CN101927002B - Medicament and coating composition - Google Patents
Medicament and coating composition Download PDFInfo
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- CN101927002B CN101927002B CN201010228164.1A CN201010228164A CN101927002B CN 101927002 B CN101927002 B CN 101927002B CN 201010228164 A CN201010228164 A CN 201010228164A CN 101927002 B CN101927002 B CN 101927002B
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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
Technical field
The present invention relates to a kind of medication coat compositions.More particularly, the abnormal flavour that the present invention relates to a kind of improved combination properties is difficult for the medication coat compositions that bedding and clothing user discovers.
Technical background
A lot of active component, for example antibiotic, has strong unpleasant taste, as the bitterness of sense of taste aspect, pungent, astringent taste etc., the stink of olfactory sensation aspect.The many-sided adverse effect of the normal generation of this offending abnormal flavour.For example, the undesirable taste of medicine can make to be difficult to swallow, or makes patient avoid Drug therapy, causes thus patient's low conformability.When medicament is mixed with the tablet of swallowed whole or capsule, the taste of active component is not problem conventionally, do not contact with mouth, and tablet can be wrapped by prevent that tablet active component within the short time in the mouth from contacting with mouth because capsule can prevent active component.But, the method for this taste-masking can not be applied to be applicable to child, old people and many other patients before administration or the dosage form of decomposing in administration process, for example chewable tablet and liquid preparation.And child, old people and many other patients have any problem when taking undecomposed Tablet and Capsula.Therefore, shelter these and need the unpleasant taste of the activating agent in the preparation decomposing before administration or in administration process, make it to possess good palatability or edibility and advise for guaranteeing that patient abides by that to take be vital.
A kind of conventional possible method of sheltering active component unpleasant taste is coating.It is coated with taste masked coating by the moulded products of the active component that contains 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 coating containing the granule of medicine is " anti-enteric coating " type, is designed to can dissolve under the low pH value in stomach but has water to indissolubility under higher in the mouth pH value.The polymer blend that this coating contains dimethylaminoethyl acrylate methyl amino-ethyl ester and natural methacrylate and cellulose esters.
US Patent No. 6663893B2 (or referring to EP1276470B1) discloses the pharmaceutical composition of a kind of bag " anti-enteric coating " taste masking.This coating contains polymer and the alkaline modifier such as dimethylaminoethyl acrylate methyl amino-ethyl ester, natural methacrylate and cellulose esters.Alkaline modifier in this coating composition can enhanced activity composition release.
US Patent No. 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.Optionally, 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 expect that this alkalescence modifier brings into play following function in this invention:, by the subenvironment buffering of coating, it 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 liquid suspension; 2), as the function of plasticizer, this function can reduce the fragility of coating; 3), play release-modifier, can strengthen in stomach the dissolution velocity of coating in acid environment, the speed that this function makes coated medicament that ingredient is delivered to body circulation is faster than other system.It is triethanolamine (TEA), basic amino acid, Talcum, ammonia soap., meglumine (meglumine), trimethylamine, calcium silicates, Magnesiumaluminumsilicate, conventional food basifier or its mixture for food industry that these two patents disclose suitable alkaline modifier example.Basic amino acid for example can be, L-arginine, L-Histidine, (Semen Maydis) alcohol soluble protein (prolamine, zein) or its mixture.
But US6663893B2 and US6551617B1 have many significant deficiency:
For example, water miscible alkaline modifier is if triethanolamine (TEA), basic amino acid are if L-arginine, meglumine, trimethylamine etc. are because of its larger water solublity, easily in oral cavity, dissolve, therefore it easily makes coating produce micropore in oral cavity, easily make medicine stripping from micropore, thereby produce the follow-up offending abnormal flavour of people that allows.In addition, although the material that these polarity are very large has strengthened in stomach the dissolution velocity of coating in acid environment, but the polymer phase capacitive in they and coating is very poor, during the two blend, there will be two interphase interfaces can be very high, the problem that mutual bonding force is very poor, (while adopting non-water-soluble matchmaker, also can cause and disperse inequality), water miscible alkaline modifier (or claiming porogen) is also by the stress concentration point becoming in coating, become the weak link in coating, coating machine intensity or mechanical performance are significantly reduced, as declines such as intensity, toughness, elasticity, easily make coating break.These drawbacks have not only limited their additions in coating, but also have a strong impact on 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; The surface and interface > > of < < high polymer, Wu Renjie chief editor, Science Press (Beijing), 104th～110 pages; The modification of inorganic filler, Jiangxi chemical industry, calendar year 2001, the 4th phase, 17th～18 pages).
And for example, although Talcum, calcium silicates, Magnesiumaluminumsilicate and zein etc. have certain hydrophobicity, relative better with the compatibility of polymer, but calcium silicates, Magnesiumaluminumsilicate have stronger adsorptivity, easily absorption medicine, hinders the stripping under one's belt of slow medicine, makes drug absorption slack-off; And, calcium silicates, Magnesiumaluminumsilicate form gel under the effects such as acid in water, and gel has slow releasing function, the further slow gastric solubleness coating of ground resistance and medicine stripping under one's belt, make drug absorption slack-off, these factors all by the bioavailability that affects medicine (referring to the relevant clause part of document works: The Merck Index, 13
thedtion; The complete works of > > of < < pharmaceutical necessities, Luo Mingsheng, Gao Tianhui chief editor, Sichuan science tech publishing house, March in 1993 the 1st edition; < < pharmaceutic adjuvant handbook > >, (original work the 4th edition), the volumes such as sieve R.C., Zheng Jun democracy Yi， 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 is only dissolved in the aqueous solution containing surfactants such as SDS (sodium lauryl sulphate) except alcohol solution.The albumen (Seed Storage Protein) that is dissolved in acid or alkali is listed in glutelin.(referring to document: Tanaka Y, et al.Isolation and characterization of protein bodies in the rice endosperm, [J] .Agric Biol Chem, 1980,44:1633～1639; Rice Prolamines extraction conditions and total content distribute, Jiang Donghua etc., Zhejiang Agriculture journal, 19 (3): 174～178,2007; The dissolution characteristics of high-lysine component research in hordein, Dong Niu etc., Botany Gazette, 1989,31 (9): 689～695; Wheat gliadin and glutelin progress, Dong Chaohua etc., the biological journal of mountain farming, 22 (2): 164～168,2003).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 industries, 09 phase in 2004; < < pharmaceutic adjuvant handbook > >, (original work the 4th edition), the volumes such as sieve R.C., Zheng Jun democracy is translated, Chemical Industry Press, January in 2005 the 1st edition, the 801st page).Because alcohol soluble protein or zein do not dissolve in diluted acid, can not generate solable matter with diluted acid effect, therefore, alcohol soluble protein or zein are difficult to performance in the effect of accelerating medicine stripping under one's belt.Equally, Talcum is also so, because it all dissolves hardly in diluted acid, diluted alkaline, can not generate water-soluble material with acid effect.
For another example, ammonia soap. has good water solublity and has certain hydrophobicity (containing hydrophobic group oleic acid base), but, it does not generate water miscible salt under acid effect under one's belt, and under room temperature, only produce the water-fast fluid oil (drip) stronger to non-water-soluble coating composition adhesiveness, this oil (dripping) is more difficult to be redissolved in intestinal or stomach, is easily adsorbed in coating, therefore it is also difficult to further to accelerate medicine stripping under one's belt; In addition, ammonia soap. chemical property is stable not, oxidizable, produces smell.
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 to be pointed out that separately especially, have the medicine of unpleasant taste may have in the preparation a small amount of or minimal residue in the outer surface of above-mentioned coating or nearly surface as from the degree of depth of surface 1～3 μ m, thereby the people who takes medicine still may feel the offending abnormal flavour of remaining medicine.
And, US Patent No. 6663893B2, US6551617B1 and US5489436 have applied the 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 certain ammonia stink and the abnormal smells from the patient of solvent characteristics.
In addition, some conventional additives that coating composition is conventional also can produce and allow the offending abnormal flavour of people, as surfactant, stabilizing agent, plasticizer, fluidizer (glidants) and pigment etc.For example there is the additive of offending abnormal flavour: surfactant is as sodium lauryl sulphate (having stronger bitterness), triacetin (mildly bitter flavor, micro-have fatty stink), spans surfactant (having fatty stink), Tweens surfactant (having special stink, micro-bitter in the mouth), polyoxyethylene surfactant (mildly bitter flavor, have fatty stink), glyceryl monostearate (mildly bitter flavor, have fatty stink); Plasticizer is as diethyl phthalate (allow the offending bitterness of people), citron ester triethyl (bitter in the mouth), Oleum Ricini (micro-smelly, lightly seasoned, but have subsequently slight peppery and disgusting taste); Fluidizer, as glyceryl monostearate, magnesium stearate (micro-have special smell taste); Stabilizing agent is as oleic acid (have Adeps Sus domestica sample stink, more have the stink of becoming sour after oxidation), hexadecanol (faint stink).
In actual applications, commodity KOLLIDON SR or the Kollicoat SR 30D of the polyvinyl acetate that conventional example provides as BASF AG, the sodium lauryl sulphate that contains a certain amount of (approximately 1%).Cellulose acetate latex contains 1.9% sodium lauryl sulphate.Aquacoat (ethylcellulose aqueous colloidal dispersion) also contains 5% hexadecanol except 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; EUDRAGIT@E coating adds magnesium stearate often.
Yet, none is taste modifier (as correctives, flavour enhancer or odor inhibition agent) or olfactory sensation improver for the example of US Patent No. 6663893B2 and the disclosed alkaline modifier of US6551617B1, can cover or suppress in other words the additive of offending abnormal flavour.And, some alkaline modifier that US Patent No. 6663893B2 (or referring to EP1276470B1) and US6551617B1 mention also have offending abnormal flavour, as L-arginine (mildly bitter flavor), L-Histidine (bitter in the mouth), ammonia soap. (have Adeps Sus domestica sample stink, more have the stink of becoming sour after oxidation; Ammonia stink), triethanolamine (micro-have ammonia stink), meglumine (being with salty and bitter taste), trimethylamine (have the smelly and fish of ammonia wake up foul smell taste).
More it needs to be noted, above-mentioned anti-" enteric coating " technology of having applied two kinds of different polymer, with respect to same polymer, in clothing film, often there is more micropore, when especially two kinds of polymer phase capacitives are bad, easily stripping from micropore of medicine, thus produce follow-up when allowing the offending abnormal flavour of people, especially this coating composition the holdup time is longer in oral cavity.
If further add routine to cover at above-mentioned coating composition, add agent, result is except increasing production cost and process complexity, the more important thing is and will affect largely the mechanical performance of coating, and by the effect of more seriously coating taste masking, because add in a large number other materials, especially with the inconsistent water miscible polar substances of coated polymeric, will the content of polymer in coating be declined significantly, and cause coating machine performance to decline greatly.
Therefore, in reality, need above-mentioned technology to overcome its defect on the basis of inheriting its advantage.
Goal of the invention
One of object of invention is difficult for regard to being to provide a kind of abnormal flavour of improved combination properties the medication coat compositions that bedding and clothing user discovers.
Particularly, the object of invention is just to provide a kind of abnormal flavour and is difficult for the medication coat compositions that bedding and clothing user discovers, medicine follow-up and/or remaining offending abnormal flavour and/or the issuable offending abnormal flavour of the additive in coating can also be covered or suppress to this coating composition, except retaining or inheriting former having superiority.
The object of invention is just to provide a kind of abnormal flavour and is difficult for the medication coat compositions that bedding and clothing user discovers, this coating composition is except retaining or inheriting former having superiority, and its original medicine release under one's belt can not be accelerated or the probability that slowed down is on the contrary eliminated or reduces.
Two of the object of invention further provides a kind of abnormal flavour to be difficult for the medication coat compositions that bedding and clothing user discovers, and this coating composition is except having above-mentioned advantage, and the mechanical performance of its coating is enhanced.
Three of the object of invention further provides a kind of abnormal flavour to be difficult for the medication coat compositions that bedding and clothing user discovers, this coating composition is except having above-mentioned advantage, and this medication coat compositions is aware the offending abnormal flavour of medicine in oral cavity time after taking is extended further.
The object of invention four further provide a kind of abnormal flavour to be difficult for the medication coat compositions that bedding and clothing user discovers, this coating composition has above-mentioned multiple advantage simultaneously, but its prescription and preparation method simplified largely, material saving, reduces production costs.
Other goals of the invention are shown in the detailed description of description below.
Summary of the invention
The present invention relates to a kind of in administration process offending abnormal flavour be difficult for the medication coat compositions that bedding and clothing user discovers, it is characterized in that said composition at least comprises:
A), the coating covered outward, this coating at least contains:
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer almost,
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer in neutrality or alkaline pH medium, and
3), at least one pharmaceutically acceptablely can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid;
B), by the coated core core that contains at least one medicine that has offending abnormal flavour of above-mentioned coating.Preferably, above-mentioned under any pH value, be all insoluble to or almost water-fast polymer and above-mentioned be dissolved in acid medium but be insoluble to or the polymer phase that is dissolved in hardly in neutrality or alkaline pH medium perhaps completely compatible.
The present invention relates to another kind offending abnormal flavour in administration process and be difficult for the medication coat compositions that bedding and clothing user discovers, it is characterized in that said composition at least comprises:
A), the coating covered outward, this coating at least contains:
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer almost,
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer in neutrality or alkaline pH medium, and
3), at least one is pharmaceutically acceptablely insoluble to or almost water-fastly can covers or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid;
B), by the coated core core that contains at least one medicine that has offending abnormal flavour of above-mentioned coating.Preferably, above-mentioned under any pH value, be all insoluble to or almost water-fast polymer and above-mentioned be dissolved in acid medium but be insoluble to or the polymer phase that is dissolved in hardly in neutrality or alkaline pH medium perhaps completely compatible.
The present invention relates to a kind of in administration process offending abnormal flavour be difficult for the medication coat compositions that bedding and clothing user discovers, it is characterized in that said composition at least comprises:
A), the coating covered outward, this coating at least contains:
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer almost,
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer in neutrality or alkaline pH medium, and
3), at least one is pharmaceutically acceptablely insoluble to or almost water-fastly can covers or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid;
B), by the coated core core of above-mentioned coating, this core core at least contains:
1), at least one has the medicine of offending abnormal flavour;
2), at least one can not form sweller and/or at least one super-disintegrant of strong gel; Preferably, also contain
3), at least one osmotic pressure active substance; More preferably, also contain
4), at least one dry adhesives.Preferably, above-mentioned under any pH value, be all insoluble to or almost water-fast polymer and above-mentioned be dissolved in acid medium but be insoluble to or the polymer phase that is dissolved in hardly in neutrality or alkaline pH medium perhaps completely compatible.
Term used herein " offending abnormal flavour " be defined as user in mouth during buccal aspect the sense of taste, olfactory sensation especially sense of taste aspect feel any offending taste, comprise hardship, salty, strong acid, strong alkali, puckery, strong salt, dry, pungent (sharp), strongly cool, hot, burning, pungent, wooden taste, 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 by adding the compound such as sweetener, flavoring agent etc. of pharmaceutically acceptable amount to hide, cover up in having the compositions of odorous compound and/or covering abnormal flavour, wherein odorous compound remains unchanged, other taste existing in thing but its taste is combined is covered, thereby make abnormal flavour be difficult for bedding and clothing user, discovers.
Term used herein " inhibition " refers to pharmaceutically in acceptable amount, can slow down or disturb sense of taste transmission mechanism, although odorous compound in compositions is remained unchanged, and user declines to the perceptual ability of compound abnormal flavour, thereby make abnormal flavour be difficult for bedding and clothing user, discover.
Term used herein " is dissolved in dilute hydrochloric acid " and refers to dilute hydrochloric acid effect and generates water miscible product, do not generate the meaning of the water-fast product of on-gaseous, refer in particular to the dilute hydrochloric acid effect of pH value 1～5 and generate water miscible product, do not generate the meaning of the water-fast product of on-gaseous.
Term used herein " water solublity or be dissolved in " refers to that the dissolubility of material in water or other solvents (temperature 25 ℃ time) is not less than 33mg/ml, is preferably not less than 50mg/ml, is more preferably not less than 100mg/ml, is not less than best 500mg/ml.
Term used herein " is insoluble to or is dissolved in hardly " and referring to that the dissolubility of material in water or other solvents (temperature 25 ℃ time) is not more than 30mg/ml, preferably be not more than 10mg/ml, more preferably be not more than 1mg/ml, be not more than best 0.1mg/ml.
" pharmaceutically acceptable " the present invention relates to refers to and in preparation, can be mixed with each other and mutually without illeffects, can not reduce preparation stability and/or effect and be applicable to part or meaning whole body administration and that can bring into play its expectation function or effect.
Detailed description of the invention
Introduce in detail the present invention below, the main component in paper coating.
Wish to be not exclusively subject to the restriction of this principle, can cover or suppress alkali compounds offending abnormal flavour and 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), cover or suppress medicine follow-up and/or remaining offending abnormal flavour and/or compositions offending abnormal flavour as issuable in the additive in coating." the offending abnormal flavour that medicine is follow-up " refers to that stripping in the micropore of medicine from coating produces herein the follow-up offending abnormal flavour of people that allows." the offending abnormal flavour of medicine remnants " refer to herein may have in the preparation a small amount of or minimal residue in the outer surface of above-mentioned coating or nearly surface as allow pill taker still may feel remaining offending abnormal flavour from the medicine that has unhappy abnormal flavour of the degree of depth of outer surface 0.01～3 μ m." compositions offending abnormal flavour as issuable in the additive in coating " refers to when compositions has offending abnormal flavour as some additive in coating and the offending abnormal flavour producing herein.
2), its original medicine discharges under one's belt the probability that can not accelerate or be slowed down on the contrary and is eliminated or reduces.For the alkali compounds of dilute hydrochloric acid and the product of dilute hydrochloric acid effect of being dissolved in of the present invention easily from coating stripping, rather than be deposited on coating surface or inside, thereby do not affect medicine and the stripping of solubility in acid polymer from coating, guarantee and promote alkali compounds better, more effectively to bring into play the effect that discharges promoter, the dissolution velocity of sour molten coating in acid environment in enhancing stomach, increase medicine speed from the stripping of coating composition in acid environment, the speed that makes the medicament of coating that ingredient is delivered to body circulation is faster.
Above-mentioned alkali compounds is better to be selected from and to be insoluble to or almost water-fastly can to cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid.It is believed that, with the water miscible Compound Phase ratio of polarity, above-mentioned be insoluble to or almost the polymer phase capacitive in water-fast alkali compounds and coating increase, during the two blend, two alternate interface energies reduce, 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 coating composition stripping in oral cavity, thereby can effectively stop medicine from coating composition stripping to oral cavity, more effectively overcome the follow-up offending abnormal flavour of medicine, thereby extended the time that is aware the offending abnormal flavour of medicine after medication coat compositions is taken in oral cavity; And above-mentioned be insoluble to or almost water-fast alkali compounds affect hardly medicine and the stripping of solubility in acid polymer from coating.
The present invention's alkali compounds (alkaline modifier) the used relatively advantage of conventional art alkali compounds (alkaline modifier) used 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 compound, as promoted, medicine is molten puts, strengthens mechanical performance, taste masking, minimizing and feel to have the multi-functionals such as the time of offending abnormal flavour, Stabilization, makes coating composition have stronger better overall performance.With a kind of compound, just can bring into play more kinds of functions, thereby can greatly reduce kind and the consumption of additive in coating, be conducive to relatively improve the content of polymer in coating, reduce the adverse effect of other additives to coating, improve mechanical performance and other performances of coating; In addition, can also greatly simplify coating prescription and preparation technology, 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, without adding again the additives such as odor mask, flavoring agent, aromatic or can significantly reduce their consumptions in this dosage form in this dosage form, thereby also can greatly simplify preparation prescription and preparation technology, material saving, reduces production costs.
Can as covering or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid, include but not limited to pharmaceutically acceptable alkaline sweetener of being of dilute hydrochloric acid, flavoring agent, unhappy odor inhibition agent and their mixture of being dissolved in the present invention.
Suitable above-mentioned alkaline sweetener preferred embodiment of the present invention as, but be not limited to this: the basic salt of glycyrrhizic acid (as trisodium glycyrrhetinate, potassium, ammonium, two glycyrrhizic acid DFPs, magnesium); Alkalescence monellin, such as thaumatin (thaumatin) (iso-electric point=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 solublity, 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 compound, as triethanolamine (TEA), basic amino acid, meglumine (meglumine), trimethylamine etc., there is better affinity, the compatibility with coated polymeric, be particularly conducive to the mechanical performance that improves 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 to this: the basic salt of flavour nucleotide, as the basic salt of the basic salt of inosinic acid, guanyl, inferior Huang (purine core) 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 odor inhibition agent preferred embodiment of suitable alkalescence of the present invention as, but be not limited to this: the basic salt of phosphorylated amino acid.Term " phosphorylated amino acid " used herein refers to the aminoacid of phosphorylation herein, and it includes, but are not limited to: phosphotyrosine, phosphoserine and phosphothreonine.Herein term used herein also including, but not limited to: containing having an appointment 2～15, comprise phosphotyrosine, phosphoserine and phosphothreonine at the physiologically acceptable ester of 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 chemical field those of ordinary skill, so they are also included within the scope of the invention.(referring to: WO98/06436).
Herein term " basic salt " used herein refers to that the hydrionic hydrogen of the dissociable one-tenth of all or part on organic acid acidic-group is by the pharmaceutically acceptable compound (containing its basic salt) alkalescence and do not produce the product of water-insoluble on-gaseous with hydrochloric acid reaction that is that 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, as calcium ion, magnesium ion, strontium ion and barium ions; 3B family metal ion in the periodic table of elements, as aluminium ion; Periodic table of elements Zhong 8 family's metal ions, as iron ion etc.; Periodic table of elements Zhong11, 12 family's metal ions, as zinc ion in the copper ion in copper family elements, gold ion etc. and zinc family elements etc.
Suitablely for of the present invention, be insoluble to or water-fast to cover or suppress alkali compounds example offending abnormal flavour and that be dissolved in dilute hydrochloric acid be above-mentioned example except ammonium salt and alkali metal salt pharmaceutically acceptable being insoluble to or water-fast polyacidic base slaine almost almost, for example: alkali salt, as calcium salt, magnesium salt, strontium salt and barium salt; 3B family slaine in the periodic table of elements, as aluminum salt; Periodic table of elements Zhong 8 family's slaines, as iron salt etc.; Periodic table of elements Zhong11, 12 family's slaines, as zinc salt in the mantoquita in copper family elements, golden salt etc. and 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 is insoluble to coating coating solution, it is 0.05～200 μ m that alkaline modifier adopts mean diameter conventionally, is preferably 0.01～100 μ m, is more preferably 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 prediction such as 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.The approximately 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 more preferably from about 3wt% to about 20wt%.The alkaline modifier of too high amount can affect the integrity of coating, and its mechanical performance is declined.
The present invention relates under any pH value, be all insoluble to or almost water-fast polymer in coating, play skeleton function, in order to strengthen the mechanical performance of coating, make coating can bear larger external force and not break at tabletting, in the process such as chewing.
Suitable under any pH value, be all insoluble to or almost water-fast polymer can, for pharmaceutically acceptable water-insoluble or almost water-insoluble block polymer or copolymer, be generally hydrophobic polymer.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, polyvinyl chloride and compositions thereof.Preferably, select cellulose esters, polyvinyl acetate and compositions thereof.More preferably, select cellulose esters.Preferred examples of polymer includes but not limited to ethyl cellulose, methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetatepropionate), celluloid, three cellulose valerates, lacceroic acid cellulose, three Palmic acid celluloses, 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 produced higher viscosity, higher viscosity often makes coating process become difficult, easily make sticky limit between particle, easily make drug release become unstable, between making batch there is larger difference in drug release), preferably adopt the latex in water liquid that is scattered in of above-mentioned polymer, pseudo-latex and emulsion, if an adoptable example is for US4557925 provided containing 80～95% polrvinyl chloride, the aqueous dispersion coating solution of the terpolymer of 0.5～19% polyvinylacetate and 0.5～10% polyvinyl alcohol, another available example is the aqueous dispersion coating solution containing 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).
Gross dry weight amount based on coating, coating composition of the present invention comprises about 3wt% being all insoluble under any pH value or water-fast polymer almost to about 97wt%.Preferably under any pH value, be all insoluble to or almost the content of water-fast polymer be about 10wt% to about 80wt%, more preferably from about 25wt% is to about 60wt%, more more preferably from about 30wt% is to about 50wt%.
Almost all sites in mouth is neutral environment, and pH value is wherein about 7.Be used in coating composition insoluble in mouth carry out cover ingredient, drug particles or drug particles agglomerate can the undesirable abnormal flavour of masking agents.But this coating must be formulated into fast decoupled under one's belt, so that active constituents of medicine is discharged in vivo.Be dissolved in acid medium but be insoluble to or be dissolved in hardly the requirement that polymer in neutrality or alkaline pH medium can meet above-mentioned coating, this base polymer can not dissolve in oral cavity, thereby can not make to be occurred allowing the offending abnormal flavour of people by its coated medicine stripping in oral cavity, and this base polymer can be dissolved in acid gastric juice and discharge medicine.Thereby can be dissolved in rapidly in gastric juice and discharge under one's belt active constituents of medicine after guaranteeing to contain the pharmaceutical composition oral administration of making us unhappy abnormal flavour; And, also there is no obvious aftertaste.
Be applicable to be of the present inventionly dissolved in acid medium but be insoluble to or be dissolved in hardly the polymer in neutrality or alkaline pH medium, be generally pharmaceutically acceptable at pH6 or more soluble in the water of low value and there is the polymer substance of film property, include but not limited to that (a) has the cellulose derivative of list or disubstituted amido, (b) there is the polythene derivative of list or disubstituted amido, (c) there is 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 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 hardly polymer in neutrality or the alkaline pH medium content in coating of the present invention is that the approximately 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 alkaline pH medium be the approximately 10wt% of coating gross weight to about 60wt%, being more preferably dissolved in acid medium but being insoluble to or being dissolved in hardly polymer in neutrality or alkaline pH medium is that the approximately 15wt% of coating gross weight is to about 50wt%.Be dissolved in acid medium but be insoluble to or be dissolved in hardly polymer in neutrality or the alkaline pH medium content in coating composition and determined by cost of material and required rate of dissolution.For example, during lower than about 10wt%, be dissolved in acid medium but be insoluble to or the polymer dissolution that is dissolved in hardly in neutrality or alkaline pH medium more difficult, and not in preferable range.Surpass 50wt%, the expense of such component makes cost too high.
The compatibility between polymer performance for completely incompatible, (part) compatible and completely compatible.Two kinds have the polymer phase of certain compatibility mixed, first mutually moistening in interface, then biphase macromolecular chain segment phase counterdiffusion by warm-up movement, and the result of diffusion, makes two kinds of polymer produce obvious Concentraton gradient on both sides, interface.This region with obvious Concentraton gradient has formed two alternate boundary layers.The thickness of boundary layer depends mainly on the compatibility of two kinds of polymer.Increase along with the compatibility, diffusion improves, and boundary is more and more fuzzyyer, and interfacial layer thickness is increasing, so that final boundary disappears completely, become homogeneous blend, reach completely compatible (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 mixed, temperature healing (solidifying) at the glass transition point higher than polymer, result can make two kinds of compatible polymer that fusion to a certain degree occurs, thereby eliminate the gap of the two, can make the micropore healing forming in coating process eliminate and final coating or the coating (heal completely or heal state to terminal) that forms complete densification.The coating of these complete densifications or coating are conducive to stop has the medicine of offending abnormal flavour from 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, extend the time that is aware the offending abnormal flavour of medicine after coating composition is taken in oral cavity.In addition, the coating of these complete densifications or clothing film can improve its mechanical performance and reach or substantially reach its maximum, can reduce its under the effect of external force, break or cracked probability to or substantially to its minima, thereby indirectly improve its taste masking performance.This low permeability and high-mechanical property have especially in the coating composition of core 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 perhaps completely compatible being all insoluble under any pH value or water-fast polymer and be dissolved in acid medium but be insoluble to or be dissolved in hardly the polymer in neutrality or alkaline pH medium almost.
The compatibility between polymer and polymer can be applied " similar compatibility " principle and evaluated or predict, as polarity or nonpolar similarity.Also can be used for evaluating the compatibility between polymer and polymer by the big or small solubility parameter of energy characterize polymers intermolecular cohesion.Generally, especially for nonpolar amorphous polymer blend, when the difference of the solubility parameters of two polymer is less than 0.5 or the difference of the solubility parameters of polymer and organic solvent while being less than 1.5, the two just can be with arbitrary proportion mixing, and the two has the good compatibility.When thering is very strong polarity and can form hydrogen bond for the co-mixing system that contains crystalline polymer or polymer molecule, can adopt the compatibility that two dimension or three solubility parameters judge system (referring to Shaw M.T., J ApplPolym Sci, 1974,18:449).
1), cosolvent method the following easier method of exemplary application of the present invention proves or predicts the compatibility between polymer and polymer:, two kinds of macromolecules are dissolved into respectively in same solvent, then mix mutually, according to two solution mixing situations, judge polymer-polymer miscibility size.2), microscopic method, with phase contrast microscope method particularly electron microscope method can directly observe its mixed compatibility.3), solution viscosity method, the viscosity of solution can disclose the compatibility of polymer blend solution, under different polymer concentrations, the percentage composition mapping with viscosity to polymer, as linear in its relation, show to reach between polymer the completely compatible of molecular level; As its pass is tied to form non-linearly, be that part is compatible; When being complete incompatible co-mixing system, the S-type curve of its relation.4), by the use of thermal means and dynamic mechanical analysis method (surveying vitrification point Tg), special recommendation the method for the present invention, polymer alloy system there will be three kinds of Tg variation tendencies, supposes that the Tg of two kinds of polymer in Binary Alloy System is respectively Tg
1and Tg
2(Tg
1< Tg
2), (1), complete compatible system: only occur a Tg, Tg
1< Tg < Tg
2; (2), complete incompatible system: occur two Tg, be respectively Tg
1and Tg
2; (3), the compatible system of part: occur two Tg
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 application, 2007, the 35th volume, the 12nd phase, 81st～83 pages; 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, 24th～29 pages; Compatibility Between Polymers prediction and the sign of Polymer Alloy Membrane, Gu Xiaoyu etc., polymer material science and engineering, in January, 2004, the 20th the 1st phase of volume, 5th～8 pages; Polyblend: the compatibility of II. polymer, Rhizoma Zingiberis Recens northern Shandong, macromolecule circular, in JIUYUE, 1993, the 3rd phase, 178th～184 pages; The compatibility of polyblend and Theoretical Calculation thereof, Lv Feijie etc., tropical agriculture science, 02 phase in 1985,15th～19 pages.
Above-mentioned under any pH value, be all insoluble to or almost water-fast polymer with above-mentioned be dissolved in acid medium but be insoluble to or be dissolved in hardly (part) between the polymer in neutrality or alkaline pH medium mutually perhaps completely compatible available example as:
A preferred embodiment is: above-mentioned under any pH value, be all insoluble to or almost water-fast polymer be selected from and under any pH value, be all insoluble to or water-fast cellulose esters almost, as ethyl cellulose, methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose and their mixture, above-mentioned be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from the cellulose derivative that (a) has list or disubstituted amido, as benzylamino-methyl cellulose, diethylamino methyl cellulose, piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate and their mixture, (b) there is the acrylate copolymer of mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture, or (c) chitosan (Chitosan), and their mixture, wherein, the cellulose derivative that has list or a disubstituted amido is for most preferably.
Another preferred embodiment is: above-mentioned under any pH value, be all insoluble to or almost water-fast polymer be selected from and under any pH value, be all insoluble to or water-fast acrylic acid (ester) base polymer almost, as methacrylic acid (ester) polymer, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, ethyl acrylate-ethyl acrylate-chlorination trimethyl amino-ethyl Methyl metacrylate 99 polymer and their mixture, above-mentioned be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from the cellulose derivative that (a) has list or disubstituted amido, as benzylamino-methyl cellulose, diethylamino methyl cellulose, piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate and their mixture, (b) there is the acrylate copolymer of mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture, or the polythene derivative (c) with 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 acrylate copolymer with mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture are for most preferably.
Another preferred embodiment is: above-mentioned under any pH value, be all insoluble to or almost water-fast polymer be selected from and under any pH value, be all insoluble to or water-fast polyvinyl acetate almost, as the terpolymer of polyvinylacetate, vinyl chloride-ethylene alcohol-vinylacetate, vinyl acetate-vinyl chloride copolymer and their mixture, above-mentioned be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from the acrylate copolymer that (a) has mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture, or the polythene derivative (b) with 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 under any pH value, be all insoluble to or almost water-fast polymer be selected from and under any pH value, be all insoluble to or water-fast polyvinyl chloride almost, as the terpolymer of vinyl acetate-vinyl chloride copolymer, polrvinyl chloride, vinyl chloride-ethylene alcohol-vinylacetate and their mixture, above-mentioned be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from the acrylate copolymer that (a) has mono-substituted amino, as Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and their mixture, or the polythene derivative (b) with 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 in water, PVP meeting Dissolution and dissociation, discharges medicament under one's belt.The polymer weight ratio that this 2-vinylpyridine (V)/styrene (S) copolymer preferably has is that V is approximately 65/35 or 80/20 with the ratio of S.Their content in coating is extremely about 30wt% of about 5wt%, preferred 10wt% to 25wt%, and this is the gross dry weight amount based on 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 accelerate 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 the gross dry weight amount based on coating.
In the coating composition the present invention relates to, can also add universal additive material.The addition of universal additive material in drug coating layer and application are that 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 improve the film forming ability of coating material, and strengthen pliability and the intensity of coating, improve the coherent condition of coating to substrate.Suitable glass transition temperature (Tg) scope is generally 0～70 ℃, is preferably 10～50 ℃, and be is best 15～40 ℃ goodly.
One ground of plasticizer for high boiling point, low volatility and can with the liquid substance of the micromolecule (Mr is about 150～800, is preferably 300～500) of Polymers Miscibility or the solid matter of low melting point.The lipophilic ester being formed to tricarboxylic acid and C1～C8 (preferred C2～C6, particularly preferably C2～C5) aliphatic alcohol by C6～C40 (preferably C6～C30, particularly preferably C10～C16) aliphatic or aromatic series one that the example of accessible plasticizer is as compatible in physiology.The example of this plasticizer is as dibutyl phthalate, diethyl phthalate, dibutyl sebacate, ethyl sebacate, citric acid triethyl group ester, acetyl triethyl citrate, glycerol triacetate, tributyl SA ester, Isosorbide Dinitrate, sucrose ester.The example of other accessible plasticizers is as glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini.
The consumption of plasticizer is according to the character of desired coating, as glass transition temperature, mechanical performance etc., the kind of plasticizer, the kind of film former (being film forming polymer), consumption etc. and determine, conventionally consumption is 5～50% (weight ratios), preferred 10～40% (weight ratios), 10～30% (weight ratios) particularly preferably, this is the gross dry weight amount based on coating ingredients.
Antitack agent (separating medium)
Antitack agent (separating medium) is generally useful hydrophobic material, and one adds in injection suspension.They stop the gathering of core between film forming stage.Preferably use Talcum, magnesium stearate or calcium stearate, the silicic acid of porphyrize, the nonionic emulsifier that Kaolin or HLB value are 3～8.0.5～100% (weight ratio) that the common consumption of antitack agent in coating of the present invention is amount of polymers.In particularly advantageous embodiment, separating medium is usingd conc forms and is added as final coating.Coated with powder type or by the suspension of 5～30% solid contents, by spraying, undertaken.
Stabilizing agent
Stabilizing agent is preferably emulsifying agent or surfactant, has certain interface active agent, and aqueous dispersion is played to Stabilization.Suitable stabilizing agent example is if any diethanolamine, monoethanolamine, triethanolamine, fatty acid, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), nonoxynolum, octoxinol, oleic acid, poloxamer, polyoxyethylene 50 stearate, polyethylene glycol fatty acid class (Polyoxyl fatty acid), polyethylene glycol alkyl ether (Polyoxyl hydrocarbon ether), polysorbate (Tween), sorbitan ester (Span), fatty acid salt, polyvidone, sodium lauryl sulfate, cetyl stearyl sodium sulfate, sucrose stearate fat, Spheron MD 30/70 and composition thereof.The content of stabilizing agent is 1～15% (weight ratio), preferred 5～10% (weight ratios), and this is the wet weight based on aqueous dispersion coating solution component.
Pigment
Seldom with solubility pigment form, add.One disperses aluminium oxide or iron oxide pigment to add.Titanium dioxide is as Chinese white.In clothing layer of the present invention, the addition of pigment is 5～60% (weight ratios) of polymeric blends amount.Yet because pigment binding ability is high, addition also can be as high as 100% (weight ratio) of polymeric blends amount.
Defoamer
One ground of defoamer is dimethicone.
In coating, the material of all uses must be pharmaceutically acceptable in principle, is nontoxic, in medicine, patient is safe from danger.
On core core the thickness of coated coating one be approximately 1 to approximately 50 micron, preferably approximately 2 to 30 microns, and more preferably from about 4 to 15 microns.This coating preferably accounts for approximately 2 to approximately 50%, preferred approximately 5 to approximately 30% of whole preparation (coating+coated pronucleus core) weight.
With regard to coating core core, elaborate below.
The core 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 core core is granule, ball, crystal, medicine carrying resin.Preferred core core is granule.The size of granule, ball or crystal is generally 0.01～2.5mm, and the size of sheet is conventionally at 2.5～30mm.
For core slug particle of the present invention, be preferably spherically, and average particulate diameter is 80～1200 microns, more preferably 100～800 microns, and more preferably 150～400 microns.This core core preferably has 0.85～1.0 sphericity, and more preferably 0.9～1.0.In the present invention, the advantage of spherical nuclei slug particle used is, can improve the coating efficiency in coating process subsequently.
In the coating composition the present invention relates to, core core is approximately 50～approximately 98% of this dosage form gross weight, preferred approximately 70～approximately 95%.Core core for coating can contain other pharmacy auxiliary agent that is up to 95% medicine and is up to 99.9% (weight ratio) conventionally.
Be applicable to the medicine with joyful taste not of the present invention and compositions such as analgesic, nonsteroidal anti-inflammatory, hydryllin, antitussive, expectorant, bronchodilator, anti-infective, CNS active drug, cardiovascular drug, antineoplastic agent, pravastatin, Bendectin, vitamin, mineral and supplement machine and manure bate, mineral salt, trace element, Chinese herbal medicine extract etc.
Be specially adapted to the example with the medicine of joyful taste not of the present invention as follows, but be not limited to this:
Analgesic, such as aspirin, have acetyl phenalgin phenol, acetyl aminophenol, phenacetin, sodium salicylate, codeine, oxycodone and the dihydrocodeinone of caffeine;
Antipyretic-antalgic agent, 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-);
CoX-2 inhibitor, as etoricoxib and celecoxib;
H2-antagonist, such as ticlopidine, cimetidine, ranitidine, famotidine, nizatidine, ebrotidine, miaow fen replaces Buddhist nun fixed (etinidine), niperitone, sulphur for fourth (nifentidine), Pi Sha, to replace fourth (pisatidine) and roxatidine for fourth (sulfotidine), tuvatidine, zaltidine (zaltidine), lupitidine, Buddhist nun's sweet smell for fourth, roxatidine, dust;
Anti-allergic agent, 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 is as brompheniramine maleate, chlorphenamine maleate, carbinoxamine maleate, Fumaric acid clemastine, mizolastine, dexbrompheniramine maleate, hydrochloric acid diphenyl hydramine (diphenylhydramine hydrochloride), azatadine maleate, Diphenhydramine citrate, diphenylpyraline hydrochloride, doxylamine succinate, promethazine hydrochloride, Pyrilamine, citric acid tripelennamine, triprolidine hydrochloride, acrivastine, brompheniramine, dexchlorpheniramine, fexofenadine, terfenadine, astemizole and nabumetone,
Antiemetics (Antiemitic), such as meclizine and its hydrochloride, and hydroxyzine hydrochloride and pamoate, and diphenhydramine hydrochloride; prochlorperazine and butadiene ene two acid, benzene and quinoline amine hydrochloride, granisetron and its hydrochloride, dronabinol, nabilone, metoclopramide, bismuth subsalicylate, and promethazine hydrochloride, metoclopramide and its halides / hydrates, chlorpromazine, trimethobenzamide and its hydrochloride, thiethylperazine and maleic acid, scopolamine, perphenazine, ondansetron and the hydrochloride salt;
Diarrhea and intestinal anti-inflammatory agent, for example loperamide, 5-aminosalicylic acid, olsalazine, sulfasalazine, budesonide;
Cathartic, as bisacodyl, sodium picosulfate;
Spasmolytic, for example bromination octyl group;
Gastric mucosa protectant, as rebamipide;
Proton pump inhibitor, such as omeprazole, pantoprazole, lansoprazole, terbinafine;
Diarrhea, as loperamide etc.;
Dopamine-receptor antagonist, as domperidone;
Diuretic, for example Hydrochlorothiazide;
Oral antidiabetic, for example glipizide, metformin, phenformin, gliclazide, glibenclamide, metformin, miglitol, repaglinide;
Antitussive is as benzonatate, caramiphen edisylate, menthol, dextromethorphan hydrobromide, Clofedanol, codeine phosphate etc.;
Bronchodilator, 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, as guaifenesin, hippo, potassium iodide, terpini hydras, Bisolvon, ambroxol etc.;
Flu and cough product, such as dextro-methorphan and its hydration Bromide and guaifenesin and its hydrochlorate;
5HT inhibitor, such as sldenafil;
Macrolide antibiotics, such as carat miramycin, Roxithromycin, azithromycin, clarithromycin, Azithromycin, erythromycin;
Ketolide antibiotics, such as Ketek, Beta-alanine, Quetiapine;
Quinolone antibiotic, 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, as bacteresulf;
Tetracycline medication, as tetracycline;
Enzyme inhibitor, as sulbactam sodium;
Antiviral agents, as nevirapine, amiloprilose HCl, acycloguanosine and amantadine
Antifungal agent, as fluconazol;
Other antimicrobials, ora, disinfectant are 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, as aliphatic alcohol, barbiturates etc.;
The non-selective CNS analeptic of whole body, as caffeine, nicotine, strychnine, Picrotoxin, pentylenetetrazole etc.;
The medicine of selectively changing CNS function, 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, as levodopa, amantadine, pergolide, carbidopa, nicergoline, selegiline etc.;
Narcotic analgesics, 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.;
Migraine agent, the active substance 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, azoles for smooth, sumatriptan and succinate and same treatment class; Dihydroergotamine, its hydride and mesyl compound, not She Gai get (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, 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, for example, as beta-Blocking agent (Propranolol, Mei Tuopuluo, bisoprolol, resistance to 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, 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, as quinidine;
Cholesterol lowering drug, for example lovastatin, pravastatin;
Antineoplastic agent, for example 5-fluorouracil, flutamide, etoposide and cyclophosphamide;
Antimalarial, as quinine;
Aeroseb-Dex, as prednisone, metacortandralone;
Vitamin, as folic acid, vitamin B1 nitrate, tretinoin element (vitamin A), vitamin C, vitamin E and zinc;
Mineral, for example ferrum, calcium and zinc salt;
Manure bate, for example docusate sodium;
Plant extract, for example Echinacea, bilobalide, Rhizoma Coptidis, Cortex Phellodendri, Semen Plantaginis etc.
For medicine of the present invention, 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 be considered it with the compatibility of coating/taste masked polymer, the taste of lipotropy filler is selected with the biological usability that dissolving is connected fast under one's belt with it.
Said medicine can be embedded in core material or otherwise as be dry mixed or wet granulation and being combined with core material.
Coating core core can also contain other pharmacy auxiliary agent except medicine, as bases such as filler, binding agent, disintegrating agent, short disintegrating agent, lubricants (comprising fluidizer, antitack agent).In addition, can also comprise solubilizing agent, suspending agent, sweeting agent, aromatic, pigment, absorbent and surfactant (as played the effects such as moistening, dispersion, solubilising, emulsifying).The ratio of each component of core core can be determined according to the kind of active component used, the kind of polymer used, drug release curve of expection etc.One is got on very well, and the gained coated drugs with said components proportioning can obtain good drug release curve and taste-masking effect.
When coating neutral and alkali 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 time, in order further to promote medicine release under one's belt, a specially suitable coating core material example is as follows: coating core material, except medicine, preferably at least contains:
1), at least one can not form sweller and/or at least one super-disintegrant of strong gel; Preferably, also contain
2), at least one osmotic pressure active substance; More preferably, also contain
3), at least one dry adhesives.
Its objective is the feature of disintegrate after making core material have coating breaks, thereby medicine is discharged under one's belt fast.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 occur the pressure that enough expansions produced and caused starting and/or being otherwise 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 coating core material is enough larger than the outer gastro-intestinal Fluid osmotic pressure of film, as large more than 4 times, to drive release and the rapid disintegrate of coating core material of medicine in coating core material.The present invention's term used herein " disintegrate rapidly " refers to substantially paroxysmally carry out disintegrate, and this burst is enough to from this to discharging the medicine of effective dose pharmaceutical preparation.
Particularly, one of object of the present invention is just to provide a kind of above-mentioned coating composition, disintegrate in 30 minutes in simulated gastric fluid (pH value 1.2, containing the hydrochloric acid solution of 1% pepsic pH value 1.2) 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, can measure with reference to two appendix XA inspection techniques disintegration of < < Chinese Pharmacopoeia > > (version in 2005) as tablet, capsule for the larger coating core material of volume; For the coating core material of small volume as granule, during because of the disintegrate of coating core material, solution turbidity will change, can enter to measure by following method: the preparation of getting coating core material or containing coating core material is inserted in the above-mentioned disintegrate medium (simulated gastric fluid (pH value 1.2)) and the appropriate containers with stirring and thermostat that fills 37 ℃, with turbidity device, measure turbidity and record turbidity over time, the turning point changing 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 entering in disintegrate medium, by coming turning point that trend in time of drug level changes as changed 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 utilized electrochemical method (as conductance method, chemical potential method), photochemical method (ultraviolet-visible luminosity absorption process, luminous chemical method, as fluorescence method, phosphorimetry) etc., the concrete similar above-mentioned nephelometry of application process.
If medicine stripping from core material is not subject to the impact of disintegrate or dissolution medium (simulated gastric fluid (pH value 1.2)), can carry out its disintegration time of indirect control and supervision by measuring the dissolution of coating composition.Thereby, now " disintegrate in 30 minutes in simulated gastric fluid (pH value 1.2; containing the hydrochloric acid solution of 1% pepsic pH value 1.2) when coating core material can 37 ℃ " can more strictly be defined as " when the medicine in coating core material can 37 ℃ in simulated gastric fluid (pH value 1.2, containing the hydrochloric acid solution of 1% pepsic pH value 1.2) in 30 minutes basic release completely ".Correspondingly, other also can more strictly be defined as:
" preferably, the medicine in coating core material can substantially discharge completely in 15 minutes in the time of 37 ℃ in simulated gastric fluid (pH value 1.2).”
" more preferably, the medicine in coating core material can substantially discharge completely in 10 minutes in the time of 37 ℃ in simulated gastric fluid (pH value 1.2).”
" best, the medicine in coating core material can substantially discharge completely in 5 minutes in the time of 37 ℃ in simulated gastric fluid (pH value 1.2).”
Term used herein " basic discharge completely " refers to that the ratio that the medicine being extracted into from medication coat compositions (as preparations such as tablet, capsule or granules) in regulation dissolution medium accounts for whole coating composition Chinese medicine is not less than 80%.
The core material drug releasing rate of above-mentioned expansion and the speed of disintegrate are controlled by following parameters: (1) is insoluble to or almost water-fastly can covers or suppress the ratio of alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid in coating and footpath size and its character; (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) form the type of the material of core material particulate matter; (7) ratio of each composition 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 coating; (12) size of the osmotic pressure in 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 that determines core material drug releasing rate and disintegrate.Be insoluble to or almost water-fast to cover or suppress the ratio of alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid in coating larger, a footpath is less, is more soluble in acidic gastric juice, and the speed of core material drug releasing rate and disintegrate is faster; Coating layer thickness is thinner, and the speed of core material drug releasing rate and disintegrate is faster; Ratio in gastric solubility polymeric material coating is larger, and the speed of core material drug releasing rate and disintegrate is faster under one's belt; Expansion rate and the degree of core material are larger, and the speed of core material drug releasing rate and disintegrate is faster; Osmotic pressure in core material is larger, and the speed of core material drug releasing rate and disintegrate is faster; Etc..
The present invention " can not form the sweller of strong gel " used 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 approximately 10～80% (w/w); More preferably with 20～60%, this is the weight based on core material.
" super-disintegrant " that the present invention is used, also referred to as superdisintegrantes, 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 is more specifically 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, the hydroxypropyl cellulose of low replacement, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or calcium, cellulose fibre, cross linked polyacrylate, crosslinked Amberlite resin, alginate, carboxymethyl starch or Microcrystalline Starch, microcrystalline Cellulose and composition thereof.The consumption of super-disintegrant in core material is preferably with approximately 5～40% (w/w); More preferably with 10～25%, this is the weight based on core material.
" dry adhesives " that the present invention is used, its effect is to make to be bonded together compared with small-particle, after guaranteeing to granulate, larger particle can keep certain form, can and guarantee that the fragility that reaches certain is beneficial to disintegrate, can also guarantee the more effective performance of effect of disintegrating agent and sweller, avoid the adverse effect of solvent to the disintegrate of disintegrating agent (sweller) (expansion) effect simultaneously.Useful dry adhesives includes, but are not limited to: starch, for example Rhizoma Solani tuber osi, wheat and maize 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, Aerosil 200 (as Aerosil), light anhydrous silicic acid; Mannitol, lactose, maltose alcohol, Sorbitol, xylitol, lactose (anhydrous or as hydrate, for example monohydrate), D-glucose, maltose, sucrose, glucose, fructose or maltodextrin; And concurrent mixture.Particularly preferably, dry adhesives is microcrystalline Cellulose.The consumption of dry adhesives in core material is preferably with approximately 10～50% (w/w); More preferably with 15～40%, this is the weight based on core material.
" the osmotic pressure active substance " that the present invention is used, also claims osmotic pressure promoter, plays the indoor osmotic pressure of regulating.Osmotic pressure active substance share with 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.Its consumption number be often related to the length that drives the release of medicine in coating core material and the power size of disintegrate rapidly and medicine quick release time.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, 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 approximately 5～70% (w/w); More preferably with 10～50%, this is the weight based on core material.
If need, also can add other additives in above-mentioned swellable coating core material.Such additive comprises but is not limited to: filler, as saccharide; Binding agent, as hydroxypropyl emthylcellulose or hydroxypropyl cellulose; Screening agent, as calcium gluconate, magnesium oxide; And lubricant, as Talcum and magnesium stearate.
Preparation method with regard to above-mentioned coating composition elaborates below.
1), prepare core core the preparation method of the coating composition the present invention relates to comprises following several basic step:; 2), to core core coating; 3), if desired, to coating heal (aging) process.
1), prepare core core
The method of preparing core core has no particular limits.Conventionally preparation method is by direct pressing method by compositions such as active medicinal matter, pharmacy auxiliary agents; the pressing method of dry, wet or sintered particles; extrude and rounding subsequently; wet or dry state pelletize or directly make ball (for example, on disk) or powder (powder bed) is bonded to the ball (particle) of non-activity material or containing on the granule of active substance, or further in a certain way as make sheet.
2), to core core coating
First prepare spray coating liquor.As an embodiment, polymer and other coating additives are dissolved or dispersed in organic solvent, make the organic spray coating liquor that contains polymer.For another example an embodiment, is dissolved or dispersed in coating additive in the aqueous dispersion of polymer, makes the aqueous dispersion spray coating liquor of polymer; If there is no compatibility reaction, can the aqueous dispersion of two or more polymer by certain mixing after, then other coating additives are dissolved or disperse and wherein, 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 aqueous dispersion suspension are generally 2～30%, and preferably 5～20%, more preferably 8～15%.Aqueous dispersion suspension also can contain a certain amount of organic solvent, and its content is often 1～20%, and preferably 1～10%, more preferably 2～5%.
Utilize the solution of above-mentioned gained or suspension by casting, soak the coating processes such as the libation at an ancient wedding ceremony, brushing or spraying to core core coating.Preferably, adopt spraying method to carry out coating.
In one embodiment, by less as being less than the core core that needs coating of 80 microns as dispersions such as fine grained, ball or medicine powder, crystal, medicine carrying resins and being suspended in the organic solution or aqueous dispersion that contains polymer mix homogeneously.Adopt spraying method to carry out coating.
In another embodiment, by larger being suspended in aerial or inserting in coating pan or other coating equipment in sugar production lines as sheet, granule, ball, medicine crystal, medicine carrying resin etc. make it as being greater than the core core that needs coating of 80 microns, core core is sprayed and stated organic solution or the aqueous dispersion that contains polymer, adopt spraying method to carry out.
Coating film forming procedure does not rely on coating process and is undertaken by energy input.This can or conduct by convection current (heat), radiation (infrared or microwave).Thus the solvent using as solvent or suspending agent for coating is evaporated, necessary words also may be applied vacuum and accelerate evaporation.The higher drying efficiency of this process need, so the present invention often adopts high efficiency coating equipment in sugar production line (as fluid bed).
The temperature that coating coating is used should be higher than the minimum film formation temperature (MFT) (minimum film formation temperature refers to the minimum temperature of polymer formation seriality clothing film, and below minimum film formation temperature, polymer particle can not be out of shape and merge and film forming) of polymer.The temperature that coating coating is used exceeds 10～20 ℃ of minimum film formation temperature conventionally.If temperature is too low, may make clothing film occur crack; Excess Temperature is too softening polymer, causes clothing film coalescence.
During coating, conventionally core core etc. is preheated to 20～90 ℃, preferably 30～70 ℃, more preferably 30～50 ℃, first with lower hydrojet speed, apply, to the coated skim clothing film of core wicking surface, then improve hydrojet speed to coating and finish.
In order to protect unsettled active component to avoid degraded in healing processing, can use the air in the airtight environment of nitrogen replacement (as airtight casing).
Most suitable or more suitable technological parameter thus art those skilled in the art is determined according to coating material and core material character and experimental result etc.Take fluidized bed coating as falling, and the process conditions such as coating temperature, fluidisation air quantity, atomizing pressure and hydrojet speed all can quantitatively be controlled according to practical situation optimization.
3), coating (if desired) is processed in healing (aging)
After coating finishes, in coating, polymer particle does not often merge completely, i.e. coating healing is still incomplete.Under the interfacial tension effect of polymer and air, deposit in process further fusion phenomenon may occur, form finer and close clothing film.Fusion phenomenon needs the long period just can complete, and conventionally adopts and applies after-baking technique to accelerate coating healing, to guarantee integrity and the taste masking effect of coating.
Healing processing (curing treating) process is generally after moisture evaporation, and clothing film is placed in to certain hour under uniform temperature or under simultaneously certain inferior condition of humidity, and the polymer particle in coating is further merged, and forms fine and close clothing film.Selected temperature should be higher than its glass transition temperature or minimum film formation temperature, preferably higher than more than 10 ℃, more preferably, higher than more than 20～30 ℃, above temperature all should be take does not make the composition in coating material soften completely or melt or clothing film coalescence do not occur as degree.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.The dissolution test data (being undertaken by the method in Chinese Pharmacopoeia two appendix in 2005) that the end time of healing processing normally contrasts healing obtains sample under certain condition and healing acceleration test obtains the sample of (for example 40 ℃ of temperature, relative humidity 75% time healing acceleration test March) are determined.Definite method of the end time of better healing processing is (as the acid medium of pH value 1.2) under certain condition, and the sample that healing is obtained carries out dissolution test, as long as the medicine of stripping detected, just can not conclude and has reached healing terminal.
Healing processing can carry out with heat treatment modes such as baking oven and fluid beds.The features such as fluid bed heat processing has efficiently, saves time can complete coating and heat treatment operation in same equipment, and the industrialization suitability is higher.Coating finishes rear elevation system temperature, and material, in the continuous fluidized drying of same fluid unit relaying, can promote film healing balance in the short time.But compare with baking oven mode, fluid bed mode is had relatively high expectations to clothing film mechanical performance, and heat treatment caudacoria healing is relatively low.Therefore the present invention preferably adopts baking oven heat treatment mode.
Under higher thermal treatment temperature, in order to prevent that low melting point substance (as ibuprofen) from may move, enter in clothing film, cause preparation release to accelerate degradation problem under phenomenon, clothing film mechanical performance, can carry out sealing coat coating to medicine carrying core material, or reduce heat treatment temperature.
Most suitable or more suitable technological parameter, as healing temperature, humidity, time thus art those skilled in the art according to experimental result etc., determine.
If film has healed completely in coating process underpants, can not heal (aging) processes, 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 at least comprises that at least one offending abnormal flavour in administration process is difficult for the coating composition that bedding and clothing user discovers, this coating composition at least comprises:
A), the coating covered outward, this coating at least contains:
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer almost,
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer in neutrality or alkaline pH medium, and
3), at least one pharmaceutically acceptablely can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid;
B), the core core that contains at least one medicine that has offending abnormal flavour being coated by above-mentioned coating.
The present invention relates to another kind of pharmaceutical preparation, it is characterized in that said preparation at least comprises that at least one offending abnormal flavour in administration process is difficult for the coating composition that bedding and clothing user discovers, this coating composition at least comprises:
A), the coating covered outward, this coating at least contains:
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer almost,
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer in neutrality or alkaline pH medium, and
3), at least one is pharmaceutically acceptablely insoluble to or almost water-fastly can covers or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid;
B), the core core that contains at least one medicine that has offending abnormal flavour being coated by above-mentioned coating.
The invention still further relates to a kind of pharmaceutical preparation, it is characterized in that said preparation at least comprises that at least one offending abnormal flavour in administration process is difficult for the coating composition that bedding and clothing user discovers, this coating composition at least comprises:
A), the coating covered outward, this coating at least contains:
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer almost,
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer in neutrality or alkaline pH medium, and
3), at least one is pharmaceutically acceptablely insoluble to or almost water-fastly can covers or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid;
B), the core core that is coated by above-mentioned coating, this core core at least contains:
1), at least one has the medicine of offending abnormal flavour;
2), at least one can not form sweller and/or at least one super-disintegrant of strong gel; Preferably, also contain
3), at least one osmotic pressure active substance; More preferably, also contain
4), at least one dry adhesives.
The pharmaceutical preparation the present invention relates to can further be processed as added some pharmaceutically acceptable excipient (as aromatic for the drug core having applied of preparing by above-mentioned either type, 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 there is liquid core or fill by powder or granule, can at once discharge or the conventional compressed tablets of delayed release, confection and caked sugar form, aerosol cream, colloid, pouch, or further processing is not directly come into operation, as the tablet of directly taking.The technology of preparing of above-mentioned whole dosage form is all that this area is known.
A preferred embodiment of above-mentioned dosage form is chewable tablet.This chewable tablet, except taste masked particle, can contain other conventional additives, as filler, comprises that water solublity can suppress carbohydrate 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, 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 prepared by the mixture 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 is preferably no more than every square centimeter of (kp/cm of approximately 15 kips
2).More preferably, the hardness of this tablet is approximately 1 to approximately 8, and first-selected approximately 2 to about 5kp/cm
2.Term used herein " hardness " is to describe the radially breaking strength detecting by conventional medicine hardness detection technique (as Schleuruger hardness detects meter).
A preferred embodiment of above-mentioned dosage form is oral liquid, is preferably liquid, aqueous suspending agent, and now, the outer alkaline modifier covering in coating of taste masking particle is above-mentioned water-insoluble alkaline modifier.In one embodiment, for example, once obtain dry 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-bis--tert-butyl-4-methyl-Phenol or BHA or the 2-tert-butyl group-4-methoxyphenol), flavoring agent (seeing above) and coloring agent etc. are to make the dosage form for liquid oral administration.Or in taste masking particle, add other suitable pharmaceutically acceptable auxiliary agent to mix and make the powder that rehydration is suspension.
Prepare liquid, aqueous suspending agent, a key problem in technology is to add basifier to make the pH value of liquid higher than the minimum pH value of dissolving acid insoluble polymer, to keep the globality of above-mentioned anti-enteric coating taste masking coating, guarantee to be scattered in the not stripping of active component in substrate after suspending in water.To can be applicable to basifier of the present invention be in aqueous solution and the pH value of aqueous suspension agent can be promoted and be maintained at about more than 5 alkali.Basifier can be selected from arbitrary following 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 is as bentonite; Zeolite; Calcium oxide; Calcium hydroxide; Calcium phosphate; Magaldrate; Hydrotalcite; DASC; Ammonia; Ammonium bicarbonate; Ammonium carbonate; Ethanolamine; Diethanolamine; Triethanolamine; Meglumine; Basic amino acid, 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 dry taste masking particle, add in advance all the components in the coating of certain coating composition, especially the material that has certain water solublity (hydrophilic), particularly be insoluble to or almost water-fastly can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid, making its aqueous solution at least saturated at temperature 0-50 ℃ in advance.So process, can make the clean stripping quantity of all the components in water in the coating of coating composition is 0, thereby guarantees the integrity of above-mentioned coating, can not allow the drug-eluting that has unhappy abnormal flavour in coating, also can not allow the moisture outside coating enter in 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, be all insoluble to or almost water-fast polymer and above-mentioned be dissolved in acid medium but be insoluble to or the polymer phase that is dissolved in hardly in neutrality or alkaline pH medium perhaps completely compatible; Above-mentioned coating composition higher than above-mentioned under any pH value, be all insoluble to or almost water-fast polymer and/or above-mentioned be dissolved in acid medium but be insoluble to or be dissolved in hardly the temperature healing (solidifying) of the glass transition point of the polymer in neutrality or alkaline pH medium, heal to terminal best.
Described thus the present invention in detail, obviously also can have various changes within the scope of the invention to those skilled in the art, the present invention is not subject to the restriction described in description.
Non-selective embodiment has further described the preferred embodiment in the scope of the invention below.These embodiment also can have many variations within the scope of the invention.
Embodiment
In the following example, medicinal tablet is prepared as follows: the granule (footpath 40～80 orders) of using coating composition coated medicament composition in 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, embodiment 7-8 coating accounts for 7.41% (weight ratio) (being granule weightening finish 8%) of whole coated granule.Embodiment 1-4 then mixes with the excipient of routine for the preparation of chew/fast instantizing tablet or dry suspension the granule of coating or powder in following ratio: coated granule 40.63%; mannitol 49.37%; microcrystalline Cellulose 7.5%; stearic acid 1%, silicon dioxide colloid 0.5%, spice 1%; should for making the final mixture of tablet, to be then pressed into final sheet be heavily the tablet of 480mg; such tablet diameters is 10.5mm, and hardness is 5～10kp approximately, brittleness approximately 0～1%.Or embodiment 2-4 and embodiment 5-8 directly make liquid suspension (pH value 7.3 left and right).
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.Then by making dry suspension or tabletting after the drug particles of coating and the mixing of other compositions, make medicinal tablets.12% thaumatin in coating (A) is changed into 12% triethanolamine, and other are constant, with legal system for reference substance 1.
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.Then by making dry suspension or tabletting after the drug particles of coating and the mixing of other compositions, make medicinal tablets.15% 3 glycyrrhizic acid dicalcium in coating (B) is changed into 15% triethanolamine, and other are constant, with legal system for reference substance 2.
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 (C) of making is implemented to apply to drug particles, described drug particles is sildenafil citrate granule (the particulate component content: sildenafil citrate 33.3% being 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%).Then by making dry suspension or tabletting after the drug particles of coating and the mixing of other compositions, make medicinal tablets.Inosinic acid calcium in coating (C) and guanyl calcium are all changed into 20% Talcum, and other are constant, with legal system for reference substance 3.
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 (D) of making is implemented to apply to drug particles, described drug particles is ranitidine hydrochloride granule (particulate component content: ranitidine hydrochloride 55.8%, microcrystalline Cellulose 18.2%, lactose 24.5%, hydroxypropyl emthylcellulose (2910) 1.5%).Then by making dry suspension or tabletting after the drug particles of coating and the mixing of other compositions, make medicinal tablets.The ammonia soap. that tyrosine phosphatase calcium in coating (D) is changed into, other are constant, with legal system for reference substance 4.
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 (E) of making is implemented to apply to drug particles, described drug particles is ranitidine hydrochloride granule (the particulate component content: ranitidine hydrochloride 55.8% being 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 (F) of making is implemented to apply to drug particles, described drug particles is sildenafil citrate granule (the particulate component content: sildenafil citrate 33.3% being 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 (G) of making is implemented to apply to drug particles, described drug particles is sildenafil citrate granule (the particulate component content: sildenafil citrate 33.3% being 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 (H) of making is implemented to apply to drug particles, described drug particles is sildenafil citrate granule (the particulate component content: sildenafil citrate 33.3% being 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 In Vitro Dissolution test
With the sample of embodiment 1-4 and reference substance pH be 7 and the pH simulated gastric fluid that is 1.2 in carry out stripping test.Table 1-4 shown embodiment 1-4 pH be approximately 7 be similar to mouthful conditional environment in and pH be approximately 1.2, be similar in the environment of stomach conditional the percent of ingredient stripping within given a period of time.
Table 1 paracetamol tablets pH be 7 and the pH solution that is 1.2 in the percent of stripping
Table 2 paracetamol tablets pH be 7 and the pH solution that is 1.2 in the percent of stripping
Table 3 sildenafil citrate sheet pH be 7 and the pH solution that is 1.2 in the percent of stripping
Table 4 ranitidine hydrochloride sheet pH be 7 and the pH solution that is 1.2 in the percent of stripping
The demonstration of stripping test result, characteristic and the reference substance of embodiment 1 example pharmaceuticals In Vitro Dissolution are suitable, are slightly better than reference substance; The characteristic of embodiment 2-4 example pharmaceuticals In Vitro Dissolution is obviously better than reference substance, and the phenomenon being delayed has appearred in the dissolving out capability of reference examples sample.Analysis result can obtain, can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid (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 in 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; Water-soluble compound with respect to polarity, almost water-fast alkali compounds (modifier) under neutrallty condition from coating the speed of stripping slower, thereby extended the time that is aware the offending abnormal flavour of medicine after medication coat compositions is taken in oral cavity.
Test case 2 sense of taste tests
Please 9 special members (testee), 1 sample making with embodiment 1～4 and reference substance are placed in respectively to their mouthful chew and keep at least 2 minutes, and the sense of taste of the test article of measuring they time while feeling bitterness and recording testee main suit in oral cavity.The variations of the time while feeling bitterness, the change of sense of taste and sense of taste power etc. are for evaluating.Acquired results is in Table 5.
The result of time when table 5 is felt bitterness and the test article sense of taste in oral cavity
Test result demonstration, the successful of covering of embodiment sample 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
With sample and the reference substance coating coating solution of preparation in embodiment 1～4, in polyfluortetraethylene plate top casting, make the thin film that thickness is 150 μ m, thin film is cut into the size of 1 * 7cm.Then under INSTRON tensile strength tester, measure tensile strength.The results are shown in Table 6.
Table 6 polymeric film tensile strength measurement result
Test result shows, the mechanical performance of sample 1,2,4 films obviously wants high compared with control film, and mechanical performance and the control film of sample 3 films are suitable.
The external granule slaking test of test case 4 and In Vitro Dissolution test
The sample of embodiment 5-8 is carried out to external granule slaking test and In Vitro Dissolution test, and wherein external granule slaking test adopts nephelometry (referring to description).The results are shown in Table 7 and table 8.
The time of table 7 coated particle disintegrate
Table 8 vitro Drug stripping result
Result shows, the disintegrate fast of embodiment sample, medicine energy Fast Stripping.
Comprehensive the above results can obtain, and the combination property of embodiment sample or general effect will be got well compared with reference substance, and overall performance is reinforced.
Claims (47)
1. in administration process, offending abnormal flavour is difficult for the medication coat compositions that bedding and clothing user discovers, and it is characterized in that said composition comprises:
A), the coating covered outward, this coating contains:
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer I almost, this polymer is selected from ethyl cellulose, methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, disuccinic acid cellulose and composition thereof
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer II in neutrality or alkaline pH medium, this polymer is selected from benzylamino-methyl cellulose, diethylamino methyl cellulose, piperidyl ethylhydroxyethylcellulose, cellulose acetate diethylamino acetate, chitosan, Eudragit E, polymethylacrylic acid dimethylamino ethyl ester and composition thereof, and
3), at least one pharmaceutically acceptablely can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid, this alkali compounds is selected from basic salt, thaumatin, mabinlin, monellin, Mai Ruo Kelin, the basic salt of inosinic acid, the basic salt of the basic salt of guanyl, hypoxanthylic acid, basic salt, the basic salt of phosphotyrosine, the basic salt of the basic salt of phosphoserine, phosphothreonine and their mixture of the basic salt of the basic salt of ribonucleotide, succinic acid, ɑ-methylfuran inosinic acid of glycyrrhizic acid
Or
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer I almost, this polymer is selected from polymethyl methacrylate, poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride) and composition thereof
2), at least one is pharmaceutically acceptable is dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer II in neutrality or alkaline pH medium, this polymer is selected from Eudragit E, polymethylacrylic acid dimethylamino ethyl ester, benzylamino-methyl cellulose, diethylamino methyl cellulose, 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, and
3), at least one pharmaceutically acceptablely can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid, this alkali compounds is selected from basic salt, thaumatin, mabinlin, monellin, Mai Ruo Kelin, the basic salt of inosinic acid, the basic salt of the basic salt of guanyl, hypoxanthylic acid, basic salt, the basic salt of phosphotyrosine, the basic salt of the basic salt of phosphoserine, phosphothreonine and their mixture of the basic salt of the basic salt of ribonucleotide, succinic acid, ɑ-methylfuran inosinic acid of glycyrrhizic acid
Or
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer I almost, this polymer is selected from terpolymer, vinyl acetate-vinyl chloride copolymer of polyvinylacetate, vinyl chloride-ethylene alcohol-vinylacetate and composition thereof
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer II in neutrality or alkaline pH medium, this polymer 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, and
3), at least one pharmaceutically acceptablely can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid, this alkali compounds is selected from basic salt, thaumatin, mabinlin, monellin, Mai Ruo Kelin, the basic salt of inosinic acid, the basic salt of the basic salt of guanyl, hypoxanthylic acid, basic salt, the basic salt of phosphotyrosine, the basic salt of the basic salt of phosphoserine, phosphothreonine and their mixture of the basic salt of the basic salt of ribonucleotide, succinic acid, ɑ-methylfuran inosinic acid of glycyrrhizic acid
Or
1), at least one pharmaceutically acceptable being all insoluble under any pH value or water-fast polymer I almost, this polymer is selected from polrvinyl chloride,
2), at least one is pharmaceutically acceptablely dissolved in acid medium but is insoluble to or is dissolved in hardly the polymer II in neutrality or alkaline pH medium, this polymer 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, and
3), at least one pharmaceutically acceptablely can cover or suppress alkali compounds offending abnormal flavour and that be dissolved in dilute hydrochloric acid, this alkali compounds is selected from basic salt, thaumatin, mabinlin, monellin, Mai Ruo Kelin, the basic salt of inosinic acid, the basic salt of the basic salt of guanyl, hypoxanthylic acid, basic salt, the basic salt of phosphotyrosine, the basic salt of the basic salt of phosphoserine, phosphothreonine and their mixture of the basic salt of the basic salt of ribonucleotide, succinic acid, ɑ-methylfuran inosinic acid of glycyrrhizic acid
Wherein, above-mentioned under any pH value, be all insoluble to or almost the content of water-fast polymer I be 10wt% to 80wt%, above-mentionedly be dissolved in acid medium but be insoluble to or the content that is dissolved in hardly the polymer II in neutrality or alkaline pH medium is 10wt% to 60wt%, the content of above-mentioned alkali compounds is 0.2wt% to 30wt%, the gross dry weight amount of above-mentioned each content based on above-mentioned coating;
What b), by above-mentioned coating, be coated contains a kind of core core that has the medicine of offending abnormal flavour.
2. according to the medication coat compositions of claim 1, it is characterized in that described under any pH value, be all insoluble to or almost water-fast polymer be selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate and composition thereof, described be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from Eudragit E.
3. according to the medication coat compositions of claim 1, it is characterized in that described under any pH value, be all insoluble to or almost water-fast polymer be selected from poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride), described be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from Eudragit E.
4. according to the medication coat compositions of claim 1, it is characterized in that described under any pH value, be all insoluble to or almost water-fast polymer be selected from polyvinylacetate, described be dissolved in acid medium but be insoluble to or the polymer that is dissolved in hardly in neutrality or alkaline pH medium is selected from Eudragit E.
5. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described alkali compounds is selected from thaumatin, mabinlin, monellin, Mai Ruo Kelin and their mixture.
6. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described alkali compounds is selected from thaumatin, mabinlin and their mixture.
7. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described alkali compounds is selected from the basic salt of pharmaceutically acceptable inosinic acid, the basic salt of the basic salt of guanyl, hypoxanthylic acid, the basic salt of ribonucleotide and their mixture.
8. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described alkali compounds is selected from the pharmaceutically acceptable basic salt of following material: the dextrorotation of the dextrorotation of the dextrorotation of phosphotyrosine or laevoisomer, phosphoserine or laevoisomer, phosphothreonine or laevoisomer, and their mixture.
9. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described alkali compounds is selected from the basic salt of pharmaceutically acceptable glycyrrhizic acid.
10. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described alkali compounds is selected from the basic salt of pharmaceutically acceptable Alpha-Methyl furan inosinic acid.
11. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described basic salt is selected from the basic salt of 3B family metal ion, periodic table of elements Zhong 8 family's metal ions or periodic table of elements Zhong11, 12 family's metal ions in pharmaceutically acceptable ammonium ion, alkali metal ion, alkaline-earth metal ions, the periodic table of elements.
12. according to the medication coat compositions of any one in claim 1 to 4, 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.
13. according to the medication coat compositions of any one in claim 1 to 4, pharmaceutically acceptable being insoluble to or almost water-fast basic salt and their mixture that it is characterized in that described alkali compounds is selected from following material: glycyrrhizic acid, inosinic acid, guanyl, hypoxanthylic acid, ribonucleotide, succinic acid, phosphotyrosine, phosphoserine, phosphothreonine.
14. according to the medication coat compositions of any one in claim 1 to 4, pharmaceutically acceptable being insoluble to or almost water-fast basic salt and their mixture that it is characterized in that described alkali compounds is selected from following material: inosinic acid, guanyl, hypoxanthylic acid, ribonucleotide.
15. according to the medication coat compositions of any one in claim 1 to 4, pharmaceutically acceptable being insoluble to or almost water-fast basic salt and their mixture that it is characterized in that described alkali compounds is selected from following material: the dextrorotation of the dextrorotation of the dextrorotation of phosphotyrosine or laevoisomer, phosphoserine or laevoisomer, phosphothreonine or laevoisomer.
16. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described alkali compounds is selected from being insoluble to of pharmaceutically acceptable glycyrrhizic acid or water-fast basic salt almost.
17. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described alkali compounds is selected from being insoluble to of pharmaceutically acceptable Alpha-Methyl furan inosinic acid or water-fast basic salt almost.
18. according to the medication coat compositions of claim 11, it is characterized in that described basic salt is selected from the basic salt of 3B family metal ion, periodic table of elements Zhong 8 family's metal ions or periodic table of elements Zhong11, 12 family's metal ions in pharmaceutically acceptable alkaline-earth metal ions, the periodic table of elements.
19. according to the medication coat compositions of claim 12, 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.
20. according to the medication coat compositions of claim 13, it is characterized in that the mean diameter of the granule of described alkali compounds is 0.05～200 μ m.
21. according to the medication coat compositions of claim 13, and the dissolubility while it is characterized in that 25 ℃ of the temperature of described alkali compounds in water is not more than 10mg/ml.
22. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described under any pH value, be all insoluble to or coating that almost water-fast polymer covers outside described in content be 25wt% to 60wt%, it is described that to be dissolved in acid medium but to be insoluble to or to be dissolved in hardly content in the coating that the polymer in neutrality or alkaline pH medium covers outside described be 15wt% to 50wt%, content in the coating that described alkali compounds covers outside described is 1wt% to 25wt%, the gross dry weight amount based on coating.
23. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that the described coated coated core core that contains at least one medicine that has offending abnormal flavour is sheet, granule, ball, crystal and/or the medicine carrying resin of rule or irregular form.
24. according to the medication coat compositions of any one in claim 1 to 4, and the medicine that has offending abnormal flavour that the coated coated core core described in it is characterized in that comprises is selected from has the not analgesic of joyful taste, NSAID (non-steroidal anti-inflammatory drug), anti-allergic agent, antihistaminic medicine, Bendectin, intestinal anti-inflammatory agent, cathartic, spasmolytic, gastric mucosa protectant, proton pump inhibitor, diarrhea, dopamine-receptor antagonist, diuretic, oral antidiabetic, antitussive, bronchodilator, selectivity β-2 antagonistic, decongestant, expectorant, macrolide antibiotics, ketolide antibiotics, quinolone antibiotic, cephalosporins, Penicillin antibiotics, sulfa drugs, tetracycline medication, enzyme inhibitor, antiviral agents, antifungal agent, the non-selective CNS inhibitor of whole body, the non-selective CNS analeptic of whole body, the medicine of selectively changing CNS function, tranquilizer, anti-Parkinson Cotard medicine, psychosis class medicine, migraine agent, antuepileptic, antidepressants, anticonvulsant, antihypertensive, Coronary Vasodilators, cardiac glycoside, anti-arrhythmic, cholesterol lowering drug, antineoplastic agent, antimalarial, Aeroseb-Dex, vitamin, mineral, manure bate.
25 as claimed in any one of claims 1 to a pharmaceutical composition for the coating 4 , wherein the core is coated with a coating containing an unpleasant odor of the drug is selected from aspirin , caffeine acetamido having phenol, phenol amino acid , codeine , oxycodone, hydrocodone , salicylates , phenylbutazone , indomethacin , phenacetin , mefenamic acid , ibuprofen, diclofenac, aceclofenac , flufenamic acid , fenoprofen , flurbiprofen , ketoprofen , naproxen and its alkali metal salts , nimesulide , piroxicam and its salts, Tenidap , two diflunisal , tolmetin sodium, celecoxib , rofecoxib , L- acetyl America cedar alcohol , tiaprofenic acid, mesalamine , etoricoxib , ticlopidine , cimetidine, Rainey cimetidine , famotidine , nizatidine , cimetidine ethyl bromide , microphone thiophene cimetidine , roxatidine , Egypt imatinib given , niperitone, sulfur cimetidine , nizatidine cutting properly , azole for Ding Lu horses cimetidine , nizatidine Jonathan , leather cimetidine , ebastine , clemastine and its fumarate , Azar cimetidine and maleic acid , and hydroxyzine pamoate salt and hydrochloride, chlorpheniramine maleate and its salts and tannins , salbutamol sulphate , sulphate and its pseudo- adrenaline hydrochloride, brompheniramine its maleate , loratadine , desloratadine ground , decarbonization ethoxy - loratadine , and phenylephrine hydrochloride and tannate , a scopolamine and nitrate salt, ammonia and benzene -propanol hydrochloride, bromine Finney Lamine its maleate , terfenadine , acrivastine , and cetirizine hydrochloride, phenindamine and its tartrate , tripelennamine and its hydrochloride, cyproheptadine and its hydrochloride, promethazine and its hydrochloride, pyrilamine and its hydrochloride salt and tannic acid, maleic acid bromide benzene chlorpheniramine maleate, chlorpheniramine maleate, carbinoxamine , clemastine fumarate , mizolastine , alcohol diphenyl amine hydrochloride , azatadine maleate , diphenhydramine citrate , hydrochloric two benzene Lalin , doxylamine succinate , pyrilamine maleate , tripelennamine citrate , triprolidine hydrochloride , bromobenzene arsenic amines right chlorpheniramine, fexofenadine , astemizole imidazole, nabumetone , and meclizine hydrochloride and diphenhydramine hydrochloride, prochlorperazine and its maleate , benzene and quinoline amine hydrochloride, Glasgow granisetron and its hydrochloride, dronabinol , nabilone , bismuth subsalicylate , metoclopramide and its halides / hydrates , trimethobenzamide and its hydrochloride, thiethylperazine and its maleate , scopolamine , perphenazine, and ondansetron hydrochloride, loperamide , 5 - amino salicylic acid , olsalazine , sulfasalazine , budesonide, Bisha can pyridine , horses can be sodium bromide, octyl bromide , rebamipide , omeprazole, pantoprazole , lansoprazole, terbinafine , domperidone , hydrochlorothiazide , glipizide , metformin , phenformin , gliclazide, glyburide , metformin , miglitol , repaglinide , benzonatate , ethanedisulfonic caramiphen , menthol, dextromethorphan hydrobromide Finland , chlorine aniline hydrochloride alcohol, codeine phosphate , Chuan Ningtan, albuterol , pirbuterol hydrochloride , metaproterenol , salbutamol, procaterol , theophylline , terbutaline , ephedrine , metaproterenol sulfate , hydrochloric acid, pseudoephedrine, phenylephrine , phenylpropanolamine , pseudoephedrine sulfate , potassium iodide, terpene hydrate , bromhexine hydrochloride , ambroxol , dextromethorphan and its hydrated bromide salt , more guaifenesin and its hydrochloride , sildenafil , Crouch vancomycin, roxithromycin , azithromycin, erythromycin , azithromycin , erythromycin, telithromycin , β- alanine , quetiapine , lomefloxacin , norfloxacin , enoxacin , ciprofloxacin, Ge Leisha star, enrofloxacin , ofloxacin, Xi Luosha star, song ofloxacin , gatifloxacin gatifloxacin , norfloxacin, cefuroxime axetil , cefaclor, the new force , cefcapene , cefadroxil , cefpodoxime , cefotiam ester , ester cephalosporin Telun horses volts , chlorofluorocarbons , sodium penicillin, ampicillin penicillin acid ester hydrochloride , toluenesulfonic Schumi amoxicillin , amoxicillin Kabbah hydrochloride , amoxicillin , ampicillin, cloxacillin , 2,6 - CFC benzoic isopenicillin , sulfisoxazole , tetracycline, sulbactam sodium , nevirapine , amiloprilose? HCL, acyclovir , fluconazole , berberine , triclosan, cetylpyridinium chloride , domiphen , quaternary ammonium salts, zinc compounds, sanguinarine, fluorides, alexidine fixed , octopamine , EDTA, benzalkonium chloride , cetylpyridinium chloride , benzene, sulfur- iodine Zhuo Ning benzydamine , chlorhexidine , caffeine, nicotine , disabilities, picrotoxin , PTZ oxazole, in the phenyl hydantoin, phenobarbital, primidone , methsuximide , phensuximide , trimethadione , diazepam , phenylacetyl urea , benzyl butyl hydantoin, acetazolamide acid bromide, Shu thiazide , gabapentin , phenytoin , chlordiazepoxide , chlorpromazine, oxazepam, medazepam , triazolam , alprazolam , and more that diazepam, lorazepam, levodopa , adamantane amines, pergolide, carbidopa, nicergoline , selegiline , morphine , heroin, hydromorphone , metopon , oxymorphone , left it south, nalorphine , naloxone, Qu ketones, donepezil , modafinil , naphthalene hair tie one, reboxetine, methoxy trimeprazine , haloperidol, haloperidol , clozapine , sertraline , sertindole , reserpine, imipramine, tranylcypromine , phenelzine Aila Dan , valproic acid and alkali metal salts double , and timolol maleate , alcohol and halogen hydrate , ergotamine and tartrate, caffeine, rizatriptan , eletriptan , azole do for Tanzania , sumatriptan succinate and , dihydroergotamine and its hydride and mesyl compounds, Mosher cover too and maleic acid , iso- US Shapu Te mucate , chloral than forests, valproic acid esters , topiramate , fluoxetine , paroxetine, nortriptyline , risperidone, citalopram Champlain , olanzapine , buspirone and its salts , carbamazepine, ethosuximide , propranolol , United Tuo Puluo , bisoprolol , Los resistant than fluorine , nifedipine, irbesartan, doxazosin mesylate , amlodipine besylate , single isosorbide dinitrate , isosorbide dinitrate , captopril , nicardipine, diltiazem , verapamil, nifedipine , vinpocetine , a captopril , enalapril , lisinopril , digoxin, digitoxin , quinidine, lovastatin , pravastatin, 5 - fluorouracil, flutamide, etoposide, cyclophosphamide, quinine, prednisone, prednisolone , folic acid, vitamin B1 nitrate, retinoic acid , vitamin C, vitamin E, zinc, iron , calcium and zinc salts, sodium docusate .
26. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that described core core also contains at least one sweller that can not form strong gel and/or at least one super-disintegrant.
27. according to the medication coat compositions of claim 26, it is characterized in that described sweller be selected from alginic acid, pectin, xanthan gum, guar gum, Tragacanth, locust bean gum, chondrus ocellatus Holmes polysaccharide, Microcrystalline Starch, microcrystalline Cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose and carboxymethyl cellulose with and slaine, and their mixture.
28. according to the medication coat compositions of claim 26, it is characterized in that the consumption of the described sweller that can not form strong gel in described core material is 10～80% (w/w), the weight based on core material.
29. according to the medication coat compositions of claim 26, it is characterized in that described super-disintegrant is selected from hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or the calcium of low replacement, cellulose fibre, cross linked polyacrylate, crosslinked Amberlite resin, alginate, carboxymethyl starch or Microcrystalline Starch, microcrystalline Cellulose and composition thereof.
30. according to the medication coat compositions of claim 26, it is characterized in that the consumption of described super-disintegrant in described core material is 5～40% (w/w), the weight based on core material.
31. according to the medication coat compositions of claim 26, it is characterized in that described core core also contains at least one osmotic pressure active substance.
32. according to the medication coat compositions of claim 31, it is characterized in that described osmotic pressure active substance is selected from lactose, fructose, glucose, sucrose, mannitol, sodium chloride, sorbitol, potassium chloride, potassium sulfate, sodium phosphate or its hydrate, sodium hydrogen phosphate or its hydrate and their mixture.
33. according to the medication coat compositions of claim 31, it is characterized in that the consumption of described osmotic pressure active substance in described core material is 5～70% (w/w), the weight based on described core material.
34. according to the medication coat compositions of claim 26, it is characterized in that described core core also contains at least one dry adhesives.
35. according to the medication coat compositions of claim 26, disintegrate in 15 minutes in simulated gastric fluid while it is characterized in that the described core core being coated by described coating can 37 ℃.
36. according to the medication coat compositions of claim 26, disintegrate in 5 minutes in simulated gastric fluid while it is characterized in that the described core core being coated by described coating can 37 ℃.
37. according to the medication coat compositions of claim 26, disintegrate in 1 minute in simulated gastric fluid while it is characterized in that the described core core being coated by described coating can 37 ℃.
38. according to the medication coat compositions of claim 26, it is characterized in that medicine in described core core is extracted into the ratio that medicine in dissolution medium accounts for whole coating composition Chinese medicine and is not less than 80% in simulated gastric fluid from coating composition in 15 minutes in the time of can 37 ℃.
39. according to the medication coat compositions of any one in claim 1 to 4, it is characterized in that the described outer coating of covering accounts for described medication coat composition total weight 2～50%, by the coated core core that contains at least one medicine that has offending abnormal flavour of described coating, accounted for described medication coat composition total weight 50～98%.
40. 1 kinds of pharmaceutical preparatioies, is characterized in that the medication coat compositions that said preparation comprises any one in claim 1～39.
41. according to the pharmaceutical preparation of claim 40, it is characterized in that its dosage form be masticable tablet, oral liquid, rehydration be suspension powder, rapidly-soluble fast solvellae, lozenge, wafer, chewing gum, be equipped with powder/granule/small-sized or micro chip/liquid filler hard-shell capsule, there is liquid core or the soft-shelled gelatin body of filling by powder or granule, can at once discharge or conventional compressed tablets, confection and caked sugar form, aerosol cream, colloid or the pouch of delayed release.
42. according to the pharmaceutical preparation of claim 40, it is characterized in that its dosage form is chewable tablet.
43. according to the pharmaceutical preparation of claim 40, it is characterized in that its dosage form is soft chewable tablet.
44. according to the pharmaceutical preparation of claim 40, it is characterized in that its dosage form is liquid, aqueous suspending agent.
45. according to the pharmaceutical preparation of claim 44, and the pH value that it is characterized in that described liquid, aqueous suspending agent 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 alkaline pH medium higher than described.
46. according to the pharmaceutical preparation of claim 44, it is characterized in that in the coating of described liquid, aqueous suspending agent that all the components is at least saturated in this aqueous solution at 0～50 ℃ of temperature.
47. according to the pharmaceutical preparation of claim 44, it is characterized in that in the coating of described liquid, aqueous suspending agent that hydroaropic substance is at least saturated in this aqueous solution at 0～50 ℃ of temperature.
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| CN201010228164.1A CN101927002B (en) | 2010-07-16 | 2010-07-16 | Medicament and coating composition |
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| CN201010228164.1A CN101927002B (en) | 2010-07-16 | 2010-07-16 | Medicament and coating composition |
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| CN101927002B true CN101927002B (en) | 2014-03-12 |
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| CN103990132B (en) * | 2014-05-07 | 2016-03-30 | 北京化工大学 | A kind of method of acrylic resin mixing water dispersion taste masking preparation |
| CN104784144B (en) * | 2015-04-28 | 2016-01-20 | 清远华能制药有限公司 | A kind of cefadroxil coated tablet and preparation method thereof |
| CN105106131A (en) * | 2015-09-16 | 2015-12-02 | 青岛华之草医药科技有限公司 | Pharmic sildenafil citrate composition dry suspension for treating impotence of males |
| CN105496967B (en) * | 2015-12-22 | 2018-07-03 | 江苏苏南药业实业有限公司 | Ranitidine hydrochloride controlled release dry suspensoid agent and preparation method thereof |
| CN109310645A (en) * | 2016-06-17 | 2019-02-05 | 宝洁公司 | Soft chewing composition comprising semen plantaginis |
| AU2017322712B2 (en) * | 2016-09-08 | 2023-12-21 | Laila Nutraceuticals | Odor masking formulations for natural compounds |
| CN109718276B (en) * | 2019-03-22 | 2021-09-28 | 上海美优制药有限公司 | Compound liquorice oral solution and preparation method thereof |
| MX2023000708A (en) * | 2020-07-16 | 2023-02-14 | Nomad Bioscience Gmbh | Products for oral consumption with reduced sugar content. |
| CN113197867A (en) * | 2021-05-07 | 2021-08-03 | 济川(上海)医学科技有限公司 | Fexofenadine taste-masking granules, taste-masking composition and taste-masking preparation containing fexofenadine taste-masking granules, and preparation method and application of fexofenadine taste-masking granules |
| CN116139088B (en) * | 2023-01-31 | 2024-04-16 | 南京海纳医药科技股份有限公司 | Sildenafil citrate-containing dry suspension and preparation method thereof |
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| CN101522176A (en) * | 2006-08-14 | 2009-09-02 | 贝林格尔.英格海姆国际有限公司 | Formulations of flibanserin and method for manufacturing the same |
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| CN101522176A (en) * | 2006-08-14 | 2009-09-02 | 贝林格尔.英格海姆国际有限公司 | Formulations of flibanserin and method for manufacturing the same |
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