inadequately, and smell is produced in easily oxidation.

Because above-mentioned and sour effect can not generate the alkali compounds of water-soluble material, in coating, can not form micropore, 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.

Need be pointed out that separately especially, have the medicine of unpleasant taste to have a small amount of or minimal residue in the preparation, thereby the people who takes medicine still may feel the offending abnormal flavour of remaining medicine in the outer surface of above-mentioned coating or nearly surface as from the degree of depth of surface 1～3 μ m.

And, U.S. Pat 6663893B2, US6551617B1 and US5489436 have used polymer such as dimethylaminoethyl acrylate methyl amino-ethyl ester, natural methacrylate in its coating composition, and these polymer can produce certain offending abnormal flavour of people that allows, as produce the certain ammonia stink and the abnormal smells from the patient of solvent characteristics.

In addition, some conventional additives that coating composition is commonly used also can produce and allow the offending abnormal flavour of people, as surfactant, stabilizing agent, plasticizer, fluidizer (glidants) and pigment etc.The additive that offending abnormal flavour arranged is for example: surfactant such as sodium lauryl sulphate (stronger bitterness is arranged), triacetin (mildly bitter flavor, little have fatty stink), spans surfactant (fatty stink is arranged), Tweens surfactant (special stink, little bitter in the mouth are arranged), polyoxyethylene surfactant (mildly bitter flavor, fatty stink is arranged), glyceryl monostearate (mildly bitter flavor, fatty stink is arranged); Plasticizer such as diethyl phthalate (allow the offending bitterness of people), citron ester triethyl (bitter in the mouth), Oleum Ricini (little smelly, lightly seasoned, but slight peppery and disgusting flavor is arranged subsequently); Fluidizer, as glyceryl monostearate, magnesium stearate (little have special stink); Stabilizing agent such as oleic acid (Adeps Sus domestica sample stink is arranged, the stink of becoming sour is more arranged after the oxidation), hexadecanol (faint stink).

In actual applications, the commodity KOLLIDON SR or the Kollicoat SR 30D of the polyvinyl acetate that example commonly used such as BASF AG provide contain the sodium lauryl sulphate of a certain amount of (about 1%).Cellulose acetate latex contains 1.9% sodium lauryl sulphate.Aquacoat (ethylcellulose aqueous colloidal dispersion) also contains 5% hexadecanol except that containing 2.7% sodium lauryl sulphate.Surelease (ethylcellulose aqueous colloidal dispersion) contains a certain amount of oleic acid.EUDRAGIT@RS, RL coating add plasticizer citron ester triethyl, fluidizer glyceryl monostearate often; The EUDRAGIT@E coating adds magnesium stearate often.

Yet, none is taste modifier (as correctives, flavour enhancer or abnormal flavour inhibitor) or olfactory sensation improver for the example of U.S. Pat 6663893B2 and the disclosed alkaline modifier of US6551617B1, can cover or suppress the additive of offending abnormal flavour in other words.And, some alkaline modifier that U.S. Pat 6663893B2 (perhaps referring to EP1276470B1) and US6551617B1 mention also have offending abnormal flavour, (Adeps Sus domestica sample stink is arranged, the stink of becoming sour is more arranged after the oxidation as L-arginine (mildly bitter flavor), L-histidine (bitter in the mouth), ammonia soap.; The ammonia stink), triethanolamine (little have ammonia stink), meglumine (being with salty and bitter flavor), trimethylamine (have the smelly and fish of ammonia wake up foul smell flavor).

More it needs to be noted, above-mentioned anti-" enteric coating " technology of having used two kinds of different polymer, with respect to a kind of polymer, often has more micropore in the clothing film, when especially two kinds of polymer phase capacitives are bad, easily stripping from micropore of medicine, thus produce follow-up allow the offending abnormal flavour of people, especially this coating composition in the oral cavity holdup time than long time.

If further adding routine at above-mentioned coating composition covers and adds agent, the result is except increasing production cost and process complexity, the more important thing is to influence the mechanical performance of coating largely, and the effect of coating taste masking more seriously, because add other materials in a large number, especially with the inconsistent water miscible polar substances of coated polymeric, the content of polymer descends significantly in the coating with making, and causes the coating machine performance to descend greatly.

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

Goal of the invention

One of purpose of invention just provides a kind of difficult medication coat compositions of being discovered by the user of abnormal flavour of improved combination properties.

Particularly, the purpose of invention just provides the difficult medication coat compositions of being discovered by the user of a kind of abnormal flavour, medicine follow-up and/or remaining offending abnormal flavour and/or the issuable offending abnormal flavour of the additive in the coating can also be covered or suppress to this coating composition except keeping or inheriting former the having superiority.

The purpose of invention just provides the difficult medication coat compositions of being discovered by the user of a kind of abnormal flavour, this coating composition is except keeping or inherit former the having superiority, and its original medicine release under one's belt can not be quickened or the probability that slowed down on the contrary is eliminated or reduce.

Two of the purpose of invention further provides a kind of abnormal flavour to be difficult for the medication coat compositions of being discovered by the user, and this coating composition is except having above-mentioned advantage, and the mechanical performance of its coating is enhanced.

Three of the purpose of invention further provides a kind of abnormal flavour to be difficult for the medication coat compositions of being discovered by the user, this coating composition is except having above-mentioned advantage, and the time of being perceived the offending abnormal flavour of medicine after this medication coat compositions is taken in the oral cavity is prolonged further.

Four of the purpose of invention further provides a kind of abnormal flavour to be difficult for the medication coat compositions of being discovered by the user, and this coating composition has above-mentioned multiple advantage simultaneously, but its prescription and preparation method simplified largely, and material saving reduces production costs.

Other goals of the invention are the detailed description of the description of face as follows.

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 said composition comprises at least:

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

1), at least a pharmaceutically acceptable under any pH value, all being insoluble to or water-insoluble polymer almost,

2), at least aly pharmaceutically acceptablely be dissolved in acid medium but be insoluble to or be dissolved in polymer in neutrality or the alkaline pH medium hardly, and

3), at least aly pharmaceutically acceptablely can cover or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid;

B), contained at least a nuclear core that the medicine of offending abnormal flavour is arranged by above-mentioned coating coating.Preferably, above-mentioned under any pH value, all be insoluble to or almost water-insoluble 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 the alkaline pH medium compatible perhaps fully.

The present invention relates to the difficult medication coat compositions of being discovered by the user of another kind offending abnormal flavour in the administration process, it is characterized in that said composition comprises at least:

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

3), at least aly pharmaceutically acceptablely be insoluble to or almost water-fastly can cover or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid;

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

B), coated the nuclear core, this nuclear core contains at least by above-mentioned coating:

1), at least a medicine that offending abnormal flavour is arranged;

2), at least a sweller and/or at least a super-disintegrant that can not form strong gel; Preferably, also contain

3), at least a osmotic pressure active substance; More preferably, also contain

4), at least a dry adhesives.Preferably, above-mentioned under any pH value, all be insoluble to or almost water-insoluble 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 the alkaline pH medium compatible perhaps fully.

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

Term used herein " is covered " and is referred to hide, cover up and/or cover abnormal flavour by the chemical compound such as sweetener, flavoring agent etc. that adds pharmaceutically acceptable amount in the compositions of odorous compound is arranged, wherein odorous compound remains unchanged, other taste that exists in the thing but its taste is combined is covered, thereby makes abnormal flavour be difficult for being discovered by the user.

Term used herein " inhibition " refers to can slow down or disturb sense of taste transmission mechanism in pharmaceutically acceptable amount, though odorous compound remains unchanged in the feasible compositions, and the user descends to the perceptual ability of chemical compound abnormal flavour, thereby makes abnormal flavour be difficult for being discovered by the user.

Term used herein " is dissolved in dilute hydrochloric acid " and is meant with the dilute hydrochloric acid effect and generates water miscible product, do not generate the meaning of the water-fast product of on-gaseous, the dilute hydrochloric acid effect that refers in particular to pH value 1～5 generates water miscible product, does not generate the meaning of the water-fast product of on-gaseous.

Term used herein " water solublity or be dissolved in " is meant that the dissolubility of material in water or other solvents (temperature 25 ℃ time) 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 500mg/ml best.

Term used herein " be insoluble to or be dissolved in hardly " is meant that the dissolubility of material in water or other solvents (temperature 25 ℃ time) is not more than 30mg/ml, preferably is not more than 10mg/ml, more preferably is not more than 1mg/ml, is not more than 0.1mg/ml best.

" pharmaceutically acceptable " that the present invention relates to is meant and can be mixed with each other in preparation and do not have illeffects mutually and can not reduce preparation stability and/or effectiveness and be applicable to the part or the whole body administration and the meaning that can bring into play its expectation function or effect.

Detailed description of the invention

Introduce the present invention below in detail, at first introduce the main component in the coating.

Wish not exclusively to be subjected to the restriction of this principle, can cover or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid in the present invention except bringing into play all possible function of former alkali compounds, also can expect to bring into play following bonus effect:

1), covers or suppress medicine follow-up and/or remaining offending abnormal flavour and/or the issuable offending abnormal flavour of the additive in compositions such as the coating." the offending abnormal flavour that medicine is follow-up " follow-up offending abnormal flavour of people that allows of being meant that stripping in the micropore of medicine from coating produces herein." the offending abnormal flavour of medicine remnants " are meant that having a small amount of or minimal residue in the preparation allows the pill taker still may feel remaining offending abnormal flavour in the outer surface of above-mentioned coating or nearly surface as from the medicine that unhappy abnormal flavour is arranged of the degree of depth of outer surface 0.01～3 μ m herein." the issuable offending abnormal flavour of the additive in compositions such as the coating " is meant when some additive in compositions such as the coating has offending abnormal flavour and the offending abnormal flavour that produces herein.

2), its original medicine discharges the probability that can not quicken or be slowed down on the contrary under one's belt and is eliminated or reduces.The product that is used for alkali compounds that is dissolved in dilute hydrochloric acid of the present invention and dilute hydrochloric acid effect is easily from the coating stripping, rather than be deposited on coating surface or inside, thereby do not influence medicine and the stripping of solubility in acid polymer from coating, assurance also promotes alkali compounds better, more effectively to bring into play the effect that discharges promoter, the dissolution velocity of sour molten coating in the acid environment in the enhancing stomach, increase medicine speed from the stripping of coating composition in acid environment, it is faster to make the medicament of coating that ingredient is delivered to body circulation speed.

Above-mentioned alkali compounds is preferable to be selected from and to be insoluble to or almost water-fastly can to cover or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid.It is believed that, compare with polar water miscible chemical compound, above-mentioned be insoluble to or almost water-fast alkali compounds and coating in the polymer phase capacitive increase, two alternate interface energies reduce during the two blend, mutual bonding force strengthens, thereby coating machine intensity or mechanical performance are strengthened.Special needs to be pointed out is, above-mentioned be insoluble to or almost water-fast alkali compounds can not or almost can not be from the coating composition stripping in the oral cavity, thereby can stop effectively medicine from the coating composition stripping to the oral cavity, more effectively overcome the follow-up offending abnormal flavour of medicine, take the offending abnormal flavour of medicine is perceived in the back in the oral cavity time thereby prolonged the medication coat compositions; And above-mentioned be insoluble to or almost water-fast alkali compounds influences medicine and the stripping of solubility in acid polymer from coating hardly.

The used alkali compounds (alkaline modifier) of the present invention advantage of the used alkali compounds (alkaline modifier) of conventional art relatively is, the present invention just can bring into play the more kinds of function that comprises all former alkali compoundss (alkaline modifier) with a kind of chemical compound, as promote that medicine is molten and put, strengthen mechanical performance, taste masking, minimizing and feel to have multi-functionals such as the time of offending abnormal flavour, Stabilization, make coating composition have stronger better overall performance.Just can bring into play more kinds of functions with a kind of chemical compound, thereby can significantly reduce the kind and the consumption of additive in the coating, help improving relatively the content of polymer in the coating, reduce the adverse effect of other additives, improve mechanical performance and other performances of coating coating; In addition, can also simplify coating prescription and preparation technology greatly, material saving reduces production costs.Because offending abnormal flavour can be covered or suppress to coating better, if coating composition need further be prepared into pharmaceutically acceptable dosage form, then need not in this dosage form, to add again additives such as odor mask, flavoring agent, aromatic or can significantly reduce their consumptions in this dosage form, thereby also can simplify preparation prescription and preparation technology greatly, material saving reduces production costs.

Can include but not limited to the pharmaceutically acceptable sweetener, flavoring agent, unhappy abnormal flavour inhibitor and their mixture that are alkalescence that is dissolved in dilute hydrochloric acid as covering or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid in the present invention.

Suitable above-mentioned alkaline sweetener preferred embodiment of the present invention as, but be not limited thereto: the basic salt of glycyrrhizic acid (as trisodium glycyrrhetinate, potassium, ammonium, two glycyrrhizic acid DFPs, magnesium); Alkalescence monellin, such as thaumatin (thaumatin) (isoelectric point, IP PI=11.7), mabinlin (mabinlin) (PI=12), monellin (monellin) (PI=9.3), Mai Ruo Kelin (miraculin) (PI=8.3～9).Wherein, above-mentioned alkaline monellin has good water-solubility, and it is believed that, its for macromolecular substances contains a certain amount of hydrophobic group because of, with respect to micromolecular water-soluble alkaline chemical compound,, have better affinity, the compatibility with coated polymeric as triethanolamine (TEA), basic amino acid, meglumine (meglumine), trimethylamine etc., be particularly conducive to the mechanical performance that improves the clothing film, thereby be preferred for the present invention.

Suitable above-mentioned alkaline flavoring agent preferred embodiment of the present invention as, but be not limited thereto: the basic salt of flavour nucleotide, as the basic salt of inosinic acid, the basic salt of guanyl, inferior Huang (purine nuclear) basic salt of thuja acid, the basic salt of ribonucleotide; The basic salt of succinic acid; The basic salt of Alpha-Methyl furan inosinic acid.

The above-mentioned unhappy abnormal flavour inhibitor preferred embodiment of suitable alkalescence of the present invention as, but be not limited thereto: the basic salt of phosphorylated amino acid.This paper term " phosphorylated amino acid " used herein refers to the aminoacid of phosphorylation, and it includes, but are not limited to: phosphotyrosine, phosphoserine and phosphothreonine.This paper term used herein also including, but not limited to: containing has an appointment 2～15 comprises phosphotyrosine, phosphoserine and the phosphothreonine physiologically acceptable ester at the dextrorotation of peptide of interior phosphorylated amino acid and composition thereof, these phosphorylated amino acids or laevoisomer or its racemic mixture, phosphorylated amino acid; The derivant of described phosphorylated amino acid; derivant comprises alkyl chain (straight chain and side chain; C1-C18); acyl chain (straight chain and side chain, C1-C18), add the substituted amino acid of halogen, sulfo-, amido, cyano group and nitro in the ester of the acid moieties of aryl, straight chain and side chain C1-C18, aminoacid.It is obviously that these and other of phosphorylated amino acid improved for the chemical field those of ordinary skill, so they are also included within the scope of the invention.(referring to: WO98/06436).

This paper term " basic salt " used herein is meant that the hydrionic hydrogen of the dissociable one-tenth of all or part on the organic acid acidic-group is alkalescence and pharmaceutically acceptable chemical compound (containing its basic salt) do not produce the product of water-insoluble on-gaseous with hydrochloric acid reaction by what ammonium ion and/or metal ion replaced.Be suitable for " metal ion " of the present invention and include but not limited to following pharmaceutically acceptable ion: alkali metal ion, as lithium ion, potassium ion and sodium ion; Alkaline-earth metal ions is as calcium ion, magnesium ion, strontium ion and barium ions; 3B family metal ion in the periodic table of elements is as aluminium ion; The 8th family's metal ion in the periodic table of elements is as iron ion etc.; The 11st, 12 family's metal ions in the periodic table of elements are as the zinc ion in the copper ion in the copper family elements, gold ion etc. and the zinc family elements etc.

Suitable being used for of the present inventionly is insoluble to or almost water-fastly can covers or suppress pharmaceutically acceptable being insoluble to or almost water-fast polyacidic base slaine except ammonium salt and alkali metal salt that alkali compounds example offending abnormal flavour and that be dissolved in dilute hydrochloric acid is above-mentioned example, for example: alkali salt, as calcium salt, magnesium salt, strontium salt and barium salt; 3B family slaine in the periodic table of elements is as aluminum salt; The 8th family's slaine in the periodic table of elements is as iron salt etc.; The 11st, 12 family's slaines in the periodic table of elements are as the zinc salt in the mantoquita in the copper family elements, golden salt etc. and the zinc family elements etc.

The example of preferred above-mentioned basic salt as, but be not limited to this: trisodium glycyrrhetinate, tripotassium, three ammoniums, two glycyrrhizic acid DFPs, three magnesium; Inosine monophosphate, dipotassium, diammonium; Inosinic acid calcium, magnesium, ferrum; Guanosine monophosphate disodium, dipotassium, diammonium; Guanyl calcium, magnesium, copper; Ribonucleotide acid disodium, dipotassium, diammonium; Ribonucleotide calcium, magnesium, zinc; Disodium succinate, potassium; Tyrosine phosphatase disodium, trisodium; Tyrosine phosphatase calcium, tyrosine phosphatase calcium sodium; Serine phosphorylation diammonium, three ammoniums; Phosphoserine zinc; Phosphothreonine disodium, trisodium.

When alkaline modifier was insoluble to the coating coating solution, it was 0.05～200 μ m that alkaline modifier adopts mean diameter usually, preferably is 0.01～100 μ m, more preferably is 0.5～50 μ m, is the granule of 1～25 μ m best.Excessive or too small particle diameter may cause the production repeatability problem that is difficult to predict such as relatively poor in production.

In coating of the present invention, add the above-mentioned alkaline modifier of effective dose.According to required rate of dissolution, effective dose is different.About 0.2wt% that alkaline modifier is coating gross dry weight amount is to about 30wt%.Preferred alkaline modifier is about 1wt% to about 25wt%, and 3wt% about 20wt% extremely more preferably from about.The alkaline modifier of too high amount can influence the integrity of coating, and its mechanical performance is descended.

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

Suitable under any pH value, all be insoluble to or almost water-insoluble polymer can be generally hydrophobic polymer for pharmaceutically acceptable water-insoluble or almost water-insoluble block polymer or copolymer.Suitable almost insoluble polymer can be selected from but be not limited to water-insoluble or almost water-insoluble cellulose esters, acrylic acid (ester) base polymer, polyvinyl acetate esters, polyvinyl chloride and compositions thereof.Preferably, select cellulose esters, polyvinyl acetate esters and compositions thereof for use.More preferably, select cellulose esters for use.Preferred examples of polymer includes but not limited to ethyl cellulose, methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetatepropionate), celluloid, three cellulose valerates, the lacceroic acid cellulose, three Palmic acid celluloses, the disuccinic acid cellulose, two Palmic acid celluloses, 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, polyethylene, polyisobutylene, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride) and compositions (referring to US6974591).

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, bigger difference appears in drug release between making batch), preferably adopt the latex in the water liquid of being scattered in of above-mentioned polymer, pseudo-latex and emulsion contain 80～95% polrvinyl chloride for US4557925 provided as an adoptable example, 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 30D or KOLLIDON SR (polyvinyl acetate).

Based on the gross dry weight amount of coating, coating composition of the present invention comprises about 3wt% all being insoluble to or water-insoluble polymer almost to about 97wt% under any pH value.Preferably under any pH value, all be insoluble to or almost the content of water-insoluble polymer be about 10wt% to about 80wt%, more preferably from about 25wt% is to about 60wt%, more more preferably from about 30wt% about 50wt% extremely.

Almost all sites in mouth is neutral environment, and pH value wherein is about 7.Be used in the mouth insoluble coating composition carry out cover ingredient, drug particles or drug particles agglomerate can the undesirable abnormal flavour of masking agents.But must being formulated under one's belt, this coating decomposes fast, so that active constituents of medicine is discharged in vivo.Be dissolved in acid medium but be insoluble to or be dissolved in the requirement that polymer in neutrality or the alkaline pH medium can satisfy above-mentioned coating hardly, this base polymer can not dissolve in the oral cavity, the offending abnormal flavour of people do not occur allowing thereby can not make, and this base polymer can be dissolved in the tart gastric juice and discharges medicine by the stripping in the oral cavity of the medicine of its coating.Thereby guaranteeing to contain can be dissolved in the gastric juice rapidly after the pharmaceutical composition oral administration of making us unhappy abnormal flavour and discharge active constituents of medicine under one's belt; And, also there is not tangible aftertaste.

Be applicable to and of the present inventionly be dissolved in acid medium but be insoluble to or be dissolved in polymer in neutrality or the alkaline pH medium hardly, be generally pharmaceutically acceptable at pH6 or more soluble and have a polymer substance of film property in the water of low value, 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, Eudragit E and their mixture.Most preferably be EudragitE.

Being dissolved in acid medium but being insoluble to or being dissolved in the content of polymer in coating of the present invention in neutrality or the alkaline pH medium hardly is that about 3wt% of coating gross dry weight amount is to about 80wt%.Preferably be dissolved in acid medium but be insoluble to or be dissolved in hardly polymer in neutrality or the alkaline pH medium be about 10wt% of coating gross weight to about 60wt%, more preferably be dissolved in acid medium but be insoluble to or be dissolved in about 15wt% about 50wt% extremely that polymer in neutrality or the alkaline pH medium is the coating gross weight hardly.Be dissolved in acid medium but be insoluble to or the content of polymer in coating composition that is dissolved in hardly in neutrality or the alkaline pH medium is determined by cost of material and required rate of dissolution.For example, when being lower than about 10wt%, being dissolved in acid medium but being insoluble to or being dissolved in polymer dissolution difficulty in neutrality or the alkaline pH medium hardly, and not in preferable range.Surpass 50wt%, the expense of such component makes cost too high.

The compatibility between polymer performance for incompatible fully, (part) compatible reach compatible fully.Two kinds have the polymer phase of certain compatibility to mix, at first moistening mutually at the interface, and the phase counterdiffusion of biphase then macromolecular chain segment by warm-up movement, the result of diffusion makes two kinds of polymer produce the significant concentration gradient on the both sides, interface.This zone with obvious Concentraton gradient has constituted 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 complete obiteration, become homogeneous blend, reach compatible fully (compatibility of polymer alloy and increase-volume, University Of Qingdao's journal, May nineteen ninety-five, the 10th volume, the 1st phase, the 91st page).Just because of this mutual scattering and permeating, after having the polymer phase of certain compatibility to mix, temperature healing (curing) at the glass transition point that is higher than polymer, the result can make two kinds of compatible polymer generation fusions to a certain degree, thereby eliminate the slit of the two, the micropore healing that forms in the coating process is eliminated and the final coating that forms complete densification or coating (promptly heal fully or heal state to terminal).The coating of these complete densifications or coating help stoping 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, farthest strengthen the effect of the offending abnormal flavour of covering medicine, prolong coating composition and take the offending abnormal flavour of medicine is perceived in the back in the oral cavity time.In addition, the coating of these complete densifications or clothing film can improve its mechanical performance and reach or reach substantially its maximum, can reduce its under the effect of external force, break or cracked probability to or substantially to its minima, thereby improve its taste masking performance indirectly.This low permeability and high-mechanical property have especially in the coating composition of nuclear core that prevents or delay to have fast disintegration property at intraorally rapidly disintegrating.

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

The compatibility between polymer and polymer can be used " similar compatibility " principle and be 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, the two just can be with the arbitrary proportion mixing, the two has 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-dimensional solubility parameter 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 with in a kind of solvent, mix mutually then, 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, linear as its relation with viscosity under different polymer concentrations, shows to reach the compatible fully of molecular level between polymer; Being tied to form non-linearly as its pass, then is that part is compatible; When being complete incompatible co-mixing system, then it concerns S-type curve.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 the bianry 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 prediction and sign between the polymer of high polymer alloy film, 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, 1985 02 phases, the 15th～19 page.

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

A preferred embodiment is: above-mentioned all be insoluble under any pH value or almost water-insoluble polymer be selected from and under any pH value, all be insoluble to or almost water-fast cellulose esters, 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 the 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-insoluble polymer be selected from and under any pH value, all be insoluble to or almost water-fast acrylic acid (ester) base polymer, 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 the 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 is 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-insoluble polymer be selected from and under any pH value, all be insoluble to or almost water-fast polyvinyl acetate esters, 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 the 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, the 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-insoluble polymer be selected from and under any pH value, all be insoluble to or almost water-fast polyvinyl chloride, 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 the 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, the polythene derivative with list or disubstituted amido is for most preferably.

The outer coating of covering of the core material of coating composition of the present invention also can 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 can dissolve and decompose in water, and medicament is discharged under one's belt.The polymer weight ratio that this 2-vinylpyridine (V)/styrene (S) copolymer preferably has is V and the ratio of S is about 65/35 or 80/20.Their content in coating is extremely about 30wt% of about 5wt%, preferred 10wt% to 25wt%, and this is based on the gross dry weight amount of coating.

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

In the coating composition that the present invention relates to, can also add the universal additive material.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.

The universal additive material that coating can also be added is described in detail as follows.

Plasticizer

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

One ground of plasticizer is liquid substance or low-melting solid matter of high boiling point, low volatility and micromolecule (Mr is about 150～800, preferably is 300～500) that can be miscible with polymer.The example of accessible plasticizer such as physiology compatible (aliphatic of preferred C6～C30, preferred especially C10～C16) or aromatic series one are to tricarboxylic acid and C1～C8 (preferred C2～C6, the especially preferred lipophilic ester that forms of the aliphatic alcohol of C2～C5) 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 certain herbaceous plants with big flowers two acid esters, Isosorbide Dinitrate, sucrose ester.The example of other accessible plasticizers such as glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini.

Plasticizer dosage 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), preferred especially 10～30% (weight ratios), 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 examining 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 interfacial activity material is promptly arranged, and aqueous dispersion is played Stabilization.The suitable stabilizers 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 pigment binding ability height, addition also can be as high as 100% (weight ratio) of polymeric blends amount.

Defoamer

One ground of defoamer is dimethicone.

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

One is about 1 to about 50 microns the thickness of the coating that coats on the nuclear core, preferred about 2 to 30 microns, and more preferably from about 4 to 15 microns.This coating preferably accounts for about 2 to about 50%, preferred about 5 to about 30% of whole preparation (coating+do not coat pronucleus core) weight.

Elaborate with regard to coating nuclear core below.

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

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

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

Be applicable to that 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 replenish machine and manure bate, mineral salt, trace element, Chinese herbal medicine extract or the like.

It is as follows to be specially adapted to the example with medicine of joyful taste not of the present invention, but is 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;

The H2-antagonist, 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;

Bendectin (Antiemitic) is such as meclizine and hydrochlorate, hydroxyzine and hydrochlorate thereof and embonate, diphenhydramine and hydrochlorate thereof; Prochlorperazine and maleate thereof, benzquinamide and hydrochlorate thereof, granisetron and hydrochlorate thereof, dronabinol, nabilone, paspertin metoclopramide, alkali formula Shui Yang Suan , promethazine and hydrochlorate, metoclopramide and halogenide/hydrate thereof, chlorpromazine, trimethobenzamide and hydrochlorate thereof, thiethylperazine and maleate thereof, scopolamine, perphenazine, ondansetron and hydrochlorate thereof;

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 antagonist is 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;

Selectivity β-2 antagonistic, 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 thing, 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 antagonists (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 or the like.

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 its with under one's belt fast the biological usability that is connected of dissolving select.

Said medicine can be embedded in the core material or otherwise as do to mix or wet granulation and combining with core material.

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

When coating neutral and alkali chemical compound is to be insoluble to or almost water-fast can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid the time, in order further to promote medicine release under one's belt, a specially suitable coating core material example is as follows: the coating core material preferably contains except medicine at least:

1), at least a sweller and/or at least a super-disintegrant that can not form strong gel; Preferably, also contain

2), at least a osmotic pressure active substance; More preferably, also contain

3), at least a dry adhesives.

Its objective is make core material have coating break the back disintegrate feature, thereby make medicine rapid release under one's belt.This coating core material can absorb enough liquid and can expand considerably, preferably also can produce sizable osmotic pressure, thereby promotes medicine release under one's belt.In other words, this coating is broken and rapidly disintegrate and discharge medicine under one's belt fast, thereby makes medicine moment " release " from core material, stripping more quickly.The present invention's term used herein " expands considerably " thereby refers to take place the pressure that enough expansions produced and caused starting and/or otherwise being convenient to drug release or core material disintegrate.The present invention's term " sizable osmotic pressure " used herein refers to that the osmotic pressure in the coating core material is enough bigger than the outer gastro-intestinal Fluid osmotic pressure of film, as big more than 4 times, with the release and the rapid disintegrate of coating core material of driving coating core material giving drugs into nose thing.The present invention's term " disintegrate rapidly " used herein refers to that the paroxysmal basically disintegrate of carrying out, this burst are enough to give the medicine that discharges effective dose the medicine preparation from this.

Particularly, one of purpose of the present invention just provides a kind of above-mentioned coating composition, disintegrate in the simulated gastric fluid (pH value 1.2 promptly contains the hydrochloric acid solution of 1% pepsic pH value 1.2) 30 minutes when its coating core material can 37 ℃.Disintegrate in 15 minutes in simulated gastric fluid (pH value 1.2) when preferably, its coating core material can 37 ℃.Disintegrate in 5 minutes in simulated gastric fluid (pH value 1.2) when more preferably, its coating core material can 37 ℃.Disintegrate in 2 minutes in simulated gastric fluid (pH value 1.2) when more preferably, its coating core material can 37 ℃.Disintegrate in 1 minute in simulated gastric fluid (pH value 1.2) when best, its coating core material can 37 ℃.

Above-mentioned disintegration time is for bigger coating core material of volume such as tablet, capsule can be with reference to " two appendix XA inspection techniques disintegration of Chinese pharmacopoeia (version in 2005) are measured; For volume less coating core material such as granule, solution turbidity will change during because of the disintegrate of coating core material, can advance measure by following method: the preparation of getting the coating core material or containing the coating core material insert the above-mentioned disintegrate medium (simulated gastric fluid (pH value 1.2)) that fills 37 ℃ and have stir and the appropriate containers of thermostat in, measure turbidity and write down turbidity over time with the turbidity device, the turning point that changes by turbidity trend is as from large to small or definite disintegration time such as change from small to big; In addition, also can monitor the drug level that enters in the disintegrate medium, by coming turning point that drug level trend in time changes as changing from small to big or concentration such as increases suddenly at definite disintegration time.Other methods that can be applicable to definite disintegration time of the present invention are as utilizing electrochemical method (as conductance method, chemical potential method), photochemical method (ultraviolet-visible luminosity absorption process, luminous chemical method, as fluorescence method, phosphorimetry) or the like, the concrete similar above-mentioned nephelometry of application process.

If medicine stripping from core material is not subjected to the influence of disintegrate or dissolution medium (simulated gastric fluid (pH value 1.2)), can come its disintegration time of indirect control and supervision by the dissolution of measuring coating composition.Thereby, " coating core material can 37 ℃ time in disintegrate in the simulated gastric fluid (pH value 1.2; promptly contain the hydrochloric acid solution of 1% pepsic pH value 1.2) 30 minutes " can more strictly be defined as " when the medicine in the coating core material can 37 ℃ in the simulated gastric fluid (pH value 1.2 promptly contains the hydrochloric acid solution of 1% pepsic pH value 1.2) 30 minutes basic release fully " at this moment.Correspondingly, other also can more strictly be defined as:

" preferably, the medicine in the coating core material can discharge fully in 15 minutes in simulated gastric fluid (pH value 1.2) in the time of 37 ℃ substantially.”

" more preferably, the medicine in the coating core material can discharge fully in 10 minutes in simulated gastric fluid (pH value 1.2) in the time of 37 ℃ substantially.”

" best, the medicine in the coating core material can discharge fully in 5 minutes in simulated gastric fluid (pH value 1.2) in the time of 37 ℃ substantially.”

Term used herein " basic discharge fully " is meant that from medication coat compositions (as preparations such as tablet, capsule or granules) stripping enters the ratio that medicine in the regulation dissolution medium accounts for whole coating composition Chinese medicine and is not less than 80%.

The speed of above-mentioned expansible core material drug releasing rate and disintegrate is controlled by following parameters: (1) is insoluble to or almost water-fastly can covers or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid ratio and the footpath size and its character in coating; (2) coating layer thickness; (3) insoluble polymer material; (4) gastric solubility polymeric material; (5) ratio of insoluble polymer material and gastric solubility polymeric material; (6) type of material of formation core material particulate matter; (7) each components in proportions of core material particulate matter; (8) expansion of core material particulate matter; (9) the intrinsic hydrophilic of core material particulate matter; (10) expansion rate of core material and degree; (11) kind of super-disintegrant and the ratio in coating thereof in the coating; (12) the osmotic pressure size in the core material; And the salinity in (13) core material.Wherein, (1), (2), (5), (6), (7), (8), (10), (11) and (12) are the most important factors of speed of decision core material drug releasing rate and disintegrate.Be insoluble to or almost water-fast can cover or suppress offending abnormal flavour and the ratio of alkali compounds that be dissolved in dilute hydrochloric acid in coating big more, a footpath is more little, is soluble in acidic gastric juice more, the speed of core material drug releasing rate and disintegrate is fast more; Coating layer thickness is thin more, and the speed of core material drug releasing rate and disintegrate is fast more; Ratio in the gastric solubility polymeric material coating is big more, and the speed of core material drug releasing rate and disintegrate is fast more under one's belt; The expansion rate of core material and degree are big more, and the speed of core material drug releasing rate and disintegrate is fast more; Osmotic pressure in the core material is big more, and the speed of core material drug releasing rate and disintegrate is fast more; Or the like.

Used " can not form the sweller of strong gel " of the present invention is pharmaceutically acceptable swelling considerably (expansion), but can not form strong gel and hinder the insolubility polymer of the release of medicine.The example of useful sweller includes, but not limited to polysaccharide, crosslinked polyacrylic acid and the cellulose of modification and their mixture.Above-mentioned polysaccharide is selected from, but is not limited to: alginic acid, pectin, xanthan gum, guar gum, Tragacanth, and the insoluble metallic salt of locust bean gum or crosslinked derivant, chondrus ocellatus Holmes polysaccharide, starch, Microcrystalline Starch, microcrystalline Cellulose, its slaine, with and the derivant of covalent cross-linking, and their mixture.The cellulose of above-mentioned modification is selected from, but is not limited to: hydroxypropyl cellulose, hydroxyethyl-cellulose, the slaine of methylcellulose and carboxymethyl cellulose and carboxymethyl cellulose, and their mixture.The consumption of sweller in core material is preferably with about 10～80% (w/w); More preferably with 20～60%, this is based on the weight of core material.

" super-disintegrant " that the present invention is used is also referred to as efficient disintegrating agent, can expand considerably, is commonly used for outside disintegrating agent (AGM) and inner disintegrating agent (AGG).Super-disintegrant is well known to those skilled in the art, and more specifically is described in Journalof Pharmaceutical Sciences (85 volumes, No.11, in November, 1996).Be preferred for super-disintegrant of the present invention and include but not limited to, low hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or calcium, cellulose fibre, cross linked polyacrylate, crosslinked Amberlite resin, alginate, carboxymethyl starch or the Microcrystalline Starch that replaces, microcrystalline Cellulose and composition thereof.The consumption of super-disintegrant in core material is preferably with about 5～40% (w/w); More preferably with 10～25%, this is based on the weight of core material.

" dry adhesives " that the present invention is used, its effect is to make than small-particle to be bonded together, bigger particle can keep certain form after guaranteeing to granulate, can and guarantee that the fragility that reaches certain is beneficial to disintegrate, can also guarantee simultaneously the more effective performance of effect of disintegrating agent and sweller, avoid the adverse effect of solvent disintegrate (expansion) effect of disintegrating agent (sweller).Useful dry adhesives includes, but are not limited to: starch, for example Rhizoma Solani tuber osi, Semen Tritici aestivi and corn starch; Polyethylene Glycol, especially molecular weight are 4000～6000 Polyethylene Glycol; Polyvinylpyrrolidone, crospolyvinylpyrrolidone; Cross-linked carboxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl emthylcellulose; Pregelatinized Starch, carboxymethyl starch; The microcrystalline Cellulose of microcrystalline Cellulose, crystalline cellulose, cellulose powder, silication; Dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, Pulvis Talci, polymolecularity silicon dioxide (as Aerosil), light anhydrous silicic acid; Mannitol, lactose, maltose alcohol, Sorbitol, xylitol, lactose (anhydrous or, for example monohydrate), D-glucose, maltose, sucrose, glucose, fructose or maltodextrin as hydrate; And concurrent mixture.Particularly preferably, dry adhesives is a microcrystalline Cellulose.The consumption of dry adhesives in core material is preferably with about 10～50% (w/w); More preferably with 15～40%, this is based on the weight of core material.

" the osmotic pressure active substance " that the present invention is used also claims osmotic pressure promoter, plays osmotic pressure in the adjusting coyote hole.The osmotic pressure active substance share with the sweller and/or the super-disintegrant that can not form strong gel, can produce synergism, can reduce their consumption and the power of enhancing drug release or core material disintegrate.The release that how much often is related to driving coating core material giving drugs into nose thing of its consumption and the power size and the length of medicine rapid release time of rapid disintegrate.Be preferred for osmotic pressure active substance of the present invention and include but not limited to lactose, fructose, glucose, sucrose, mannitol, sodium chloride, sorbitol, potassium chloride, potassium sulfate, sodium phosphate 12H ₂O, sodium hydrogen phosphate 7H ₂O, sodium hydrogen phosphate 12H ₂O, disodium hydrogen phosphate,anhydrous, sodium phosphate H ₂O and composition thereof is as lactose-fructose, glucose-fructose, sucrose-fructose, mannitol-fructose, lactose-sucrose, lactose-glucose, mannitol-glucose, glucose-sucrose, mannitol-sucrose, mannitol-lactose.The consumption of osmotic pressure active substance in core material is preferably with about 5～70% (w/w); More preferably with 10～50%, this is based on the weight of core material.

If desired, also can add other additives in the above-mentioned swellable coating core material.Such additive comprises but is not limited to: filler, as saccharide; Binding agent is as hydroxypropyl emthylcellulose or hydroxypropyl cellulose; Screening agent is as calcium gluconate, magnesium oxide; And lubricant, as Talcum and magnesium stearate.

Preparation method with regard to above-mentioned coating composition elaborates below.

1), preparation nuclear core the preparation method of the coating composition that the present invention relates to comprises following several basic step:; 2), to nuclear core coating; 3), in case of necessity, to coating heal (wearing out) handle.

1), preparation nuclear core

Preparing the method for examining core 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 the 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 nuclear core coating

At first prepare spray coating liquor.As an embodiment, polymer and other coating additives are dissolved or dispersed in the organic solvent, make the organic spray coating liquor that contains polymer.An embodiment is 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 not compatibility reaction, can the aqueous dispersion of two or more polymer by certain mixing after, again 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 certain amount of organic solvent, and its content often is 1～20%, and preferably 1～10%, more preferably 2～5%.

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

In one embodiment, with less as less than dispersions such as the nuclear core of 80 microns need coating 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 bigger as making it be suspended in aerial greater than the nuclear core of 80 microns need coating such as sheet, granule, ball, medicine crystal, medicine carrying resin etc. or inserting in coating pan or other coating equipment, the nuclear core is sprayed and 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 finish by convection current (heat), radiation (infrared or microwave) or conduction.To fall as the solvent evaporation of solvent or suspending agent use for coating thus, necessary words also may be used the vacuum accelerated evaporation.The higher drying efficiency of this process need, so the present invention often adopts high efficiency coating equipment (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 is meant 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 low excessively, may make the clothing film crack occur; The too high then too softening polymer of temperature causes the clothing film coalescence.

During coating, usually nuclear core etc. is preheated to 20～90 ℃, preferably 30～70 ℃, more preferably 30～50 ℃, apply with low hydrojet speed earlier, after examining wicking surface and having coated skim clothing film, improve hydrojet speed to coating again and finish.

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

Optimum 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.With fluidized bed coating is to fall, and process conditions such as coating temperature, fluidisation air quantity, atomizing pressure and hydrojet speed all can quantitatively be controlled according to practical situation optimization.

3), coating (in case of necessity) is handled in healing (wearing out)

After applying end, polymer particle often merges fully in the coating, i.e. coating healing is still incomplete.Under the interfacial tension effect of polymer and air, deposit in the process further fusion phenomenon may take place, form fine and close more clothing film.Fusion phenomenon needs the long period just can finish, and adopts usually to apply after-baking technology to quicken the coating healing, with integrity and the taste masking effect of guaranteeing coating.

After healing is handled (curing treating) process and is generally water evaporates, place the clothing film under the uniform temperature or certain hour under simultaneously certain inferior condition of humidity, the polymer particle in the coating is further merged, form fine and close clothing film.Selected temperature should be higher than its glass transition temperature or minimum film formation temperature, preferably be higher than more than 10 ℃, more preferably be higher than more than 20～30 ℃, above temperature all should be not make the softening fully or fusing of composition in the coating material or clothing film coalescence degree of being not take place.Selected humidity is generally relative humidity 30～100%, and preferably 40～95%, more preferably 50～90%.The required time is extremely tens of hours a few hours, preferably 20～72 hours, and preferably 24～48 hours.It is definite that the end time that healing is handled normally contrasts sample that healing under certain condition obtains obtains the sample of (for example 40 ℃ of temperature, 75% time healing acceleration of relative humidity are tested March) with the healing acceleration test dissolution test data (being undertaken by the method in Chinese Pharmacopoeia two appendix in 2005).Definite method of the end time that better healing is handled is (as the acid medium of pH value 1.2) under certain condition, and the sample that healing is obtained carries out dissolution test, just can not conclude and has reached the healing terminal point as long as detect the medicine of stripping.

Healing is handled and can be carried out with heat treatment modes such as baking oven and fluid beds.Characteristics such as the fluid bed heat processing has efficiently, saves time can be finished coating and heat treatment operation in same equipment, the industrialization suitability is higher.Coating finishes back elevation system temperature, and material can promote film healing balance in same fluid unit relaying afterflow drying in the short time.But compare with the baking oven mode, the fluid bed mode is had relatively high expectations to funeral film mechanical performance, and heat treatment caudacoria healing degree is relatively low.So the present invention preferably adopts the baking oven heat treatment mode.

Under the higher thermal treatment temperature, enter in the clothing film in order to prevent that low melting point substance (as ibuprofen) from may move, cause the preparation release to accelerate degradation problem under phenomenon, the clothing film mechanical performance, can carry out the sealing coat coating to the medicine carrying core material, perhaps reduce heat treatment temperature.

Optimum or more suitable technological parameter, as healing temperature, humidity, time thus the art those skilled in the art determine according to experimental result etc.

If film has healed fully in coating process underpants, can not heal (wearing out) handles, as the preparation with Surelease (EC) aqueous dispersion coating.

The present invention relates to a kind of pharmaceutical preparation, it is characterized in that said preparation comprise at least at least a in the administration process offending abnormal flavour be difficult for the coating composition discovered by the user, this coating composition comprises at least:

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

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

The present invention relates to another kind of pharmaceutical preparation, it is characterized in that said preparation comprise at least at least a in the administration process offending abnormal flavour be difficult for the coating composition discovered by the user, this coating composition comprises at least:

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

The invention still further relates to a kind of pharmaceutical preparation, it is characterized in that said preparation comprise at least at least a in the administration process offending abnormal flavour be difficult for the coating composition discovered by the user, this coating composition comprises at least:

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

B), by the nuclear core that above-mentioned coating coats, this nuclear core contains at least:

1), at least a medicine that offending abnormal flavour is arranged;

3), at least a osmotic pressure active substance; More preferably, also contain

4), at least a dry adhesives.

The pharmaceutical preparation that the present invention relates to can further be processed as adding some pharmaceutically acceptable excipient (as aromatic for the drug core that has applied for preparing by above-mentioned arbitrary mode, sweeting agent, filler) pharmaceutically acceptable any dosage form of making, for example, prepare masticable tablet, the conventional liq of suspension (or oral liquid), 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 discharge or postpone the conventional compressed tablets of release at once, 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 all is that this area is known.

A preferred embodiment of above-mentioned dosage form is a 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 the mixture preparation of taste masked particle by compacting.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 every square centimeter of (kp/cm of about 15 kips ²).More preferably, the hardness of this tablet is about 1 to about 8, and first-selected about 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).

A preferred embodiment of above-mentioned dosage form is an oral liquid, preferably is liquid, aqueous suspending agent, and at this moment, the outer alkaline modifier that covers in the coating of taste masking particle is above-mentioned water-insoluble alkaline modifier.In one embodiment, for example, in case obtained exsiccant taste masking particle, the pharmaceutically acceptable auxiliary agent of taste masking particle and other is mixed, for example sweeting agent is (as maltose alcohol, saccharin sodium or sucrose), antiseptic (as methyl parahydroxybenzoate or propyl p-hydroxybenzoate), thickening agent is (as glycerol, PEG, Xanthan gum, sanlose), antioxidant is (as sodium sulfite, alpha-tocopherol, BHT or 2,6-two-tert-butyl group-4-methylphenol or BHA or the 2-tert-butyl group-4-methoxyphenol), flavoring agent (seeing above) and coloring agent etc. are to make the dosage form that is used for the liquid oral administration.Perhaps in the taste masking particle, add other suitable pharmaceutically acceptable auxiliary agent mixing and make the powder that rehydration is a suspension.

Prepare liquid, aqueous suspending agent, a key problem in technology is to add basifier to make the pH value of liquid be higher than the minimum pH value of dissolving acid insoluble polymer may, to keep the globality of above-mentioned anti-enteric coating taste masking coating, guarantee after suspending in water, to be scattered in the not stripping of active component in the substrate.Can be applicable to basifier of the present invention and be in aqueous solution and the pH value of aqueous suspension agent can be promoted and be maintained at about alkali more than 5.Basifier can be selected from arbitrary following chemical compound: alkali metal hydroxide, phosphate, carbonate and bicarbonate, for example sodium bicarbonate; Magnesium hydroxide; Magnesium phosphate; Magnesium carbonate; Basic magnesium carbonate; Magnesium glycinate; Magnesium silicate; Magnesiumaluminumsilicate; Alkaline earth such as bentonite; Zeolite; Calcium oxide; Calcium hydroxide; Calcium phosphate; Magaldrate; Hydrotalcite; DASC; Ammonia; Ammonium bicarbonate; Ammonium carbonate; Ethanolamine; Diethanolamine; Triethanolamine; Meglumine; Basic amino acid is as lysine; Citrate; Tetrasodium ethylenediamine tetraacetate and hydrate thereof; And composition thereof etc.The citrate of preferred meglumine, lysine and sodium and potassium and carbonate and composition thereof.Can use the basifier of one or more these classes, consumption will be brought up to the pH value of suspending agent more than 5.0, preferably more than 6.0, more preferably more than 7.0.

Prepare liquid, aqueous suspending agent, another key problem in technology is before above-mentioned exsiccant taste masking particle, add all the components in the coating of certain coating composition in advance, the material that certain water solublity (hydrophilic) especially arranged, particularly be insoluble to or almost water-fastly can cover or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid, make its aqueous solution in advance at least temperature 0-50 ℃ saturated down.So handle, can make that the clean stripping quantity of all the components in water is 0 in the coating of coating composition, thereby guarantee the integrity of above-mentioned coating, can not allow the medicine stripping that unhappy abnormal flavour is arranged in the coating, also can not allow the outer moisture of coating enter in the core material, guarantee the integrity of coating composition.

Prepare liquid, aqueous suspending agent, another key problem in technology be above-mentioned under any pH value, all be insoluble to or almost water-insoluble 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 the alkaline pH medium compatible perhaps fully; Above-mentioned coating composition be higher than above-mentioned under any pH value, all be insoluble to or almost water-insoluble polymer and/or above-mentioned be dissolved in acid medium but be insoluble to or be dissolved in hardly the temperature healing (curings) of the glass transition point of the polymer in neutrality or the alkaline pH medium, heal to terminal best.

Described the present invention thus 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.

Below non-selective embodiment further described preferred embodiment in the scope of the invention.These embodiment also can have many variations within the scope of the invention.

Embodiment

In the following example; medicinal tablet is following to be prepared: the granule (footpath 40～80 orders) of using coating composition coated medicament composition in the fluid bed coater; after coating procedure finishes; embodiment 1-4 coating accounts for 23.08% (weight ratio) (being drug particles or powder weightening finish 30%) of whole coated granule; embodiment 5 coatings account for 13.04% (weight ratio) (being granule weightening finish 15%) of whole coated granule; embodiment 6 coatings account for 9.09% (weight ratio) (being granule weightening finish 10%) of whole coated granule, and embodiment 7-8 coating accounts for 7.41% (weight ratio) (being granule weightening finish 8%) of whole coated granule.Embodiment 1-4 the granule that applies or powder then are used to prepare with routine chew/excipient of fast instantizing tablet or dry suspension is by following mixed: coated granule 40.63%; mannitol 49.37%; microcrystalline Cellulose 7.5%; stearic acid 1%, silicon dioxide colloid 0.5%, spice 1%; this final mixture that is used to make tablet is pressed into final sheet then and heavily is the tablet of 480mg; such tablet diameters is 10.5mm, the about 5～10kp of hardness, brittleness about 0～1%.Perhaps embodiment 2-4 and embodiment 5-8 directly make liquid suspension (about pH value 7.3).

Embodiment 1

The coating (A) that cellulose acetate by 60%, 28% cellulose acetate diethylamino acetate and 12% thaumatin (thaumatin) are made is implemented to apply to drug particles, and described drug particles is acetaminophen (APAP) granule.Make dry suspension or tabletting after then the drug particles that will apply and other compositions mix, make medicinal tablets.12% thaumatin in the coating (A) is changed into 12% triethanolamine, and other are constant, are equipped with reference substance 1 with legal system.

Embodiment 2

The coating (B) that Eudragit NE30D by 58%, 27% Eudragit E 100 and 15% 3 glycyrrhizic acid dicalcium are made is implemented to apply to drug particles, and described drug particles is acetaminophen (APAP) granule.Make dry suspension or tabletting after then the drug particles that will apply and other compositions mix, make medicinal tablets.15% 3 glycyrrhizic acid dicalcium in the coating (B) is changed into 15% triethanolamine, and other are constant, are equipped with reference substance 2 with legal system.

Embodiment 3

Ethyl cellulose by 54%, 26% Eudragit E 100,10% inosinic acid calcium (38～74 μ m, or 200～400 order) and 10% guanyl calcium (38～74 μ m, or 200～400 order) coating of making (C) is implemented to apply to drug particles, described drug particles is sildenafil citrate granule (the particulate component content: sildenafil citrate 33.3% that is made by dry granulation, microcrystalline Cellulose 33%, low-substituted hydroxypropyl cellulose 14.5%, sorbitol 17.2%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%).Make dry suspension or tabletting after then the drug particles that will apply and other compositions mix, make medicinal tablets.Inosinic acid calcium in the coating (C) and guanyl calcium are all changed into 20% Talcum, and other are constant, are equipped with reference substance 3 with legal system.

Embodiment 4

KOLLIDONE SR by 25.78%, 25.78% ethyl cellulose, 25.0% Eudragit E 100, the monoglyceride of 8.44% acetoxylation and 15% tyrosine phosphatase calcium (38～74 μ m, or 200～400 order) coating of making (D) is implemented to apply to drug particles, described drug particles is a ranitidine hydrochloride granule (particulate component content: ranitidine hydrochloride 55.8%, microcrystalline Cellulose 18.2%, lactose 24.5%, hydroxypropyl emthylcellulose (2910) 1.5%).Make dry suspension or tabletting after then the drug particles that will apply and other compositions mix, make medicinal tablets.The ammonia soap. that tyrosine phosphatase calcium in the coating (D) changes into, other are constant, are equipped with reference substance 4 with legal system.

Embodiment 5 (disintegration-type granule fast)

KOLLIDONE SR by 25.78%, 25.78% ethyl cellulose, 25.0% poly-acetal diethylamino vinylacetate, (particle diameter is 23～38 μ m for the monoglyceride of 8.44% acetoxylation and 15% tyrosine phosphatase calcium, or 400～600 order) coating of making (E) is implemented to apply to drug particles, described drug particles is ranitidine hydrochloride granule (the particulate component content: ranitidine hydrochloride 55.8% that is made by dry granulation, microcrystalline Cellulose 27.7%, cross-linking sodium carboxymethyl cellulose 14.5%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%).

Embodiment 6 (disintegration-type granule fast)

Ethyl cellulose by 42%, 38% piperidyl ethylhydroxyethylcellulose, (particle diameter is 10～18 μ m to 20% Alpha-Methyl furan inosinic acid zinc, or 800～1340 order) coating of making (F) is implemented to apply to drug particles, described drug particles is sildenafil citrate granule (the particulate component content: sildenafil citrate 33.3% that is made by dry granulation, microcrystalline Cellulose 36.2%, low-substituted hydroxypropyl cellulose 20.5%, lactose 8%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%).

Embodiment 7 (disintegration-type granule fast)

(particle diameter is 2.6～6.5 μ m for cellulose acetate by 40%, 45% Eudragit E 100 and 15% 3 glycyrrhizic acid dicalcium, or 2000～5000 order) coating of making (G) is implemented to apply to drug particles, described drug particles is sildenafil citrate granule (the particulate component content: sildenafil citrate 33.3% that is made by dry granulation, microcrystalline Cellulose 42.2%, low-substituted hydroxypropyl cellulose 22.5%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%).

Embodiment 8 (disintegration-type granule fast)

Eudragit NE30D by 34%, 46% Eudragit E 100, (particle diameter is 1.3～2.6 μ m to 10% inosinic acid calcium, or 5000～10000 order) and 10% guanyl calcium (particle diameter is 1.3～2.6 μ m, or 5000～10000 order) coating of making (H) is implemented to apply to drug particles, described drug particles is sildenafil citrate granule (the particulate component content: sildenafil citrate 33.3% that is made by dry granulation, microcrystalline Cellulose 36.2%, polyvinylpolypyrrolidone 18.5%, lactose 10%, silicon dioxide 0.5%, sodium stearyl fumarate 1.5%).

Test case 1 external stripping test

With the sample of embodiment 1-4 and reference substance pH be 7 and pH carry out the stripping test in 1.2 the simulated gastric fluid.Table 1-4 has shown that embodiment 1-4 is about 7 promptly to be similar in the mouth in the conditions environmental and pH is about 1.2 at pH, promptly is similar in the environment of condition in the stomach percent of ingredient stripping in given a period of time.

Table 1 paracetamol tablets pH be 7 and pH be the percent of stripping in 1.2 the solution

Table 2 paracetamol tablets pH be 7 and pH be the percent of stripping in 1.2 the solution

Table 3 sildenafil citrate sheet pH be 7 and pH be the percent of stripping in 1.2 the solution

Table 4 ranitidine hydrochloride sheet pH be 7 and pH be the percent of stripping in 1.2 the solution

The stripping test result shows that the characteristic and the reference substance of the external stripping of embodiment 1 example pharmaceuticals are suitable, slightly are better than reference substance; The characteristic of the external stripping of embodiment 2-4 example pharmaceuticals obviously is better than reference substance, and the phenomenon that quilt is delayed has appearred in the dissolving out capability of reference examples sample.Analysis result can get, can cover or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid (promptly generating the modifier of water-soluble substances with the dilute hydrochloric acid effect of pH value 1～5) and can increase medicine speed from the stripping of coating composition in acid environment among the present invention; And with alkali compounds (modifier) that the dilute hydrochloric acid effect of pH value 1～5 does not generate water-soluble substances can slow down on the contrary medicine in acid environment from the speed of the stripping of coating composition; With respect to polar water-soluble chemical compound, almost water-fast alkali compounds (modifier) under neutrallty condition from coating the speed of stripping slower, take the offending abnormal flavour of medicine is perceived in the back in the oral cavity time thereby prolonged the medication coat compositions.

The test of test case 2 senses of taste

Please 9 special members (testee), place their mouth to chew and kept at least 2 minutes respectively 1 sample that makes with embodiment 1～4 and reference substance, and measure they and record testee main suit's the sense of taste of test article in the oral cavity time when feeling bitterness.The variation of the time when feeling bitterness, the change of sense of taste and sense of taste power etc. is used to estimate.Gained the results are shown in Table 5.

The result of time when table 5 is felt bitterness and the test article sense of taste in the oral cavity

Test result shows that the effect of covering of embodiment sample obviously is better than reference substance; The alkali compounds (modifier) that can cover or suppress offending abnormal flavour in coating can improve the mouthfeel of pharmaceutical composition very effectively.

Test case 3 film measuring mechanical properties

Sample and reference substance coating coating solution with preparation among the embodiment 1～4 are made the thin film that thickness is 150 μ m in the polyfluortetraethylene plate top casting, thin film are cut into the size of 1 * 7cm.Under INSTRON tensile strength tester, measure tensile strength then.The results are shown in Table 6.

Table 6 polymeric film tensile strength measurement result

Test result shows that the mechanical performance of sample 1,2,4 films obviously wants high than control film, and the mechanical performance and the control film of sample 3 films are suitable.

Test case 4 external granule slaking tests and external stripping test

Sample to embodiment 5-8 carries out external granule slaking test and external stripping test, and nephelometry (referring to description) is adopted in wherein external granule slaking test.The results are shown in Table 7 and table 8.

The time of table 7 coated particle disintegrate

The external stripping result of table 8 medicine

The result shows, the disintegrate fast of embodiment sample, medicine stripping fast.

Comprehensive The above results can get, and the combination property of embodiment sample or general effect will be got well than reference substance, and overall performance is reinforced.

Claims

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 said composition comprises:

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

1), at least a pharmaceutically acceptable under any pH value, all being insoluble to or water-insoluble polymer almost,

2), at least aly pharmaceutically acceptablely be dissolved in acid medium but be insoluble to or be dissolved in polymer in neutrality or the alkaline pH medium hardly, and

3), at least aly pharmaceutically acceptablely can cover or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid;

B), contained at least a nuclear core that the medicine of offending abnormal flavour is arranged by what above-mentioned coating coated.
2. according to the medication coat compositions of claim 1, it is characterized in that described under any pH value, all be insoluble to or almost water-insoluble polymer and described be dissolved in acid medium but be insoluble to or the polymer phase that is dissolved in hardly in neutrality or the alkaline pH medium compatible perhaps fully.
3. according to the medication coat compositions of claim 1 or 2, it is characterized in that described all be insoluble under any pH value or almost water-insoluble polymer be selected from and under any pH value, all be insoluble to or almost water-fast cellulose esters base polymer, describedly be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or the alkaline pH medium is selected from the cellulose derivative with list or disubstituted amido, the acrylate copolymer with mono-substituted amino.
4. according to the medication coat compositions of claim 1 or 2, it is characterized in that described under any pH value, all be insoluble to or almost water-insoluble polymer be selected from ethyl cellulose, methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose and composition thereof describedly is dissolved in acid medium but is insoluble to or the polymer that is dissolved in hardly in neutrality or the alkaline pH medium is selected from the benzylamino-methyl cellulose, diethylamino methyl cellulose, the piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetic acid, chitosan (Chitosan), Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and composition thereof.
5. according to the medication coat compositions of claim 1 or 2, it is characterized in that described all be insoluble under any pH value or almost water-insoluble polymer be selected from and under any pH value, all be insoluble to or almost water-fast acrylic acid (ester) base polymer, describedly be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or the alkaline pH medium is selected from acrylate copolymer, the cellulose derivative with list or disubstituted amido with mono-substituted amino, the polythene derivative with list or disubstituted amido.
6. according to the medication coat compositions of claim 1 or 2, it is characterized in that described under any pH value, all be insoluble to or almost water-insoluble polymer be selected from methacrylic acid (ester) polymer, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride) and composition thereof, describedly be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or the alkaline pH medium is selected from Eudragit E, the polymethylacrylic acid dimethylamino ethyl ester, the benzylamino-methyl cellulose, diethylamino methyl cellulose, the piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate, 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.
7. according to the medication coat compositions of claim 1 or 2, it is characterized in that described all be insoluble under any pH value or almost water-insoluble polymer be selected from and under any pH value, all be insoluble to or almost water-fast polyvinyl acetate esters polymer, described be dissolved in acid medium but be insoluble to or be dissolved in polymer in neutrality or the alkaline pH medium hardly be selected from polythene derivative, have acrylate copolymer of mono-substituted amino and composition thereof with list or disubstituted amido.
8. according to the medication coat compositions of claim 1 or 2, it is characterized in that described under any pH value, all be insoluble to or almost water-insoluble polymer be selected from polyvinylacetate, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl acetate-vinyl chloride copolymer and composition thereof describedly is dissolved in acid medium but is insoluble to or the polymer that is dissolved in hardly in neutrality or the alkaline pH medium is selected from 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, Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and composition thereof.
9. according to the medication coat compositions of claim 1 or 2, it is characterized in that described all be insoluble under any pH value or almost water-insoluble polymer be selected from and under any pH value, all be insoluble to or almost water-fast poly chlorine polyvinyl, described be dissolved in acid medium but be insoluble to or be dissolved in polymer in neutrality or the alkaline pH medium hardly be selected from polythene derivative, have acrylate copolymer of mono-substituted amino and composition thereof with list or disubstituted amido.
10. according to the medication coat compositions of claim 1 or 2, it is characterized in that described under any pH value, all be insoluble to or almost water-insoluble polymer be selected from polrvinyl chloride, describedly be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or the alkaline pH medium is selected from 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, Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and composition thereof.
11., it is characterized in that described alkali compounds is selected from the pharmaceutically acceptable sweetener, flavoring agent, unhappy abnormal flavour inhibitor and their mixture that are alkalescence that is dissolved in dilute hydrochloric acid according to medication coat compositions any in the claim 1 to 10.
12., it is characterized in that described alkali compounds is selected from the basic salt of the basic salt of the basic salt of the basic salt of pharmaceutically acceptable alkaline monellin, glycyrrhizic acid, flavour nucleotide, succinic acid, phosphorylated amino acid and their mixture according to medication coat compositions any in the claim 1 to 10.
13., it is characterized in that described alkali compounds is selected from thaumatin (thaumatin), mabinlin (mabinlin), monellin (monellin), Mai Ruo Kelin (miraculin) and their mixture according to medication coat compositions any in the claim 1 to 10.
14., it is characterized in that described alkali compounds is selected from the basic salt of the basic salt of pharmaceutically acceptable inosinic acid, guanyl, inferior Huang (purine nuclear) basic salt of thuja acid, the basic salt of ribonucleotide and their mixture according to medication coat compositions any in the claim 1 to 10.
15. according to medication coat compositions any in the claim 1 to 10, it is characterized in that described alkali compounds is selected from the pharmaceutically acceptable basic salt of following material: phosphotyrosine, phosphoserine, phosphothreonine and containing had an appointment 2～15 and comprised phosphotyrosine, phosphoserine and phosphothreonine at peptide of interior phosphorylated amino acid and composition thereof, and their dextrorotation or laevoisomer or its racemic mixture, physiologically acceptable ester and derivant and their mixture.
16., it is characterized in that described alkali compounds is selected from the basic salt of pharmaceutically acceptable glycyrrhizic acid according to medication coat compositions any in the claim 1 to 10.
17., it is characterized in that described alkali compounds is selected from the basic salt of pharmaceutically acceptable Alpha-Methyl furan inosinic acid according to medication coat compositions any in the claim 1 to 10.
18., it is characterized in that described basic salt is selected from the basic salt of the 11st, 12 family's metal ions in the 8th family's metal ion in 3B family metal ion in pharmaceutically acceptable ammonium ion, alkali metal ion, alkaline-earth metal ions, the periodic table of elements, the periodic table of elements or the periodic table of elements according to medication coat compositions any in claim 12 or 14 to 17.
19., it is characterized in that described basic salt is selected from the basic salt of ammonium ion, lithium ion, potassium ion, sodium ion, calcium ion, magnesium ion, strontium ion, barium ions, aluminium ion, iron ion, copper ion, gold ion, zinc ion and hybrid ionic thereof according to medication coat compositions any in claim 12 or 14 to 17.
20., it is characterized in that described alkali compounds is selected from a kind ofly pharmaceutically acceptablely to be insoluble to or almost water-fastly can to cover or suppress offending abnormal flavour and alkali compounds that be dissolved in dilute hydrochloric acid according to medication coat compositions any in the claim 1 to 10.
21., it is characterized in that described alkali compounds is selected from pharmaceutically acceptable being insoluble to or the almost water-fast sweetener, flavoring agent, unhappy abnormal flavour inhibitor and their mixture that are alkalescence that is dissolved in dilute hydrochloric acid according to medication coat compositions any in the claim 1 to 10.
22., it is characterized in that described alkali compounds is selected from the pharmaceutically acceptable of following material and is insoluble to or almost water-fast basic salt and their mixture: glycyrrhizic acid, flavour nucleotide, succinic acid, phosphorylated amino acid according to medication coat compositions any in the claim 1 to 10.
23., it is characterized in that described alkali compounds is selected from the pharmaceutically acceptable of following material and is insoluble to or almost water-fast basic salt and their mixture: inosinic acid, guanyl, inferior Huang (purine nuclear) thuja acid, ribonucleotide according to medication coat compositions any in the claim 1 to 10.
24. according to medication coat compositions any in the claim 1 to 10, it is characterized in that described alkali compounds is selected from the pharmaceutically acceptable of following material and is insoluble to or almost water-fast basic salt and their mixture: phosphotyrosine, phosphoserine, phosphothreonine and containing had an appointment 2～15 and comprised phosphotyrosine, phosphoserine and phosphothreonine in peptide of interior phosphorylated amino acid and composition thereof, and their dextrorotation or laevoisomer or its racemic mixture, physiologically acceptable ester and derivant.
25., it is characterized in that described alkali compounds is selected from being insoluble to of pharmaceutically acceptable glycyrrhizic acid or almost water-fast basic salt according to medication coat compositions any in the claim 1 to 10.
26., it is characterized in that described alkali compounds is selected from being insoluble to of pharmaceutically acceptable Alpha-Methyl furan inosinic acid or almost water-fast basic salt according to medication coat compositions any in the claim 1 to 10.
27. the medication coat compositions any according to claim 22 to 26 is characterized in that described basic salt is selected from the basic salt of the 11st, 12 family's metal ions in the 8th family's metal ion in 3B family metal ion in pharmaceutically acceptable alkaline-earth metal ions, the periodic table of elements, the periodic table of elements or the periodic table of elements.
28., it is characterized in that described basic salt is selected from the basic salt of calcium ion, magnesium ion, strontium ion, barium ions, aluminium ion, iron ion, copper ion, gold ion, zinc ion and hybrid ionic thereof according to medication coat compositions any in the claim 22 to 26.
29. according to medication coat compositions any in the claim 20 to 28, the particulate mean diameter that it is characterized in that described alkali compounds is 0.05～200 μ m.
30., it is characterized in that the dissolubility in water (temperature 25 ℃ time) of described alkali compounds is not more than 10mg/ml according to medication coat compositions any in the claim 20 to 29.
31. according to medication coat compositions any in the claim 1 to 30, it is characterized in that described under any pH value, all be insoluble to or almost in the coating outside described, covered of water-insoluble polymer content be about 10wt% about 80wt% extremely, described be dissolved in acid medium but be insoluble to or be dissolved in hardly in the coating that the polymer in neutrality or the alkaline pH medium covers content outside described be about 10wt% about 60wt% extremely, content in the coating that described alkali compounds covers outside described is that about 0.2wt% is to about 30wt%, based on the gross dry weight amount of coating.
32. according to medication coat compositions any in the claim 1 to 31, it is characterized in that described under any pH value, all be insoluble to or almost in the coating outside described, covered of water-insoluble polymer content be about 25wt% about 60wt% extremely, described be dissolved in acid medium but be insoluble to or be dissolved in hardly in the coating that the polymer in neutrality or the alkaline pH medium covers content outside described be about 15wt% about 50wt% extremely, content in the coating that described alkali compounds covers outside described is that about 1wt% is to about 25wt%, based on the gross dry weight amount of coating.
33., it is characterized in that described coated coating contains that at least a the nuclear core of the medicine of offending abnormal flavour is arranged is sheet, granule, ball, crystal and/or the medicine carrying resin of rule or irregular form according to medication coat compositions any in the claim 1 to 32.
34., it is characterized in that the medicine that offending abnormal flavour is arranged that the nuclear core of described coated coating comprises is selected from and has the not analgesic of joyful taste according to medication coat compositions any in the claim 1 to 33; the antipyretic-antalgic agent; NSAID (non-steroidal anti-inflammatory drug); the CoX-2 inhibitor; the H2-antagonist; anti-allergic agent; the antihistaminic medicine; Bendectin; diarrhea and 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; the 5HT inhibitor; macrolide antibiotics; ketolide antibiotics; quinolone antibiotic; cephalosporins; Penicillin antibiotics; sulfa drugs; tetracycline medication; enzyme 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; narcotic analgesics; psychosis class medicine; the migraine agent; antuepileptic; antidepressants; anticonvulsant; antihypertensive; antihypertensive and Coronary Vasodilators; calcium antagonists (calcium channel blocker); ACE inhibitor; anti-heart stricture of vagina pain medicine; cardiac glycoside; anti-arrhythmic; cholesterol lowering drug; antineoplastic agent; antimalarial; Aeroseb-Dex; vitamin; mineral; manure bate; plant extract.
35. according to medication coat compositions any in the claim 1 to 34, it is characterized in that the medicine that offending abnormal flavour is arranged that the nuclear core of described coated coating comprises 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, head is embraced for the peace ester, 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, carbamazepine, fluoxetine Hydrochloride, Sertraline, 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.
36., it is characterized in that described nuclear core also contains at least a sweller and/or at least a super-disintegrant that can not form strong gel according to medication coat compositions any in the claim 1 to 35.
37. medication coat compositions according to claim 36, it is characterized in that described sweller is selected from alginic acid, pectin, xanthan gum, guar gum, Tragacanth and locust bean gum and their insoluble metallic salts or crosslinked derivant, chondrus ocellatus Holmes polysaccharide, Microcrystalline Starch, microcrystalline Cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose and carboxymethyl cellulose with and slaine, and their mixture.
38., it is characterized in that the described consumption of sweller in described core material that can not form strong gel is about 10～80% (w/w), based on the weight of core material according to the medication coat compositions of claim 36.
39., it is characterized in that described super-disintegrant is selected from low hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or calcium, cellulose fibre, cross linked polyacrylate, crosslinked Amberlite resin, alginate, carboxymethyl starch or the Microcrystalline Starch that replaces, microcrystalline Cellulose and composition thereof according to the medication coat compositions of claim 36.
40., it is characterized in that the consumption of described super-disintegrant in described core material is 5～40% (w/w), based on the weight of core material according to the medication coat compositions of claim 36.
41. according to medication coat compositions any in the claim 36 to 40, disintegrate in 15 minutes in simulated gastric fluid (hydrochloric acid solution that contains 1% pepsic pH value 1.2) when it is characterized in that the described nuclear core that is coated by described coating can 37 ℃.
42., it is characterized in that when medicine in the described nuclear core can 37 ℃ in simulated gastric fluid (hydrochloric acid solution that contains 1% pepsic pH value 1.2) in 15 minutes that from coating composition stripping enters the ratio that medicine in the dissolution medium accounts for whole coating composition Chinese medicine and is not less than 80% according to medication coat compositions any in the claim 36 to 40.
43. according to medication coat compositions any in the claim 1 to 42, it is characterized in that the described outer coating of covering account for described medication coat composition total weight about 2～about 50%, being coated to contain by described coating at least aly has the nuclear core of the medicine of offending abnormal flavour to account for described medication coat composition total weight about 50～about 98%.
44. a pharmaceutical preparation is characterized in that said preparation comprises medication coat compositions any in the aforementioned claim.
45., it is characterized in that its dosage form is that masticable tablet, oral liquid, rehydration are 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, conventional compressed tablets, confection and caked sugar form, aerosol cream, colloid or the pouch that has liquid core or the soft-shelled gelatin body of filling with powder or granule, can discharge or postpone release at once be housed according to the pharmaceutical preparation of claim 44.
46., it is characterized in that its dosage form is a chewable tablet according to the pharmaceutical preparation of claim 44 or 45.
47., it is characterized in that its dosage form is soft chewable tablet according to the pharmaceutical preparation of claim 44 or 45.
48., it is characterized in that its dosage form is liquid, aqueous suspending agent according to the pharmaceutical preparation of claim 44 or 45.
49. according to the pharmaceutical preparation of claim 48, the pH value that it is characterized in that described liquid, aqueous suspending agent is higher than and describedly is dissolved in acid medium but is insoluble to or is dissolved in hardly the minimum dissolving pH value of the polymer in neutrality or the alkaline pH medium.