CN101919803A - A kind of controlled release preparation - Google Patents

Abstract

The controlled release preparation covered with film-coated clothing that the present invention has disclosed a kind of improved combination properties is the controlled release preparation that discharges of zero level particularly, and this controlled release preparation outer is overlying on to contain with the individual molecule state in the polymer release-control clothing film of the core material that contains medicine and/or on average be substituted number (or DS) with hydroxyl on the dispersive water miscible every glucose unit of micelle state and is not less than 5 cyclodextrin derivative.The present invention has disclosed the preparation method of this controlled release preparation.In the said preparation drug release receptor and external influence less relatively, drug release is very fast relatively, the time stickiness less relatively, drug bioavailability is higher, drug release storage-stable and production repeatability are enhanced; And the clothing film mechanical strength of preparation also is enhanced, or the like.

Description

A kind of controlled release preparation

Technical field

The present invention relates to a kind of controlled release preparation.More particularly, the controlled release preparation covered with film-coated clothing that the present invention relates to a kind of improved combination properties is the controlled release preparation that discharges of zero level particularly, and this controlled release preparation outer is overlying on to contain with the unimolecule state in the polymer release-control clothing film of the core material that contains medicine and/or on average be substituted number (or DS) with hydroxyl on the dispersive water miscible every glucose unit of micelle state and is not less than 5 cyclodextrin derivative.The invention still further relates to a kind of preparation method of controlled release preparation.

Background technology

Some insoluble polymers particularly pass through the coating control drug release in the controlled release preparation that zero level discharges at controlled release preparation.Because the water-insoluble of polymer, usually need in the clothing film, form permeability (permeability) that micropore improves clothing film be beneficial to the on the low side and preparation total surface area of the dissolubility of the infiltration of moisture and the release of medicine, particularly medicine than hour.

So far, this class technology has the representative of three classes, now is summarized as follows respectively.

The one, be representative with US4629619: this type of technology disperses water miscible porogen and is suspended in the organic solvent that contains insoluble polymer, by coating water-soluble substances is present in the clothing film of insoluble polymer, the water miscible porogen in this clothing film is formed bigger micropore by the Digestive system dissolving in digestive tract.When being preparations shaping, one of defective of this technology used organic solvent.A large amount of uses of organic solvent, will there be obvious limitation in technology: 1. dangerous, inflammable and explosive property is arranged; 2. there is harm in toxicity to environment and operator's health; 3. molten coal price lattice are expensive and reclaim difficult.So the necessary supporting explosion protection system of industrialization equipment, air pollution surveillance system and solvent recovery system.Technologic shortcoming is that coating solution viscosity is big, and solid content is low, the time-consuming power consumption of coating process, and the necessary residual quantity of controlling organic solvent in the product.

The 2nd, be representative with US5472712 and US5639476: this type of technology is dissolved in water miscible porogen in the aqueous dispersion (Aqueous polymeric dispersion) that contains insoluble polymer, by coating water-soluble substances is present in the clothing film of insoluble polymer, the water-soluble substances in this clothing film is formed very little micropore by the Digestive system dissolving in digestive tract.The advantage of this technology is to have avoided with an organic solvent.But many defectives are arranged also: the water solublity porogen exists in the clothing film with the unimolecule form, the pore size of micropore is limited by the molecular size of water solublity porogen, and the molecular size of most water solublity porogen and most drug molecule size are very nearly the same, even it is littler, so be unfavorable for penetrating of most medicine, applicable medicament categories and limited amount system.And, when the permeability of coating membrane can satisfy application request, particularly on the low side the and preparation total surface area of the dissolubility of medicine hour, its mechanical strength very a little less than; In addition, wayward when actual available coating membrane is produced, the production repeatability is relatively poor relatively.

The 3rd, US6974591 is representative: this type of technology is usually disperseed porogen water insoluble but that dissolve in the Digestive system of acidity or alkalescence and is suspended in the aqueous dispersion (Aqueous polymeric dispersion) that contains insoluble polymer, by coating porogen is present in the clothing film of insoluble polymer, the porogen in this clothing film is formed bigger micropore by the Digestive system dissolving in digestive tract.This technology combines the advantage of preceding two class technology to a certain extent, has also overcome the shortcoming of preceding two class technology to a certain extent.But the defective of this technology is quite a few: as, 1), what of the height of the acid or alkaline power of Digestive system or pH value and digestion liquid measure the dissolving of the formation of micropore or porogen be limited by, yet, how much usually coming and go of the height of the pH value of patient's Digestive system and digestion liquid measure, it is very many to influence its factor, as patient's body constitution, health, diet, the influence of patient's factor such as different time endogenous cause of ill physiological rhythm in a day for another example, the height of the pH value of Digestive system is also different; Even the power of peristalsis of the digest tract function also influences significantly in the formation of micropore or the dissolving of porogen, and the power of peristalsis of the digest tract function is subjected to the influence of more multifactor body constitution as the patient, health, diet and physiological rhythm etc. equally.2), the dissolving of the formation of micropore or porogen needs the relatively long time, the free list of medicine reveals relatively long time stickiness.3), the drug release of preparation (production) repeatability is or/and storage-stable is relatively poor.This technology also uses the solvable but water-insoluble polymer of some Digestive systems as porogen.It is compatible and compatible fully that these polymer porogen and the common great majority of the insoluble polymer clothing of Digestive system membrane material show as part.When two kinds of polymer are in contact with one another, at first moistening mutually at the interface, the phase counterdiffusion of biphase then macromolecular chain segment by warm-up movement, the result of diffusion makes two kinds of polymer produce the significant concentration gradient on the both sides, interface.This zone with obvious Concentraton gradient has constituted two alternate boundary layers.The thickness of boundary layer depends mainly on the compatibility of two kinds of polymer.Increase along with the compatibility, diffusion improves, and boundary is more and more fuzzyyer, and interfacial layer thickness is increasing, so that final boundary complete obiteration, become homogeneous blend, reach compatible fully (compatibility of polymer alloy and increase-volume, University Of Qingdao's journal, May nineteen ninety-five, the 10th volume, the 1st phase, the 91st page).Just because of this mutual scattering and permeating between polymer, interface prolongation in time between macromolecular porogen of result and clothing film becomes more and more fuzzyyer, the micropore that can form also in time prolongation becomes more and more fuzzyyer, it is non-constant that pore size also becomes, it is unstable that thereby the release behavior that makes medicine becomes, drug release storage-stable variation.Yet the two is complete when incompatible, can cause granulous porogen also will become stress concentration point in the clothing film again, becomes the weak link in the clothing film, and clothing film mechanical strength is significantly reduced.

In addition, with US4629619, US6974591 is the technology of representative, wherein with the polar small-molecule substance of Digestive system solubility as general porogen, with the insoluble non-polar polymer of Digestive system is general clothing membrane material, so it is very high biphase interface energy to occur during the two blend, the problem that the mutual compatibility and bonding force are very poor, the result causes and disperses inequality, granulous porogen also will become the stress concentration point in the clothing film, become the weak link in the clothing film, clothing film mechanical strength is significantly reduced.These drawbacks have not only limited the addition of porogen in the clothing film, but also have a strong impact on the formulation products performance.(China Light Industry Press publishes for " polymer chemistry and physics ", Wang Zijie chief editor, 1992 04 month the 1st edition, the 345th page; " surface of high polymer and interface ", Wu Renjie chief editor, Science Press (Beijing), the 104th～110 page; Surface Modification Of Inorganic Fillers, Jiangxi chemical industry, calendar year 2001, the 4th phase, the 17th～18 page).

Also it needs to be noted, with US4629619, US6974591 is the technology of representative, be the pore particle to be disperseed to be suspended in disperse in the solvent, because the effect of gravity, this suspension are prone to the Concentraton gradient that changes with height, in other words at differing heights, the concentration of particle is different, thereby make the quantity of the pore particle in the coating membrane between the preparation individuality difference occur, thereby the drug release between the preparation individuality is prone to the problem of production poor reproducibility.More seriously, between the different production batch, the mean diameter of pore particle is difficult to accomplish the same, even mean diameter is the same, the internal particle of pore particle distributes also can be different (be a certain particle diameter under number of particles with batch changing), and this will cause the problem that poor reproducibility appears in more serious thing release occurring between preparation batch.

Except above-mentioned technology, the technology employing is also arranged or attempt adopting water soluble Beta-cyclodextrin in the clothing film of controlled release preparation, to make porogen or pore former.For example, WO2001012163 includes water-soluble substanceses (making porogen) such as poly-(ethylene glycol) 3350 (PEG 3350), sorbitol, sucrose, polyhydric alcohol, xylitol, mannitol, carbohydrate, sugar, lactose, maltose, glucose, water soluble Beta-cyclodextrin, urea in the clothing film of the controlled release preparation of listing.For another example, WO0041704 prepares other osmotic tablet according to embodiment 2, and assesses their dissolution characteristic.Evaluated pore former comprises poly-(ethylene glycol) 3350 (PEG 3350), sorbitol, sucrose, polyhydric alcohol, xylitol, mannitol, carbohydrate, sugar, lactose, maltose, glucose, water soluble Beta-cyclodextrin and urea etc.But above-mentioned two technology are not described further or study the water soluble Beta-cyclodextrin of making porogen or pore former.

Therefore, also need the particularly controlled release preparation technology of preparing of zero level release of a kind of controlled release preparation in the reality, the advantage of above-mentioned prior art can be inherited or further be developed to this technology, can overcome many defectives of above-mentioned prior art again.

Goal of the invention

The controlled release preparation that main purpose of the present invention just provides a kind of improved combination properties is controlled release preparation of discharging of zero level and preparation method thereof particularly.The advantage of above-mentioned prior art can be inherited or further be developed to this preparation method, can overcome or alleviate many defectives of above-mentioned prior art again, as can be not with an organic solvent when the formulation preparation, it is less relatively to reach external influence in the said preparation drug release receptor, drug release is very fast relatively, the time stickiness less relatively, drug bioavailability is higher, drug release storage-stable and production repeatability are enhanced; And the clothing film mechanical strength of preparation also is enhanced, or the like.

Other purposes of the present invention see following description for details.

Summary of the invention

1), contain the core material of at least a medicine the controlled release preparation covered with film-coated clothing that the present invention also provides a kind of improved combination properties is the controlled release preparation that discharges of zero level particularly, and this controlled release preparation comprises:; 2), be overlying on the clothing film of above-mentioned core material outward, this clothing film include pharmaceutically acceptable be insoluble to or the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid and at least a with non-particulate form only with the unimolecule state and/or be scattered in the water miscible average substitution degree (DS) that allows on wherein any physiology with the micelle state and be not less than 5/n (the glucose unit number that contains in the circulus of n representative ring dextrin herein, n 〉=6 are positive integer) cyclodextrin derivative.

1), preparation contains the core material of at least a medicine the controlled release preparation covered with film-coated clothing that the present invention also provides a kind of improved combination properties is the preparation method of the controlled release preparation that discharges of zero level particularly, and this method comprises following several basic step:; 2), with include at least a following cyclodextrin derivative pharmaceutically acceptable be insoluble to or the aqueous dispersion of the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid to above-mentioned core material bag clothing film, above-mentioned cyclodextrin derivative is that the water miscible average substitution degree (DS) that allows on any physiology is not less than 5/n (the glucose unit number that contains in the circulus of n representative ring dextrin herein, n 〉=6, be positive integer) cyclodextrin derivative, above-mentioned cyclodextrin derivative all is dissolved in the aqueous dispersion of above-mentioned polymer; 3), in case of necessity, to above-mentioned clothing film heal (wearing out) handle.

That the term " clothing film " that the present invention uses is meant the hydrophobicity that contains q.s (polymer) material on the nuclear core outer surface that is coated on controlled release preparation and have sufficient mechanical strength and keep controlled release preparation its contained medicine or be in harmony the treatment activating agent when placing the not disruptive coating membrane of aqueous solution drug release process, this coating membrane can delay to discharge above-mentioned controlled release preparation to be placed in aqueous solution.

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

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

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

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

The specific embodiment

Porogen in the clothing film that the present invention relates to is the cyclodextrin derivative that the water miscible average substitution degree (DS) that allows on any physiology is not less than 5/n (the glucose unit number that contains in the circulus of n representative ring dextrin, n 〉=6 are positive integer) herein.

The present invention's term " porogen " used herein is meant and helps to form the hole or improve the permeability of clothing film or the material of water permeability in clothing film of the present invention, porogen is can be from clothing film in applied environment dissolved or leach (dissolved, extracted or leached) and come out and form the hole.

The present invention's term " water solublity " used herein is meant that the dissolubility (25 ℃ of temperature) in water is not less than 30mg/ml, preferably is not less than 100mg/ml, more preferably is not less than 500mg/ml, is not less than 1000mg/ml best.

Cyclodextrin has circulus, and known have multiple homologue (containing in the ring as 6-12 glucose unit), and they are the cyclic compounds that are formed by connecting by α-1,4 glycosidic bond.Prove that through X-ray diffraction and nuclear magnetic resonance research the stereochemical structure of cyclodextrin is last narrow wide both ends open ring-type hollow circle tube down.Its primary hydroxyl group is positioned at a little end opening place, cavity, and secondary hydroxyl group is arranged in a big end opening place, cavity (" novel pharmaceutical formulation and new technique ", Lu Bin, People's Health Publisher, April in 1998 the 1st edition, the 29th page).Three kinds common contains glucose unit to count the cyclodextrin of minimum is alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, their (bobbin) outer circumference diameter is respectively 1.46nm, 1.54nm, 1.75nm, (bobbin) ring highly is 0.79nm (" pharmaceutic adjuvant handbook, Handbook of Pharmaceutical Excipients " (original work the 4th edition), sieve R.C., P.J She Siji, P.J. Wei Le compiles, and Zheng Jun democracy is translated, Chemical Industry Press, January in 2005 the 1st edition, the 220th page).Obviously, the outer circumference diameter of these cyclodextrin is more many greatly than general water-soluble porogen such as sodium chloride (diameter 0.28nm), potassium chloride (diameter 0.32nm), glucose (diameter 0.72nm), aminoacid (diameter 0.66nm), carbamide (diameter 0.32nm) etc., some deficiency but its bobbin ring height (or pipe range) seems is used and is subjected to certain restriction.

Wish not exclusively to be limited by following theory or principle.Because primary alconol, secondary hydroxyl group all are positioned at bobbin openings at two ends place, cavity and can be replaced by other groups, so at least 5 (or 9) hydroxyls are replaced by other long and/or bigger groups in the bobbin structure of cyclodextrin, at least one side of bobbin structure that just can guarantee cyclodextrin has the individual hydroxyl of 3 (or 5) to be substituted that (3 or more a plurality of substituted radical can surround a bobbin, 5 or more a plurality of substituted radical can surround the bobbin of rounding more), the bobbin structure that is equivalent to cyclodextrin like this is extended and/or periphery is exaggerated.Hydroxyl in the bobbin structure is replaced manyly more by other groups, and the bobbin that is extended is got over rounding; Substituted radical is long more, and bobbin ring height (or pipe range) prolongs manyly more; Substituted radical is big more, and the bobbin ring amplifies manyly more; When being replaced abundantly by other groups, the hydroxyl in the bobbin structure (is substituted if any being not less than the individual hydroxyl of 2n+5 (or 3), bobbin structure has the individual substituent group in 5 (or 3) at least than small end, individual n substituent group is arranged at most, the bigger end of bobbin structure has the individual substituent group of n+5 (or 3) at least, individual 2n substituent group is arranged at most, the glucose unit number that contains in the circulus of n representative ring dextrin herein), the bobbin two ends all can more intactly be extended.Thereby this kind cyclodextrin derivative can form longer bigger pipeline after the clothing film stripping.Therefore, be scattered in water soluble cyclodextrin derivant that the many groups of clothing film replace with molecularity and make porogen and generally comprise that with the water-soluble porogen that molecularity is scattered in clothing film other conventional cyclodextrin have more bigger advantages with this.For example 1), can obtain longer bigger duct, help penetrating of bigger drug molecule, thereby the medicine kind number of limited use reduces, rate of releasing drug increases, higher in other words bioavailability; For another example 2), owing to can obtain longer bigger duct, the mechanical performance of clothing film will strengthen.In addition, because cyclodextrin derivative is water miscible, can be dissolved in rather than suspendible be scattered in the preparation clothing film aqueous polymer dispersion in, be scattered in the clothing film with molecular forms, so also have superiority: 3), promptly can avoid when producing with an organic solvent improving the mechanical performance (as carrying the porogen that relates to) of clothing film again with respect to US5472712 and US5639476; 4), can also overcome or significantly (as the influence of the intestines and stomach pH value) in the ameliorate body, externally (thereby be subjected to weight to influence skewness because of the solvent in the water insoluble dispersion during as preparation and then make the rate of releasing drug inequality, thereby during storage between polymer mutually diffusion make the rate of releasing drug instability) all multifactor influence to the medicine stripping, overcome or significantly alleviate thing and discharge and the production repeatability occurs or/and storage-stable variation (as carrying the porogen that relates to) with respect to US-6974591 or US4629619; 5), can also significantly reduce the time stickiness (as carry the porogen that relates to respect to US-6974591) that the free list of medicine reveals.

As the porogen in the clothing film, can use the water miscible average substitution degree (DS) that allows on any physiology to be not less than (3+2k among the present invention ₁)/n preferably is not less than (3+2k ₂)/n more preferably is not less than (2n+k ₃)/n is not less than (2n+k best ₄The cyclodextrin derivative of)/n, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin, n 〉=6 (preferably, 7≤n≤12, more preferably, and 9≤n≤12), 1≤k ₁≤ 3 (n-1)/2,3≤k ₂≤ 3 (n-1)/2,3≤k ₃≤ n, 5≤k ₄≤ n, n, k ₁, k ₂, k ₃, k ₄Be positive integer, its value is the bigger the better, substituted radical on the glucose unit in this cyclodextrin derivative includes but not limited to hydroxyalkyl, alkyl carboxyl, the carboxyl alkoxyalkyl, alkyl carboxylic oxygen base alkyl, the alcoxyl carboxyalkyl, hydroxy alkoxy alkyl, alkyl amine group, alkyl cation (as the quaternary ammonium alkyl ion), the alkyl anion is (as alkylsurfuric acid and salt thereof, alkyl sulfonic acid and salt thereof, alkyl phosphoric acid and salt thereof, alkyl phosphorous acid and salt thereof, alkyl phosphonic acid and salt thereof, phostonic acid and salt thereof, alkylthio phosphoric acid and salt thereof, described salt preferably is selected from Na salt, K salt, Li salt and/or NH ₄Salt), glycosyl (preferably being oligosaccharyl) and their mixed group.Substituted radical in the above-mentioned cyclodextrin derivative preferably also contains the lipophilic group of some, as unsubstituted alkyl, cycloalkyl, aralkyl and their mixed group, be insoluble to or the polymer affinity or the compatibility water-soluble hardly and harmonization of the stomach intestinal digestion liquid to improve contain in above-mentioned cyclodextrin derivative and the above-mentioned clothing film pharmaceutically acceptable, be beneficial to improve the mechanical performance of clothing film; In addition, also help and prevent or slow down these water-soluble substanceses and under the dampness effect, from polymeric film, separate out (promptly so-called " scum " phenomenon) because of the compatibility is very poor, help preventing or slow down discharging repeatability or bad stability, because of water-soluble substances stays micropore after separating out easily from polymeric film, micropore dwindles under effects such as surface tension and other factors such as steam or healing fully, thereby makes the release behavior of medicine become unstable.The quantity of above-mentioned lipophilic group accounts for the 0.5-50% of the whole substituted radical quantity of above-mentioned cyclodextrin derivative, preferably 2-30% usually.In above definition, term " alkyl " means usually and comprises and contain 1-30, preferably 3-24, more preferably 4-20, the alkyl of the saturated or unsaturated straight or branched of 6-18 carbon atom best, preferably be saturated hydrocarbyl, for example methyl, ethyl, 1-Methylethyl, 1,1-dimethyl ethyl, propyl group, 2-methyl-propyl, butyl, amyl group, hexyl, octyl group, decyl, dodecyl, myristyl, cetyl, octadecyl etc.In above definition, " average substitution degree (DS) is represented substituted average number of hydroxyl in each glucose unit to term, because each glucose unit of cyclodextrin is 2,3,6 all have three hydroxyls is to utilize, so DS is 3 to the maximum.

One is preferred for cyclodextrin derivative example of the present invention and is, at the described ethers cyclodextrin derivative that satisfies above-mentioned definition of Drugs Future:9 (8) 577-578 (1984), for example satisfy hydroxypropyl-cyclodextrin, hydroxyl butyl-cyclodextrin, hydroxyethyl-cyclodextrin and side chain (branching) cyclodextrin derivative (as glucosyl group cyclodextrin, didextrose basic ring dextrin, three glucityl cyclodextrin, malt-base cyclodextrin, two malt-base cyclodextrin, three Fructus Hordei Germinatus glycosyl cyclodextrin) of above-mentioned definition and composition thereof as M.Nogradi.Specially suitable example is as 2-ethoxy-cyclodextrin, 2-hydroxypropyl-cyclodextrin and (2-carboxyl methoxyl group) propyl group-cyclodextrin of satisfying above-mentioned definition, didextrose basic ring dextrin, three glucityl cyclodextrin, two malt-base cyclodextrin, three Fructus Hordei Germinatus glycosyl cyclodextrin and composition thereof.Particularly preferred example of this apoplexy due to endogenous wind is the hydroxyl cyclobutenyl ether ring dextrin that satisfies above-mentioned definition, as described in WO-2001/044305.

Another preferably can be used for cyclodextrin derivative example of the present invention as satisfying the polyethers cyclodextrin derivative of above-mentioned definition, for example described in the U.S. Pat 3459731.For preparing them, usually unsubstituted cyclodextrin and oxyalkylene are reacted in the presence of base catalyst, preferably under superatmospheric pressure He under the high temperature, react.Because the hydroxylic moiety of cyclodextrin can be oxidized alkene replace, and oxyalkylene itself can with another oxyalkylene molecular reaction, so represent measuring of substituting agent average mol in each glucose unit with molar average substitution value (MS) in the present invention.MS can be greater than 3, in theory without limits.Be used for the polyethers cyclodextrin derivative of the present composition, MS is generally 1.5 to 24, preferably is 2 to 12, more preferably is 3 to 9.

One more preferably is applicable to the present invention, and the example that particularly is applicable to medicine for external use is the Quaternised ammonium cyclodextrin derivant (QACD) that satisfies above-mentioned definition, as US-524109, and US-3453257, WO-2003/105867 is described.An one instantiation is as satisfying chlorination 3-(the trimethyl ammonium)-2-hydroxypropyl-beta-schardinger dextrin-of above-mentioned definition.

One is applicable to that more preferably example of the present invention is as sulphur butyl (ether) cyclodextrin that satisfies above-mentioned definition and salt thereof such as sodium salt, potassium salt, as described in US-5134127-A.

One is applicable to that especially preferably example of the present invention is the cyclodextrin that contains sulfoalkyl ether base and alkylether radicals (SAE-AE-CD) derivant that satisfies above-mentioned definition, preferably, for the average substitution degree (DS) of the sulfoalkyl ether base that satisfies above-mentioned definition be not less than 3/n and be not higher than 3 and the average substitution degree (DS) of alkylether radicals be not less than 2/n and be not higher than 3 cyclodextrin (SAE-AE-CD) derivant, more preferably, for the average substitution degree (DS) of the sulfoalkyl ether base that satisfies above-mentioned definition be not less than 5/n and be not higher than 3 and the average substitution degree (DS) of alkylether radicals be not less than 4/n and be not higher than 3 cyclodextrin (SAE-AE-CD) derivant, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin.Its preferred instantiation is as satisfying above-mentioned definition:

SBEx-Mey-β-CD, SBEx-Ety-β-CD, SBEx-Pry-β-CD, SPEx-Mey-β-CD, SPEx-Ety-β-CD, SPEx-Pry-β-CD, SEEx-Mey-β-CD, SEEx-Ety-β-CD, SEEx-Pry-β-CD, SPtEx-Mey-β-CD, SPtEx-Ety-β-CD, SPtEx-Pry-β-CD, SHEx-Mey-β-CD, SHEx-Ety-β-CD, SHEx-Pry-β-CD, SBEx-Ety-γ-CD, SBEx-Pry-γ-CD, SBEx-Mey-γ-CD, SPEx-Mey-γ-CD, SPEx-Ety-γ-CD, SPEx-Pry-γ-CD, SEEx-Mey-γ-CD, SEEx-Ety-γ-CD, SEEx-Pry-γ-CD, SPtEx-Mey-γ-CD, SPtEx-Ety-γ-CD, SPtEx-Pry-γ-CD, SHEx-Mey-γ-CD, SHEx-Ety-γ-CD, SHEx-Pry-γ-CD, and composition thereof, wherein, 5≤x≤21 are (for β-CD) or 24 (for γ-CD), 4≤y≤21 are (for β-CD) or 24 (for γ-CD), above-mentioned symbol and abridge as follows: CD: cyclodextrin, SBE: sulfo group butyl ether, SPE: sulfo group propyl group ether, SEE: sulfo group ethyl ether, SPtE: sulfo group amyl group ether, SHE: sulfo group hexyl ether, Et: ethyl ether, Me: methyl ether, Pr: propyl group ether, x, y represents each substituent substitution value.

The cyclodextrin derivative that most preferably is fit to use among the present invention is, discloses as WO-96/20222, satisfies the sulfate cyclodextrin derivative of the senior alkyl of above-mentioned definition.The average substitution degree (DS) that it is characterized in that its senior alkyl be not less than 3/n and be not higher than 3 and sulphuric acid alkali average substitution degree (DS) be not less than 2/n and be not higher than 3, preferably, the average substitution degree of its senior alkyl (DS) be not less than 5/n and be not higher than 3 and sulphuric acid alkali average substitution degree (DS) be not less than 4/n and be not higher than 3, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin.Senior alkyl described herein is generally lipoid, aliphatic series or the aromatics carbochain that carbon number is C6-C30.Carbochain described herein preferably is a linear carbon chain, its general expression preferably is-OC (=O)-(CH ₂) _n-CH ₃, wherein n is at least 6, preferably be 6-24 and/or-OC (=O)-(CH ₂) _m-CH=CH-(CH ₂) _m-CH ₃, wherein m is at least 6, preferably is 6-24; Preferably be-OC (=O)-(CH ₂) ₁-CH ₃, wherein 1 is 6-24.The preferred embodiment of above-mentioned Linear Carbon chain type is-OC (=O)-(CH ₂) ₁₀-CH ₃And-OC (=O)-(CH ₂) ₇-CH=CH-(CH ₂) ₇-CH ₃Linear carbon chain.Above-mentioned cyclodextrin derivative, its sulfate group is-OSO ₃R, wherein, R is for forming the atom and/or the molecule of univalent cation, and R preferably is selected from H, Na, K, Li and/or NH ₄Above-mentioned cyclodextrin derivative, the preferable hydroxyl that contains, wherein the merging sum of senior alkyl, sulfate group and hydroxyl is no more than N, further is that wherein N is the hydroxyl value that obtains the cyclodextrin of derivant from it.Preferred embodiment is as satisfying the sulphuric acid sodio of above-mentioned definition _x-dodecyl (Laurel) _y-β (or γ)-cyclodextrin, sulphuric acid ammonium _x-spiny dogfish alkyl _y-β (or γ)-cyclodextrin, sulphuric acid potassio _x-cetyl _y-β (or γ)-cyclodextrin, and composition thereof, wherein, the index number x of group, y are its substitution value, ((for γ-CD), 5≤y≤21 are (for β-CD) or 24 (for γ-CD) for β-CD) or 24 in 4≤x≤21.

At for example chemistry and pharmacy circular 28:1552-1558 (1980), the pharmacy skill is reported NO.6452 (March 28 nineteen eighty-three), the international English edition 19:344-362 (1980) of applied chemistry, US-3459731, EP-A-0149197, EP-A-0197571, US-4535152 has narrated other cyclodextrin among WO-90/12035 and the GB-2189245.Other is addressed the cyclodextrin that is used for the present composition and provides the list of references of preparation, purification and analysis of data about cyclodextrin to comprise: " cyclodextrin technology ", Jozsef Szejtii, Kluwer Academic Publishers (1988), wherein a chapter " cyclodextrin in the medicine "; " cyclodextrin chemistry ", M.L.Bender etc., Springer-Verlag, Berlin (1978); " carbohydrate chemistry progress ", the 12nd volume, M.L.Wolfrom compiles, Academic press, New York, a chapter " schardinger dextrin " DexterFrench wherein, 189-260 page or leaf; " cyclodextrin and contain complex ", J.Szejtli, Akakemiai Kiado, Budapest, Hungary (1982}; I.Tabushi is at chemical research report (Acc.Chem.Research) 1982,15, P66-72; W.Sanger is at applied chemistry (AngeWandte Chemie) 92, P343-361 (1981); A.P.Croft and R.A.Bartsch be at tetrahedron (Tetra-hedron), and 39, P1417-1474 (1983); Irie etc. are at study of pharmacy (Pharmaceutical Research), 5, P713-716 (1988); Pitha etc. are in Inpharm magazine (Int.J.Pharm.), 29,73, (1986); DE-3118218; DE-3317064; EP-A-94157; US-4659696; US-43839920; Quaternised ammonium cyclodextrin derivant (QACD) (US-524109, US-3453257, WO-2003/105867); The polymer and their preparation method (Comprehensive Supra molecular Chemistry, the 3rd volume, editors such as J.L.Atwood, Pergamon Press (1996)) that contain cyclodextrin; U.S. Pat-5608015.

Usually, low water soluble cyclodextrin derivant or the unsubstituted water soluble Beta-cyclodextrin that replaces of water soluble cyclodextrin derivant that does not contain the height replacement of (as the amount that accounts for the whole substituted radical of above-mentioned cyclodextrin derivative is not higher than 25%) lipophilic group or that the lipophilic groups mass contg is lower, help stoping hydrophobic group on the polymer chain to enter cavity (cave) in the cyclodextrin derivative molecule, help cyclodextrin derivative stripping from clothing film (polymer), thereby reduce the drug release time lag time of preparation.

If possible, cavity (cave) in employed water miscible cyclodextrin derivative among the present invention (normally the height of higher (as the amount that accounts for the whole substituted radical of above-mentioned cyclodextrin derivative is higher than 50%) of lipophilic groups mass contg replace the water soluble cyclodextrin derivant) molecule preferably " is taken " by in advance, be water miscible cyclodextrin derivative enclose in advance, can reduce the time lag time (lag time) of the drug release of controlled release preparation like this.Wish not exclusively to be limited by this theory or principle, because of the cavity (cave) in the water miscible cyclodextrin derivative molecule can " be taken " by the hydrophobic group on the polymer chain in the clothing film, be that hydrophobic group on the polymer chain enters the cavity (cave) in the cyclodextrin derivative molecule, the time of cyclodextrin derivative stripping from clothing film (polymer) is extended even the stripping difficulty, thus stickiness when making the certain drug release of preparation performance.Above-mentioned water miscible cyclodextrin derivative usually by its pharmaceutically acceptable material of energy enclose, as the medicine in the core material and/or pharmaceutically receptible adjuvant such as preferred fat-soluble adjuvant enclose in advance.Be can be used as immediate release section by first release by the medicine in the core material of its enclose.Suitable is used for by the adjuvant example of enclose such as vegetable and animals oils lipid, semi-synthetic oils and fats, natural or artificial wax class, senior fat (C8-C24) acid, senior fat (C8-C24) acid esters and senior alkyl (C8-C24) alcohol, senior alkyl (C8-C24) ether, polyoxyethylene senior alkyl (C8-C24) ether (as polyoxyethylene oleyl ether), the senior fat of sorbitan (C8-C24) acid esters (spans), the senior fat of polyoxyethylene sorbitol acid anhydride (C8-C24) acid esters (Tweens), the senior fat of polyoxyethylene (C8-C24) acid esters is (as polyoxyethylene monooleate, polyethyleneglycol or two stearate) and composition thereof.Preferred exemplary fat-soluble adjuvant includes but not limited to cetyl esters wax, sorbitan mono-laurate, anhydrous sorbitol list myristinate, sorbitan monostearate, PGML, propylene glycol list myristinate, propylene glycol monopalmitate, propylene glycol monostearate, the anhydrous sorbitol monopalmitate, capryl alcohol, decanol, lauryl alcohol, tetradecyl alchohol, hexadecanol, octadecanol, cetomacrogol emulsifying wax, emulsifing wax, lauric isopropropanolamide, sad, capric acid, dodecylic acid, tetradecanoic acid, hexadecanoic acid, octadecanoid acid, ethylene glycol monostearate, self-emulsifying monostearate, the diethylene glycol monolaurate, microwax, glyceryl monostearate, coconut monoethanolamide, monocaprin, hydrogenated vegetable oil, cera alba, yellow beeswax, the glycerol monopalmitate, butyl p-hydroxybenzoate behenic acid, Brazil wax, Cera Chinensis, cholesterol ester stearic acid, terpene resin, castor oil hydrogenated, the cholesterol cetylate, propyl p-hydroxybenzoate, dodecyl gallate, gallateoctylester, volatile oil, fatsoluble vitamin, cholic acid and derivant thereof, and composition thereof.

Porogen be the above-mentioned consumption of cyclodextrin derivative in clothing film thus in the technical field technical ability those skilled in the art according to the character of medicine and desired rate of releasing drug decision.Porogen is that the consumption of above-mentioned cyclodextrin derivative is usually according to decisions such as the kind of its particle diameter, clothing film polymer and consumption thereof, the character of medicine, desirable rate of releasing drug, be generally 0.5%～80% (weight ratio), 1%～60% (weight ratio) preferably, preferably be 3%～50% (weight ratio), more preferably be 5%～40% (weight ratio), this is based on the dry weight of clothing film component.

Because the consumption of porogen is the principal element of the porosity of influence or decision clothing film, therefore, the porosity of clothing film is usually located at 0.5%～80%, preferably 1%～60%, preferably be 3%～50% (, more preferably be 5%～40%.Term used herein " porosity " is meant that the left space of porogen dissolving or degraded back in the clothing film accounts for the ratio of the volume of former complete clothing film.For simple and Convenient Calculation, and because of the dissolving or the degraded of porogen do not influence the inherent or external size of former clothing film, " porosity " also can account for the ratio of the weight of whole former clothing film with the weight of the porogen in the clothing film and represent approx.So " porosity " can be calculated with following two kinds of computing formula in the present invention:

Formula 1:

Formula 2:

Be fit to that pharmaceutically acceptable in the clothing film of the present invention is insoluble to or the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid can be generally hydrophobic polymer for pharmaceutically acceptable water-insoluble or almost water-insoluble block polymer or the copolymer that is scattered in the aqueous solution.Suitable polymers can be selected from but be not limited to be insoluble to or cellulose esters, acrylic acid (ester) base polymer, polyvinyl acetate esters, polyvinyl chloride and the compositions thereof of water-soluble hardly and harmonization of the stomach intestinal digestion liquid.The suitable polymers example of preferred example includes but not limited to ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, the lacceroic acid cellulose, three Palmic acid celluloses, the disuccinic acid cellulose, two Palmic acid celluloses, polyvinylacetate, methacrylic acid (ester) polymer, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, Merlon, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, vinyl acetate-vinyl chloride copolymer, polrvinyl chloride, polyethylene, polyisobutylene, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride); Wherein, preferred cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate); More preferably cellulose acetate.This is because they have stronger mechanical performance.

Can adopt the commercial latex of supplying of above-mentioned polymer, pseudo-latex and emulsion bag clothing film, (EC) has as ethyl cellulose:

With

Acrylic resin has:

RE30D reaches

RL30D, acetate fiber rope (CA) has: CA398-10 latex, polyvinyl acetate has: Kollicoat SR 30D and KOLLIDON SR.

Another adoptable example contains the aqueous dispersion coating solution of the terpolymer of 80～95% polrvinyl chloride, 0.5～19% polyvinylacetate and 0.5～10% polyvinyl alcohol for US4557925 provided.

Another available example is the aqueous dispersion coating solution that contains 50～100% polrvinyl chloride and 0～50% polyvinylacetate copolymer.

The ratio of clothing film polymer in drying is according to the kind of selected polymer, the kind and the decisions such as consumption, the character of medicine, selected dosage form and desirable release pattern thereof thereof of porogen, be generally 20%～99.5% (weight ratio), 40%～99% (weight ratio) preferably, 50%～97% (weight ratio) more preferably, 60%～95% (weight ratio) best, this is based on the dry weight of clothing film component.

For mechanical performance and the drug release stability that improves or strengthen clothing film, the dimensional stability and the intensity of the toughness of the glassy state that polymer occurs when especially improving temperature and being lower than its glass transition temperature (Tg) and impact resistance and/or the elastomeric state that polymer occurs when improving temperature and being higher than its glass transition temperature (Tg), the present invention can add mechanical performance improving agent such as the reinforcing agent of polymer and/or flexibilizer at clothing film.

Can be used for reinforcing agent of the present invention and include but not limited to pharmaceutical acceptable fillers reinforcing agent, fiber enhancer and composition thereof.

The appropriate filler reinforcing agent can be the rigid inorganic particle and the rigidity organic filler of surface modification.The rigid inorganic particle includes but not limited to the thin or ultra-fine grain of carbonate, Sulfates, metal-oxide, metal powder, carbon element chemical compound, silicon-containing compound and composition thereof.Rigid inorganic particle preferred examples includes but not limited to attapulgite, soap clay, calcium carbonate, calcium sulfate, barium sulfate, white carbon black, silicon dioxide, kaolin, Muscovitum, Talcum, calcium phosphate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium trisilicate.The mean diameter of above-mentioned inorganic particulate is usually less than (containing) 1 μ m, preferably less than (containing) 400nm, more preferably less than (containing) 100nm, more more preferably less than (containing) 20nm, best less than (containing) 5nm.Nano level particle (less than 100nm) can improve intensity, toughness, impact resistance and dimensional stability simultaneously, is preferred therefore.Above-mentioned inorganic particulate has preferably been handled with surfactant such as fatty acid, resinic acid and salt thereof, ester or with coupling agent treatment such as silane coupler or on particle surface as utilize the anhydride chemistry to connect to widen molecule or other suitable methods have carried out surface modification.Wherein, above-mentioned inorganic particulate is handled with surfactant such as fatty acid, resinic acid and salt thereof, ester and is carried out surface modification for more preferably.Rigidity organic filler preferred examples includes but not limited to polymethyl methacrylate (PMMA), polystyrene (PS), methyl methacrylate/styrol copolymer (MMA/ST) and styrene/acrylonitrile copolymer (SAN).

Can be used for fiber enhancer of the present invention and comprise pharmaceutically acceptable inorfil, organic fiber and metallic fiber.Inorfil is to be the chemical fibre that raw material is made with the mineral, available example such as glass fibre, quartz glass fibre, boron fibre, ceramic fibre and metallic fiber etc.Available organic fiber example such as synthetic fibers such as aramid fiber, Orlon fiber, polyester fiber, nylon fiber, vinylon fiber, polypropylene fibre, polyimide fiber etc.; Natural organic fiber such as cotton fiber, sisal fiber, the wood fiber etc.The example of metallic fiber is as metal synthetic fibers such as silver, copper, nickel.With natural organic fiber, metallic fiber serves as preferred.

Flexibilizer can have the composite of reduction fragility and improve the composite shock resistance.Can be used for of the present invention can for endurable active toughener also can nonactive flexibilizer class.Endurable active toughener be meant contain on its strand can with matrix resin reactive activity group, it can form network structure, increases a part of flexible chain, thereby improves the shock resistance of composite.Then to be that a class and matrix resin are fine mix but do not participate in the flexibilizer of chemical reaction nonactive flexibilizer.In order with organism the compatibility preferably to be arranged and to reduce production costs, nonactive flexibilizer is preferred.

Be used for flexibilizer of the present invention and can be suitable rubber-like flexibilizer, thermoplastic elastomer (TPE) class flexibilizer and other flexibilizer and composition thereof.The example of rubber-like flexibilizer such as liquid polysulfide rubber, liquid polybutadiene rubber, acrylonitrile-butadiene rubber, EP rubbers and butadiene-styrene rubber etc.A thermoplastic elastomer (TPE) normally class shows caoutchouc elasticity, synthetic material that at high temperature again can plasticizing forming at normal temperatures.The example of thermoplastic elastomer (TPE) includes but not limited to polyurethanes, phenylethylene, TPO, polyesters, a rule 1,2-polybutadiene and polyamide-based etc., preferred polyester class and TPO.Other flexibilizer includes but not limited to Versamid and low molecular nonactive flexibilizer, as the phthalic acid esters.

Preferably, the present invention can add flexibilizer and reinforcing agent simultaneously at the aqueous dispersion suspension, to obtain the clothing film of very good mechanical properties more comprehensively.

The common consumption 0.5%～40% of mechanical performance improving agent (weight ratio), preferably 1%～25%, more preferably 2%～15%, this is based on the dry weight of clothing membrane component.

In the coating solution that the present invention relates to, can add the universal additive material.The addition of universal additive material in the drug coating layer and application are that the professional is familiar with.General additive comprises but is not limited to antitack agent (separating medium), stabilizing agent, pigment, defoamer, antioxidant, short penetrating agent, polishing material, spice or flavoring agent.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.They add before processing in the polymer of preparation, can influence the permeability of clothing layer, and this can be used as additional adjusting parameter equally.

Soluble but being described below of commonly used additive in water-insoluble clothing film and the clothing film of Digestive system.

Plasticizer

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

Can utilize in case of necessity that plasticizer of different nature is for example water miscible, in the water in indissoluble or the water insoluble plasticizer regulate the rate of releasing drug of clothing film.

Plasticizer is typically liquid substance or low-melting solid matter of high boiling point, low volatility and micromolecule (Mr is about 150～800, preferably is 300～500) that can be miscible with polymer.The example of accessible plasticizer such as physiology compatible by C ₆～C ₄₀(preferred C ₆～C ₃₀, preferred especially C ₁₀～C ₁₆) aliphatic or aromatic series one is to tricarboxylic acid and C ₁～C ₈(preferred C ₂～C ₆, preferred especially C ₂～C ₅) the lipophilic ester that forms of aliphatic alcohol.The example of this plasticizer such as dibutyl phthalate, diethyl phthalate, dibutyl sebacate, ethyl sebacate, citric acid triethyl group ester, acetyl triethyl citrate, glycerol triacetate, tributyl certain herbaceous plants with big flowers two acid esters, Isosorbide Dinitrate, sucrose ester.The example of other accessible plasticizers such as glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini.

Plasticizer dosage is according to the character of desired clothing film, as glass transition temperature, mechanical performance etc., the kind of plasticizer, the kind of film former (being the water-insoluble film forming polymer), consumption etc. and decide, usually consumption is 5～50% (weight ratios), preferred 10～40% (weight ratios), preferred especially 10～30% (weight ratios), this is based on the dry weight of clothing membrane component.

Antitack agent (separating medium)

Antitack agent (separating medium) is generally useful hydrophobic material, and spray in the suspension general the adding.They stop the gathering of examining between film forming stage.The preferred Talcum that uses, magnesium stearate or calcium stearate, the silicic acid of porphyrize, Kaolin or HLB value are 3～8 nonionic emulsifier.Common consumption in clothing layer of the present invention is 0.5～100% (weight ratio) of polymer.In particularly advantageous embodiment, separating medium adds as final coating with conc forms.Undertaken by spraying coated with powder type or by the suspension of 5～30% solid contents.The amount of requirement when being manufactured in the polymeric layer lacked, and accounts for 0.1～2% of pharmaceutical dosage form weight.

Stabilizing agent

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

Pigment

Be generally used in the clothing film.Seldom add with the solubility pigment form.Generally aluminium oxide or iron oxide pigment are disperseed to add.Titanium dioxide is as Chinese white.The addition of pigment is 20～60% (weight ratios) of polymeric blends in clothing layer of the present invention.Yet because pigment binding ability height, addition also can be as high as 100% (weight ratio).

Defoamer

Defoamer is typically dimethicone.

In the particularly advantageous embodiment, directly be used as final coating with conc forms.Carry out coated with powder morphology or with the aqueous suspension spraying of 5～30% solid contents.Requirement is lower than the consumption when being manufactured in the polymeric layer, accounts for 0.1～2% of pharmaceutical dosage form weight.

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

Explain with regard to core material below.

Can be used for sheet, granule, ball, crystal, medicine carrying resin that core material of the present invention includes but not limited to rule or irregular form.Granule, ball or crystalline size are generally 0.01～2.5mm, and the size of sheet is usually at 2.5～30mm.They contain the bioactive substance (or active substance) that is up to 95% and other pharmacy auxiliary agent that is up to 99.9% (weight ratio) usually.

Being used for active component of the present invention (or medicine or bioactive substance) has no particular limits usually.As the used active component of the present invention, can be above-mentioned any pharmaceutically or the threpsology on have material therapeutical effect or preventive effect.The available active component example of the present invention is listed below:

-medicine for central nervous system:

-central stimulants: idebenone, phendimetrazine, piracetam, pyritinol, vinpocetine, dimefline, aniracetam, meclofenoxate, caffeine, modafinil, pentetrazole.

-analgesic: bucinnazine, buprenorphine, dihydroetorphine, floctafenine, dicentrine, codeine, rotundine, morphine, Ergotamine, meptazinol, methadone, nefopam, Pethidine, piminodine, oxycodone, hydromorphinol, tramadol, sumatriptan, tetrahydropalmatine, dextropropoxyphene, dextromethorphan, levorphanol, levomoramide.

-antipyretic analgesic: aspirin, acetaminophen, phenacetin, oxyphenbutazone, tiaramide, magnesium salicylate, imidazole salicylate, isopropylantipyrine.

-anti-inflammation analgesia medicine: alminoprofen, acemetacin, azapropazone, ampiroxicam, orgotein, olsalazine, benorylate, pirprofen, ibuprofen, bucillamine, aceclofenac; bufexamac; diflunisal; fenbufen; flurbiprofen; flufenamic acid; Guacetisal; clidanac; mefenamic acid; meclofenamic acid; aurothioglucose; auranofin; leflunomide; clofenamic acid; loxoprofen; Aristolochic Acid; meloxicam; mesalazine; nabumetone; naproxen; niflumic acid; etodolac; zaltoprofen; guaiazulene; etofenamate; isoxicam; ketoprofen; tenoxicam.

-antigout drug: glucosamine, benzbromarone, allopurinol, colchicine, probenecid, irtemazole.

-antiparkinsonian drug: benzhexol, biperiden, doreptide, entacapone, amantadine, carbidopa, quinagolide, rasagiline, memantine, selegiline, tolcapone, bromocriptine, levodopa, mofegiline, moxifensine, pareptide, donepezil.

-psychosis: alizapride, anisopirol, azaperone, amperozide, amisulpride, ocaperidone, oxaflumazine, oxypertine, prochlorperazine, fluphenazine, haloperidol, droperidol, flupentixol, fluspirilene, risperidone, rimcazole, tiapride, thioridazine, clozapine, clopipazan, clopenthixol, chlorprothixene, loxapine, mosapramine, nemonapride, pipotiazine, pimozide, pramipexole, remoxipride, sulpiride, penfluridol, zotepine, bromperidol, olanzapine.

-antianxiety drugs: alprazolam, estazolam, buspirone, flutazolam, lorazepam, chlormezanone, metaxalone, zuclopenthixol, etizolam, fludiazepam.

-antidepressant: amitriptyline, amoxapine, amfebutamone, opipramol, desipramine, demexiptiline, fluvoxamine, fluoxetine, carpipramine, clomipramine, maprotiline, mianserin, paroxetine, methylphenidate, protriptyline, trimeprimine, Sertraline, Herba Hyperici perforati extract sheet, viloxazine, venlafaxine, sibutramine, citalopram, isocarboxazid.

-antuepileptic: oxcarbazepine, beclamide, phenytoin, valproic acid and sodium thereof, magnesium salt, paramethadione, carbamazepine, carzenide, lamotrigine, riluzole, primidone, topiramate, ethadione, etazepine, ethotoin, ethosuximide, zonisamide, tiagabine, mephenytoin.

-tranquilizer, hypnotic, anticonvulsant and other: oxazolam, barbital, phenobarbital, glutethimide, Quetiapine, nizofenone, gastrodine, bromisoval, etomidate, acegastrodine, Zaleplon, zopiclone, zolpidem, betahistine, vincamine, flunarizine, flumedroxone, flurotyl, cyclandelate, pentoxifylline, dihydroergotamine mesilate, rizatriptan, methysergide, naratriptan, xantinol nicotinate, nicergoline, kallidinogenase, nicotinic acid, iprindole, eletriptan, epoprostenol, iprazochrome, papaverine, Zolmitriptan, levetiracetam.

-automonic thing: arotinolol, alprenolol, atenolol, esmolol, benzatropine, bisoprolol, scopolamine, spectinomycin hydrochloride, carteolol, carvedilol, labetalol, metoprolol, moprolol, thymoxamine, nadolol, Anisodamine, celiprolol, cetamolol, timolol, tamsulosin, sotalol, Yohimbine, Anisodine, carvedilol, tamsulosin, tropicamide, propantheline bromide.

-circulatory system drug:

-calcium antagonists: anipamil, barnidipine, benidipine, bepridil, devapamil, falipamil, cinnarizine, lacidipine, Manidipine, tiapamil, verapamil, dexverapamil.

The medicine of-treatment chronic cardiac insufficiency: bucladesine, digoxin, denopamine, strophanthin K, dobutamine, docarpamine, thevetin, milrinone, enoximone, levosimendan, alifedrine.

-anti-arrhythmic: aprindine, amiodarone, pilsicainide, disopyramide, flecainide, quinidine, modecainide, moracizine, procainamide, Propafenone, Ivabradine, itrocainide, bretylium tosilate, mexiletine, stirocainide.

-control angina pectoris medicine: oxyfedrine, isosorbide mononitrate, ligustrazine, diltiazem, erythrityl tetranitrate, hexobendine, adenosine cyclophosphate, lidoflazine, muscone, dipyridamole, pentaerithrityl tetranitrate, nitroglycerin, imolamine, etafenone, adenosine cyclophosphate.

-peripheral vasodilators: apovincamine, vincamine, pinacidil, vinconate, vintoperol, dagapamil, buflomedil, fasudil, gallopamil, hydralazine, cadralazine, minoxidil, nicorandil, naftidrofuryl, trapidil, dihydralazine, urapidil, brovincamine, inositol nicotinate, elnadipine, different third ground, iproxamine, papaveroline, stevaladil, levemopamil, zolertine.

-hypotensor: alfuzosin, alacepril, anaritide, amlodipine, betanidine, benazepril, Rhomotoxin, bunazosin, bendazol, delapril, dilevalol, bupicomide, doxazosin, irbesartan, felodipine, fosinopril, tetrandrine, methyldopa, daidzein, pentolinium tartrate, captopril, Candesartan, quinapril, clonidine, lisinopril, ramiprilat, rilmenidine, reserpine, spirapril, lofexidine, mecamylamine, nilvadipine, nicardipine, nimodipine, nitrendipine, nisoldipine, pargyline, perindopril, trandolapril, terazosin, temocapril, tolonidine, cilazapril, nifedipine, valsartan, isradipine, Elisartan, enalkiren, enalapril, enalaprilat, Eprosartan, indoramine, levlofexidine, zofenopril, zofenoprilat, telmisartan.

-blood lipid regulation medicine and antiatherosclerotic: atorvastatin, acipimox, phenylpropanolamine, felypressin, bezafibrate, pyricarbate, beclobrate, dalvastatin, Elastase, dopamine, dopexamine, fenofibrate, fluvastatin, ciprofibrate, gemfibrozil, colestipol, colestyramine, crilvastatin, clinofibrate, lecimibide, clofibrate, aluminum clofibrate, lovastatin, mevastatin, Nicanartine, nicofibrate, pravastatin, probucol, cerivastatin, simvastatin, linoleic acid, etofylline clofibrate, dextrothyroxine sodium, Hyodeoxycholic Acid.

-medicine for respiratory system: aminophylline, ambroxol, orciprenaline, oxeladin, benproperine, bitolterol, benzonatate, pirbuterol, sodium dibunate, dimethoxanate, deptropine, erdosteine, fenoterol, pholcodine, hexoprenaline, clenbuterol, clobutinol, Mabuterol, montelukast, picoperine, terbutaline, guaifenesin, sulfogaiacol, xamoterol, levopropoxyphene, isoaminile, acetylcysteine, ketotifen, terbutaline, tulobuterol, eprazinone, terpinol.

-medicine for digestive system:

-antacid and treatment peptic ulcer disease medicine: omeprazole, balsalazide, ornoprostil, enprostil, famotidine, dihydroxyaluminum aminoacetate, bismuth potassium citrate, lansoprazole, rabeprazole, sucralfate, almagate, bismuth aluminate, hydrotalcite, rosaprostol, roxatidine, misoprostol, nizatidine, pirenzepine, plaunotol, pantoprazole, troxipide, sofalcone, telenzepine, vitamin U, irsogladine, ecabet.

-gastrointestinal antispasmodic medicine: adiphenine.

-digestant: ociltide, Pancreozymin amylase, citric acid, carnitine, pepsin, cisapride, trypsin, pancreatin, pancreatic lipase.

-Bendectin, emetic and the intestines and stomach promote medicine: ondansetron, domperidone, granisetron, metoclopramide, clebopride, tropisetron, itopride, Bergeninum, levosulpiride, luteolin, lerisetron, lintopride, moguisteine, mosapride.

-liver and gall diseases adjuvant drug: orazamide, chenodeoxycholic acid, febuprol, anethol trithione, inositol, inosine, bifendate, armillarisin A, tiopronin, thioctic acid, Malotilate, glucurolactone, oleanolic acid, hymecromone, nicotinylmethylamide, dehydrocholic acid, sodium dehydrocholate, deoxycholic acid, lactulose, silibinin, silymarin, cianidanol, ademetionine, ursodesoxycholic acid, protoporphrin disodium.

-medicine for urological system: amiloride, azosemide, triamterene, bemetizide, polythiazide, bumetanide, piretanide, furosemide, cyclopenthiazide, the clorexolone, spirorenone, metyrapone, spironolactone, mefruside, lypressin, indapamide, epitizide, ethoxzolamide, etacrynic acid, sodium etacrynate, etozolin, ethiazide, acetazolamide, isopropamide iodide, ibopamine, Desmopressin, diclofenamide (dichlorphenamide), teprenone, metyrapone.

-influence the medicine of blood and hemopoietic system: Sarpogrelate, ethylidenedicoumarol, the two bean ethyl esters of second, warfarin, phenindione, acenocoumarol, ferrous sulfate, Ferrous gluconate, calcium folinate, folic acid, iron dextran, mecobalamin, ferrous fumarate, gleptoferron, sodium ferulate, nucleotide, anethole, Rubidate, batilol, berbamine, acadesine, anagrelide, ataprost, ozagrel, Beraprost, pirmagrel, dazmegrel, dazoxiben, furegrelate, limaprost, clopidogrel, Rolafagrel, midazogrel, modipafant, nafagrel, pamicogrel, Alprostadil, troxerutin, ticlopidine, trifenagrel, Satigrel, sunagrel, cilostazol, ciprostene, nicogrelate, oxagrelate, itazigrel, oxybenzene sulphur ester calcium.

-allergy preparations:

-antihistaminic: acrivastine, alimemazine, astemizole, oxatomide, oxomemazine, diphenhydramine, phenindamine, propiomazine, buclizine, dimenhydrinate, the promethazine teoclate, azelastine, bufrolin, dorastine, doxylamine, embramine, pheniramine, fexofenadine, dimetindene, loratadine, clemastine, cloperastine, chlorphenamine maleate, mebhydrolin, meclizine, mequitazine, niaprazine, Cyproheptadine, setastine, ebastine, emedastine, epinastine, dexbrompheniramine, zafirlukast, levocabastine.

-anaphylaxis medium sustained-release agent and other: azatadine, amlexanox, lodoxamide, tranilast, sodium cromoglicate, cetirizine, zaprinast, probicromil, proxicromil, tazanolast.

-adrenocortical hormone and thyroliberin: deflazacort, dexamethasone, methylprednisolone, meprednisone, cortisone, triamcinolone.

-gonadal hormone and short gonadal hormone: bicalutamide, estrone, estriol, medroxyprogesterone acetate, danazol, furazabol, flutamide, dienestrol, hexestrol, diethylstilbestrol, megestrol, medroxyprogesterone, raloxifene, nilutamide, gestrinone, toremifene, stanozolol, norgestrel.

-pancreas hormone and other influence the medicine of blood glucose: acarbose, pioglitazone, metformin, voglibose, glibenclamide, glyclopyramide, glipizide, glyprothiazole, glibornuride, gliquidone, glimepiride, gliclazide, tolbutamide, miglitol, troglitazone, repaglinide, tolazamide.

-thyroid hormones medicine and antithyroid drug: orotirelin, posatirelin, azetirelin, liothyronine, dibromotyrosine, thyropropic acid, thyromedan, thyroglobulin, montirelin, mipimazole, diotyrosine, tiratricol, levothyroxine, levothyroxine sodium, aminothiazole, propylthiouracil, iodothiouracil, methylthiouracil, thiamazole, carbimazole, thibenzazoline.

-antimicrobial agents/antibiotic:

-penicillins: amoxicillin, ampicillin, bacampicillin, oxazacillin, flucloxacillin, hetacillin, ciclacillin, sulbenicillin, carindacillin, cloxacillin, lenampicillin, nafcillin, pivampicillin, pivmecillinam, penicillin V, sultamicillin, dicloxacillin, talampicillin.

-cephalosporins: Loracarbef, cefalexin, cefprozil, cefpodoxime, ceftibuten, cefaclor, cefixime, cefradine, cefbuperazone, cefaloglycin, cefadroxil, cefroxadine, cefteram, cefdinir.

-beta-lactamase inhibitor: clavulanic acid, sulbactam, brobactam.

-aminoglycoside: paromomycin, kanamycin, gentamycin, neomycin.

-Tetracyclines and other: demeclocycline, doxycycline, guamecycline, metacycline, minocycline, oxytetracycline, tetracycline, chloromycetin.

-Macrolide: azithromycin, triacetyloleandomycin, dirithromycin, erythromycin, erythromycin ethylsuccinate, kitasamycin, josamycin, clarithromycin, Roxithromycin, rokitamycin, spiramycin, meleumycin, midecamycin, erythromycin stinoprate, erythromycin estolate, acetylspiramycin.

-other bacterial-infection resisting medicines: levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, polymyxin E, clindamycin, lincomycin, fosfomycin, mikamycin, nysfungin, fibrauretin, berberine, hemsleyadin, Sodium Houttuyfonate.

-antituberculotic: pyrazinamide, aminosalicylic acid, sodium aminosalicylate, prothionamide, cycloserine, rifabutin, rifapentine, rifampicin, ethambutol, isoniazid.

-antifungal agent: flucytosine, fluconazol, griseofulvin, miconazole, itraconazole, ketoconazole, nystatin.

-antiviral agents: acyclovir, famciclovir, valaciclovir, lamivudine, ribavirin, Moroxydine, zidovudine, doxifluridine, didanosine, zalcitabine.

-antitumor drug: busulfan, cyclophosphamide, lomustine, semustine, thioguanine, mercaptopurine, idarubicin, aminoglutethimide, tamoxifen, Anastrozole, procarbazine, cantharidin, capecitabine, letrozole, melphalan.

-influence the medicine of body's immunity: actarit, propagermanium, azathioprine, mizoribine, tacrolimus.

-protein: DNA enzyme, alginase, superoxide dismutase and lipase, polypeptide, oligopeptide.

-nucleotide.

-vitamin and Amitin: vitamin A, B, C, D, E, K etc. and derivant thereof, aminoacid;

-appetrol: aminorex, amfepramone, amfepentorex, amfecloral, ortetamine, benfluorex, difemetorex, benzfetamine, propylhexedrine, chlorphentermine, fenisorex, fenbutrazate sweet smell, fluorine Lamine, oxazimedrine, fenproporex, phentermine, furfenorex.

-other drug: finasteride, Alendronate sodium, alosetron, orlistat, epristeride, epalrestat, tolterodine, tolrestat.

More preferably be used for exemplary drugs of the present invention and include but not limited to LECOZOTAN (SRA-333), the amoxicillin, the amoxycillin with clavulanate potassium compound recipe, A Sidamo, aspirin-ligustrazine phosphate compound recipe, aspirin-dipyridamole compound recipe, piperazine ferulate, acyclovir, acetaminophen-pseudoephedrine hydrochloride-dexbrompheniramine maleate compound recipe, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, aceclofenac, isosorbide mononitrate-aspirin compound recipe, isosorbide mononitrate, diazepam, metformin-rosiglitazone compound recipe, famciclovir, felodipine, fenofibrate, fexofenadine hydrochloride-pseudoephedrine hydrochloride compound recipe, fluvastatin sodium, acipimox and compound recipe, felodipine-spectinomycin hydrochloride compound recipe, lovastatin-nicotinic acid compound recipe, the vitamin B6 compound recipe, cetirizine-pseudoephedrine hydrochloride compound recipe, fexofenadine hydrochloride-pseudoephedrine hydrochloride compound recipe, guaifenesin-pseudoephedrine-dextromethorphan compound recipe, quetiapine fumarate, Metoprolol fumarate, the fumaric acid emedastine, glipizide-metformin hydrochloride compound recipe, gliquidone, glimepiride-metformin compound recipe, gliclazide, potassium citrate, Tamoxifen Citrate, Tamoxifen Citrate, the succinic acid desmethylvenlafaxine, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, Tolterodine tartrate, Zolpidemtar Trate, clarithromycin, kurarinone, ranolazine, ribavirin, benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, loratadine-acetaminophen-pseudoephedrine compound recipe, loratadine-pseudoephedrine compound recipe, rosiglitazone, Roxithromycin, lovastatin, Trimebutine Maleate, enalapril maleate-felodipine compound recipe, mesalazine, medetofazone, mizolastine, naftopidil, naproxen sodium, Ni Ketating, nimesulide, nitrendipine, nisoldipine, Paliperidone, Perprazole, darifenacin hydrobromide, galanthamine hydrobromide, huperzine A, bicyclol, stavudine, gastrodine, ketoprofen, cefaclor, cefixime, vitamin C controlled-releasing vaginal sheet, vitamin E Nicotinate, pseudoephedrine-naproxen sodium compound, urapidil, nicotinic acid, nicotinic acid-simvastatin compound recipe, BUPROPIONE HCl, ambroxol hydrochloride, ditropan XL, Betahistine Hydrochloride, metformin hydrochloride, valaciclovir hydrochlordide, ciprofloxacin, labetalol hydrochloride, Licardipine Hydrochloride, paroxetine hydrochloride, minipress, propafenone hydrochloride, propranolol hydrochloride, dihydromorphinone hydrochloride, tramadol hydrochloride, Trimetazidine Hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, albuterol hydrochloride, levofloxacin hydrochloride, ofloxacin, etodolac, indapamide, guaifenesin, guaifenesin-pseudoephedrine hydrochloride compound recipe, levodropropizine, bezafibrate, piribedil, theophylline, vincamine, dihydroergotoxine methanesulfonate, Carclura, spectinomycin hydrochloride, dihydrocodeine bitartrate, the carbidopa and levodopa compound recipe, morphine sulfate, the sulphuric acid celebrating is mould greatly, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, diclofenac sodium, verapamil, dimension ferrum, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetacin, theophylline-albuterol compound recipe, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, ibuprofen and codeine, Malotilate, naproxen, lithium carbonate, cefalexin, alfuzosin hydrochloride, Buflomedil Hydrochloride, the hydrochloric acid Ticlopidine, ibudilast, dextromethorphan, ZHENGQINGFENGTONGNING, the single nitre Coronex of 5-, sodium valproate, Benserazide, gentamycin sulfate-zirconium dioxide compound recipe, chlorphenamine maleate, barnidipine, bunazosin, gallopamil, methylphenidate hydrochloride, oxycodone hydrochloride.

Be used for active matter of the present invention and comprise its pharmaceutically available salt form of following active component, free acid form, free alkali form, hydrate, various crystal formation and optical isomer.

Core material can also contain other pharmacy auxiliary agent except active substance, as slow controlled-release material, porogen, filler, binding agent, disintegrating agent, short disintegrating agent, lubricant (comprising fluidizer, antitack agent), osmotic pressure active substance (being osmotic pressure promoter), short osmopolymer bases such as (permeation-promoter).In addition, can also comprise solubilizing agent, suspending agent, sweeting agent, aromatic, pigment, absorbent and surfactant (as playing effects such as moistening, dispersion, solubilising, emulsifying).Pharmacy auxiliary agent and consumption thereof thus the art those skilled in the art according to selections such as the character of practical situation such as medicine, desirable rate of releasing drug.

The present invention relates to the particularly preparation method of the controlled release preparation that discharges of zero level of controlled release preparation that a kind of clothing film coats.Elaborate with regard to each basic step in the preparation method of controlled release preparation below.

1), preparation contains the core material of at least a medicine

The method that preparation contains the core material of at least a medicine has no particular limits.Usually preparation method is with active medicinal matter and/or does not have composition such as pharmacy auxiliary agent by direct pressing method; do, the pressing method of wet or sintered particles; extrude and rounding subsequently; wet or dry state pelletize or directly make ball (for example on the disk) or powder (powder bed) is bonded to the ball (particle) of non-activity material or contains on the granule of active substance, perhaps further in a certain way as make sheet.

2), to core material bag clothing film

The cyclodextrin derivative that porogen is promptly satisfied the water miscible replacement that allows on any physiology of above-mentioned definition all is dissolved in the aqueous dispersion of polymer of above-mentioned water and the insoluble film property of Digestive system, add or do not add active medicinal matter and other other additives of clothing film, mix homogeneously in case of necessity.The content of polymer in the aqueous dispersion suspension is generally 2～30%, and preferably 5～20%, more preferably 8～15%.The aqueous dispersion suspension also can contain certain amount of organic solvent, and its content often is 1～20%, and preferably 1～10%, more preferably 2～5%.

The aqueous dispersion suspension that utilizes above-mentioned gained is by casting, dip, brush or coating process such as spraying preparing the clothing layer to core material.Preferably adopt spraying method to carry out.Film forming procedure does not rely on coating process and is undertaken by energy input.This can finish by convection current (heat), radiation (infrared or microwave) or conduction.Thus will be for coating evaporate as the water that suspending agent uses, necessary words also may be used the vacuum accelerated evaporation.The higher drying efficiency of this process need, so the present invention often adopts high efficiency coating equipment (as fluid bed, high-efficiency coating pot).

The amount of clothing film material is generally 0.5～50% (weight) of the amount before the core material coating, is preferably 5～30% (weight), best 10～20% (weight); Coatings thickness is generally 5～500 μ m, is preferably 50～300 μ m, more preferably 100～200 μ m.

The core material surface temperature should be higher than aqueous dispersion minimum film formation temperature (MFT) (minimum film formation temperature is meant that aqueous dispersion forms the minimum temperature of seriality clothing film, and below minimum film formation temperature, polymer particle can not be out of shape and merge and film forming) during coating.The core material surface temperature exceeds 10～20 ℃ of minimum film formation temperature usually in the present invention.If the core material surface temperature is low excessively, may make the clothing film crack occur, influence the preparation drug release feature; The too high then too softening polymer of core material surface temperature causes the clothing film coalescence.

During the aqueous dispersion coating, core material is preheated to 20～90 ℃ usually, preferably 30～70 ℃, more preferably 30～50 ℃, earlier with low hydrojet speed coating, coated skim clothing film to the core material surface after, improve hydrojet speed to coating again and finish, this operation can avoid moisture to infiltrate core material inside, causes storage process core material character to change.

Before the aqueous dispersion coating, also can carry out the sealing coat coating to core material according to reality, this helps: 1. avoid the hydrolysis in the coating process of water sensitivity medicine; 2. avoid water soluble drug to migrate to the clothing film with water evaporates; 3. improve the profile pattern of core material, reduce porosity, guarantee clothing film seriality; 4. improve the core material surface hydrophobic, be beneficial to sprawling of aqueous coatings liquid; 5. improve the core material friability, avoid the broken phenomenon in the coating process.According to practical situation, can select water-soluble material (as Gonak and hydroxypropyl fibrinolytic liquid) or polymer organic solution to carry out the sealing coat coating.Yet this arbitrary coating all should be fully thin, in order to avoid the Release Performance of harm preparation.

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

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

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

After coating finished, polymer particle did not often merge fully in the clothing film, i.e. film healing is still incomplete.Under the interfacial tension effect of polymer and air, deposit in the process further fusion phenomenon may take place, form fine and close more clothing film.Fusion phenomenon needs the long period just can finish, and adopts coating after-baking technology quickening the healing of clothing film usually, relatively stable with rate of release between guaranteeing batch.

After healing is handled (curing treating) process and is generally water evaporates, place the clothing film under the uniform temperature or certain hour under simultaneously certain inferior condition of humidity, the polymer particle in the clothing film is further merged, form fine and close clothing film.Selected temperature should be higher than its glass transition temperature or minimum film formation temperature, preferably be higher than more than 10 ℃, more preferably be higher than more than 20～30 ℃, above temperature all should be not make the softening fully or fusing of composition in the coating material or clothing film coalescence degree of being not take place.Selected humidity is generally relative humidity 30～100%, and preferably 40～95%, more preferably 50～90%.The required time is extremely tens of hours a few hours, preferably 20～72 hours, and preferably 24～48 hours.The end time that healing is handled normally contrasts sample that healing under certain condition obtains, and obtain the dissolution test data (being undertaken by Chinese Pharmacopoeia two appendix XD drug release determination methods in 2005) of sample of (for example 40 ℃ of temperature, 75% time healing acceleration of relative humidity are tested March) with the healing acceleration test definite.

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

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

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

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

Can wrap the skim coating material with the surperficial globality of improving preparation or prevent that preparation bonds mutually in storage process with the preparation of above-mentioned either party's method preparation.Suitable coating material includes but not limited to disaccharide such as sucrose, polysaccharide such as maltodextrin and pectin and cellulose derivative such as hydroxypropyl emthylcellulose and hydroxypropyl cellulose, yet, arbitrary coating all should fully approach and be water miscible, with the Release Performance of obstruction free preparation.

Pharmaceutical dosage form with above-mentioned either party's method preparation can directly use basically, as directly oral.Pack into as in capsule, bag (sachet) or the suitable many measuring containers with the also available measuring equipment of small pieces, granule or the ball of above-mentioned preparation.If possible, obtain by compacting mixing the back with other auxiliary agent with the granule of above-mentioned preparation or ball, preparation decomposes taking the back, and most of junior unit that coats discharges.Can consider equally aggregation is embedded in Polyethylene Glycol or the lipid with preparation inspection agent or vagina medicinal agent type.The tablet that coats is packed with hemispherical container or multi-dose container, directly takes out before patient takes.

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

Embodiment

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

Embodiment 1

1, preparation sample

1), preparation label:

With diltiazem, adipic acid, citric acid, sodium chloride, lactose and polyvidone mixing, carry out pelletize with ethanol solution; Wet granular material was forced 18 mesh sieves also dry 24 hours; Behind the granulate, mix the back mold pressing again with stearic acid, magnesium stearate and make the label of 420mg, with one 7/16 " dark arc concave circle (deep concave) punch die compressed tablet.

2), label is pressed following prescription and technology coating:

Coating fluid prescription:

The solids content of aqueous dispersion is 16 (weight) %.With label coating on Hicoater/Fruend coating machine.Coating conditions parameter: spray speed, 1ml/min; Inlet temperature, 70～80 ℃; Outlet temperature, 40～42 ℃; 40 ℃ of label temperature; Clothing layer thickness 250～350 μ m.

4), healing clothing film

Healing is handled and is carried out in airtight baking oven.The healing temperature is 50 ℃, and healing time is 30 hours, gets sample 1.

2, preparation reference examples sample

Sulphur butyl (ether)-beta-schardinger dextrin-(DS=1.30～1.45) in the coating fluid prescription is changed into sulphur butyl (ether)-beta-schardinger dextrin-(DS=0.12～0.15) and potassium hydrogen tartrate, and (average footpath: 56 μ m), the condition that reaches as stated above prepares reference examples sample 1,2 respectively.

Embodiment 2

Sulphur butyl (ether)-beta-schardinger dextrin-(DS=1.30～1.45) in embodiment 1 coating fluid prescription is changed into hydroxyl cyclobutenyl ether ring dextrin (DS=2.43～2.56) preparation embodiment 2, change hydroxyl cyclobutenyl ether ring dextrin (DS=0.23～0.36) and urea production reference examples sample 3,4 again into, other equal embodiment 1.

Embodiment 3

Sulphur butyl (ether)-beta-schardinger dextrin-(DS=1.30～1.45) in embodiment 1 coating fluid prescription is changed into sulphuric acid sodio x-dodecyl y-beta-schardinger dextrin-(wherein, x=4～9, y=5～11) preparation embodiment 3, change sulphuric acid sodio x-dodecyl y-beta-schardinger dextrin-again into (wherein, x=1～2, y=1～2) and cellulose acetate diethylamino acetate (average footpath: 56 μ m) preparation reference examples sample 5,6, other equal embodiment 1.

Embodiment 4

1, preparation sample

1), preparation label;

(a), get nifedipine and be scattered in 5 times in the acetone of its amount, add polyvidone, mix thoroughly; Add 3 times of isopropyl alcohols again, add polysorbate 80 at last to the nifedipine amount, mix thoroughly liquid A.

(b), get sodium chloride, microcrystalline Cellulose and hydroxypropyl emthylcellulose and insert in the fluid bed, behind the mixing, spray into the liquid A that has mixed thoroughly and granulate; Drying is less than 2.5% until loss on drying and gets granule B.

(c), get 85 (wt) % granule B, 5.0 (wt) % sodium chloride, 9.0 (wt) % PEO (

WSR-NF, molecular weight 7,000,000) and magnesium stearate (above ratio is based on the above-mentioned four kinds of particulate gross weights) mixing of 1 (wt) %, " stamping of standard radian, the heavy 307mg of sheet with 0.3410.

2), preparation coating solution:

Cellulose acetate added making 5% solution in acetic acid ethyl ester-ethanol (95: 5) as oil phase, is water with the lauryl sodium sulfate aqueous solution of 3mg/ml; Use the high speed dispersing emulsification machine, low whipping speed is not less than 3000 rev/mins the following water of condition and slowly is added dropwise to and forms w/o type Emulsion in the oil phase, continues to drip the colostrum until forming the O/W type.Colostrum is passed through high pressure homogenization machine, 6 times repeatedly.Use Rotary Evaporators at 40 ℃, under the reduced pressure organic solvent is removed from gained Emulsion.

3), coating:

Add the diacetine that adds hydroxypropyl-gamma-cyclodextrin (DS=2.63～2.75) in the aqueous dispersion and use at the above-mentioned cellulose acetate that makes as plasticizer, cellulose acetate wherein: hydroxypropyl-cyclodextrin: diacetine is 1: 2: 1 (weight ratio), is diluted with water to contain 3% cellulose acetate suspension and make coating solution.With the coating solution that makes to label bag clothing film.The weightening finish of clothing film coating is 6%.

With timing automatic film coating machine coating, the coating conditions parameter is: about 20 seconds of spraying time, about 30～40 seconds of blasting time, 50～70 ℃ of blast temperatures, 45～50 ℃ of label temperature.

4), healing clothing film

Healing is handled and is carried out in airtight baking oven.The healing temperature is 65 ℃, and healing time is 30 hours.

2, preparation reference examples sample

Hydroxypropyl-gamma-cyclodextrin in the coating fluid prescription (DS=2.63～2.75) is changed into hydroxypropyl-gamma-cyclodextrin (DS=0.63～0.85) and magnesium phosphate, and (average footpath: 56 μ m), the condition that reaches as stated above prepares reference examples sample 7,8 respectively.

Embodiment 5

Hydroxypropyl-gamma-cyclodextrin in embodiment 4 coating fluid prescription (DS=2.63～2.75) is changed into SHEx-Pry-γ-CD (wherein, SHE represents sulfo group hexyl ether, Pr represents the propyl group ether, x, y represent each substituent substitution value, x=4～9, y=5～11) preparation embodiment 5, change SHEx-Pry-γ-CD again into (wherein, SHE represents sulfo group hexyl ether, Pr represents the propyl group ether, and x, y represent each substituent substitution value, x=1～2, y=1～2) and sodium chloride prepare reference examples sample 9,10, other are all with embodiment 4.

The test of test example 1 release in vitro degree

Sampling method: get 12 tablet preparations at each batch sample,, get 9 batches of samples (every batch of production technology is identical, and the used supplementary material of all batches all comes from same batch products) altogether, i.e. n=9 in every batch of rate of releasing drug of its meansigma methods.

Diltiazem hydrochloride adopts Chinese Pharmacopoeia version oar in 2005 method (appendix X C dissolution second method) to measure.Rotating speed is 50r/min, and temperature is (37 ± 1) ℃, and mediator is simulated gastric fluid (pH1.2 hydrochloric acid solution) 900mL.Embodiment and reference examples sample are directly dropped into respectively in the stripping rotor, the 5mL that takes a sample at regular intervals, and replenish with volume stripping mediator.Decide the release of medicine in the monitoring of the wavelength place of 238nm with the HPLC method.

Nifedipine adopts Chinese Pharmacopoeia version oar in 2005 method (appendix X C dissolution second method) to measure.Rotating speed is 50r/min, and temperature is (37 ± 1) ℃, and mediator is simulated gastric fluid (pH1.2 hydrochloric acid solution) 900mL.Embodiment and reference examples sample are directly dropped into respectively in the stripping rotor, the 5mL that takes a sample at regular intervals, and replenish with volume stripping mediator.Decide the release of medicine in the monitoring of the wavelength place of 237nm with the HPLC method.

Measurement result sees Table 1-5.

Table 1 embodiment 1 and reference examples 1,2 example pharmaceuticals rate of release test results thereof

(n=9)

Table 2 embodiment 2 and reference examples 3,4 example pharmaceuticals rate of release test results thereof (n=9)

Table 3 embodiment 3 and reference examples 5,6 example pharmaceuticals rate of release test results thereof

(n=9)

Table 4 embodiment 4 and reference examples 7,8 example pharmaceuticals rate of release test results thereof

(n=9)

Table 5 embodiment 5 and reference examples 9,10 example pharmaceuticals rate of release test results thereof

(n=9)

Result of the test shows, the embodiment formulation samples is faster than the reference examples example pharmaceuticals rate of release of making porogen with small-size molecules, suitable with the reference examples example pharmaceuticals rate of release of making porogen with the particulate matter that dissolves in Digestive system, but the drug release repeatability is than height.

Test example 2 preparation medicines discharge stability test

Sample in 6,10 the 1st batches of working sample: embodiment 3,5 and the reference examples.

Detection method: sample is inserted 40 ℃ of temperature, under the acceleration environment of relative humidity 85%, medicament contg and drug release rate when sampling regularly and mensuration preparation do not carry out the drug release test (are measured 12, in meansigma methods), wherein, drug release rate (%)=stripping enters medication amount * 100% in medication amount/preparation in the dissolution medium.Stripping enters the method for testing of the medication amount in the dissolution medium: referring to test example 1; Medication amount method of testing in the preparation: medicine is measured with the HPLC method after extracting in the preparation fully.Test result sees Table 6 and 7.

Table 6 embodiment 3 and 10 hours release amount of medicine test result of reference examples 6 samples

Table 7 embodiment 5 and 10 hours release amount of medicine test result of reference examples 9 samples

Never the embodiment 3 that carried out dissolution test and reference examples 60 month and quicken to get clothing film on the sample June, with microscope it is observed, found that reference examples 6 quickens to have taken place to interpenetrate with respect to 0 month sample between porogen in the clothing film of samples in June and clothing film, the interface thickens; The embodiment sample is not found above-mentioned phenomenon.

Quicken the March of reference examples 10, particularly quickens test specimen surface appearance in June " scum " phenomenon, and " scum " rate is respectively 23%, 57%, and embodiment sample " scum " rate difference 2%, 5%.The stripping residue of getting the embodiment 5 that carried out dissolution test and reference examples 10 0 month and quickening the sample in June is in the clothing film frozen drying clothing film behind the moisture, with microscope it is observed, the stripping residue that found that the acceleration sample in June of reference examples 10 is that the micropore in the clothing film dwindles largely with respect to 0 month sample.The embodiment sample is not found above-mentioned phenomenon.

The result shows that embodiment has better storage-stable than reference examples.

Test example 3 preparation clothing film measuring mechanical properties

Make the thin film that thickness is 150 μ m with preparation sample and the used release-controlled film coating solution of reference examples sample among the embodiment in the polyfluortetraethylene plate top casting, thin film is cut into the size of 1 * 7cm.Under INSTRON tensile strength tester, measure tensile strength then.The results are shown in Table 9.

Table 9 function performance measurement result

The result shows, contains thin film with the water miscible cyclodextrin derivative of the dispersive higher replacement of molecular forms and contains with the dispersive low water miscible cyclodextrin derivative that replaces of molecular forms and with the thin film of the dispersive water miscible material of molecular forms and have more excellent mechanical performance.

Test example 4 preparation vivo releasing tests

12 men's health trial volunteers, once oral embodiment sample of intersection and reference examples sample are each 1 at random, carry out human bioavailability research, and blood drug level is measured with liquid chromatography (HPLC) or liquid-matter coupling method (HPLC-MS/MS).Test result sees Table 10,11, reaches 12.

Release test result in the table 10 diltiazem hydrochloride body (meansigma methods ± SD, n=6)

Release test result (I) in the table 11 nifedipine body (meansigma methods ± SD, n=6)

Release test result (II) in the table 12 nifedipine body (meansigma methods ± SD, n=6)

The result shows that the embodiment sample has release behavior in the better body than the reference examples sample.The result also shows, reference examples 6,8 samples in vivo the degree of variation of drug release behavior greater than other samples, this hinting influence their absorption in vivo influence factors will be more than other samples.

Claims (27)

1. the controlled release preparation of an improved combination properties, this controlled release preparation comprises:

1) core material that, contains at least a medicine;

2) be overlying on the clothing film of above-mentioned core material, outward, this clothing film comprise pharmaceutically acceptable be insoluble to or the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid and at least a with non-particulate form only with the unimolecule state and/or be scattered in the water miscible average substitution degree (DS) that allows on wherein any physiology with the micelle state and be not less than (3+2k ₁The cyclodextrin derivative of)/n, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin, n 〉=6,1≤k ₁≤ 3 (n-1)/2, n, k ₁Be positive integer.

2. according to the controlled release preparation of claim 1, it is characterized in that described cyclodextrin derivative is that the water miscible average substitution degree (DS) that allows on any physiology is not less than (3+2k ₂The cyclodextrin derivative of)/n, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin, n 〉=6,3≤k ₂≤ 3 (n-1)/2, n, k ₂Be positive integer.

3. according to the controlled release preparation of claim 1 or 2, it is characterized in that described cyclodextrin derivative is that the water miscible average substitution degree (DS) that allows on any physiology is not less than (2n+k ₃The cyclodextrin derivative of)/n, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin, n 〉=6,3≤k ₃≤ n, n, k ₃Be positive integer.

4. according to controlled release preparation any in the claim 1 to 3, it is characterized in that described cyclodextrin derivative is that the water miscible average substitution degree (DS) that allows on any physiology is not less than (2n+k ₄The cyclodextrin derivative of)/n, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin, n 〉=6,5≤k ₄≤ n, n, k ₄Be positive integer.

5. according to controlled release preparation any in the claim 1 to 4, it is characterized in that described cyclodextrin derivative is selected from the hydroxyalkyl cyclodextrin derivant, the hydroxy alkoxy alkyl cyclodextrin derivative, the glycosyl cyclodextrin derivative, quaternary ammonium alkyl ion cyclodextrin derivative, the alkyl amine group cyclodextrin derivative, alkyl carboxyl cyclodextrin derivative and salt thereof, carboxyl alkoxyalkyl cyclodextrin derivative and salt thereof, alkyl carboxylic oxygen base alkyl cyclodextrins derivant and salt thereof, alcoxyl carboxyalkyl cyclodextrin derivative and salt thereof, alkylsurfuric acid cyclodextrin derivative and salt thereof, alkyl sulfonic acid cyclodextrin derivative and salt thereof, alkyl phosphoric acid cyclodextrin derivative and salt thereof, alkyl phosphorous acid cyclodextrin derivative and salt thereof, alkyl phosphonic acid cyclodextrin derivative and salt thereof, phostonic acid cyclodextrin derivative and salt thereof, alkylthio phosphoric acid cyclodextrin derivative and salt thereof, and their mixed group.

6. according to controlled release preparation any in the claim 1 to 5, it is characterized in that also further containing on the glucose unit in the described cyclodextrin derivative unsubstituted alkyl, cycloalkyl, aralkyl and their mixed group.

7. according to the controlled release preparation of claim 5 or 6, it is characterized in that described alkyl is selected from the alkyl that contains 1-30 carbon atom.

8. according to controlled release preparation any in the claim 5 to 7, it is characterized in that described alkyl is selected from the alkyl that contains 3-24 carbon atom.

9. according to controlled release preparation any in the claim 5 to 8, it is characterized in that described alkyl is selected from the alkyl that contains 6-18 carbon atom.

10. according to the controlled release preparation of claim 6, the quantity that it is characterized in that described unsubstituted alkyl, cycloalkyl, aralkyl and their mixed group accounts for the 0.5-50% of substituted radical quantity on the glucose unit in the described cyclodextrin derivative.

11., it is characterized in that described cyclodextrin derivative is selected from hydroxyethyl-cyclodextrin, hydroxypropyl-cyclodextrin, hydroxyl butyl-cyclodextrin, didextrose basic ring dextrin, three glucityl cyclodextrin, two malt-base cyclodextrin, three Fructus Hordei Germinatus glycosyl cyclodextrin and composition thereof according to controlled release preparation any in the claim 1 to 5.

12., it is characterized in that described cyclodextrin derivative is selected from hydroxyl cyclobutenyl ether ring dextrin and/or sulphur butyl (ether) cyclodextrin and salt thereof according to controlled release preparation any in the claim 1 to 5.

13. according to controlled release preparation any in the claim 1 to 5, it is characterized in that described cyclodextrin derivative is selected from cyclodextrin (SAE-AE-CD) derivant that contains sulfoalkyl ether base and alkylether radicals, the average substitution degree (DS) of the sulfoalkyl ether base of this cyclodextrin (SAE-AE-CD) derivant be not less than 3/n and be not higher than 3 and the average substitution degree (DS) of its alkylether radicals be not less than 2/n and be not higher than 3, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin.

14. according to controlled release preparation any in the claim 1 to 5, it is characterized in that described cyclodextrin derivative is selected from SBEx-Mey-β-CD, SBEx-Ety-β-CD, SBEx-Pry-β-CD, SPEx-Mey-β-CD, SPEx-Ety-β-CD, SPEx-Pry-β-CD, SEEx-Mey-β-CD, SEEx-Ety-β-CD, SEEx-Pry-β-CD, SPtEx-Mey-β-CD, SPtEx-Ety-β-CD, SPtEx-Pry-β-CD, SHEx-Mey-β-CD, SHEx-Ety-β-CD, SHEx-Pry-β-CD, SBEx-Ety-γ-CD, SBEx-Pry-γ-CD, SBEx-Mey-γ-CD, SPEx-Mey-γ-CD, SPEx-Ety-γ-CD, SPEx-Pry-γ-CD, SEEx-Mey-γ-CD, SEEx-Ety-γ-CD, SEEx-Pry-γ-CD, SPtEx-Mey-γ-CD, SPtEx-Ety-γ-CD, SPtEx-Pry-γ-CD, SHEx-Mey-γ-CD, SHEx-Ety-γ-CD, SHEx-Pry-γ-CD, and composition thereof, wherein, 5≤x≤21 are (for β-CD) or 24 (for γ-CD), 4≤y≤21 are (for β-CD) or 24 (for γ-CD), above-mentioned symbol and abbreviation are defined as follows: CD: cyclodextrin, SBE: sulfo group butyl ether, SPE: sulfo group propyl group ether, SEE: sulfo group ethyl ether, SPtE: sulfo group amyl group ether, SHE: sulfo group hexyl ether, Et: ethyl ether, Me: methyl ether, Pr: propyl group ether, x, y represents each substituent substitution value.

15. according to controlled release preparation any in the claim 1 to 5, it is characterized in that described cyclodextrin derivative is selected from the sulfate cyclodextrin derivative of the senior alkyl that contains lipoid, aliphatic series or aromatics carbochain that carbon number is C6-C30, the average substitution degree of the senior alkyl of this cyclodextrin derivative (DS) be not less than 3/n and be not higher than 3 and its sulphuric acid alkali average substitution degree (DS) be not less than 2/n and be not higher than 3, wherein, the glucose unit number that contains in the circulus of n representative ring dextrin.

16., it is characterized in that described sulfate group is selected from-OSO according to the controlled release preparation of claim 15 ₃R, wherein, R is selected from H, Na, K, Li and/or NH ₄

17. according to the controlled release preparation of claim 15 or 16, it is characterized in that the senior alkyl of described cyclodextrin derivative is selected from linear carbon chain, its general expression is-OC (=O)-(CH ₂) _n-CH ₃, wherein, n is 6 to 24, and/or-OC (=O)-(CH ₂) _m-CH=CH-(CH ₂) _m-CH ₃, wherein, m is 6 to 24.

18., it is characterized in that described cyclodextrin derivative is selected from the sulphuric acid alkali according to controlled release preparation any in the claim 1 to 5 _x-dodecyl _y-β (or γ)-cyclodextrin, sulphuric acid alkali _x-myristyl _y-β (or γ)-cyclodextrin, sulphuric acid alkali _x-cetyl _y-β (or γ)-cyclodextrin, sulphuric acid alkali _x-spiny dogfish alkyl _y-β (or γ)-cyclodextrin and composition thereof, wherein, the index number x of group, y are its substitution value, and 4≤x≤21 are (for β-CD) or 24 (for γ-CD), 5≤y≤21 are (for β-CD) or 24 (for γ-CD), described salt is selected from sodium, potassium or ammonium salt.

19. according to controlled release preparation any in the aforementioned claim, it is characterized in that described cyclodextrin derivative in advance enclose its can enclose pharmaceutically acceptable material.

20. according to controlled release preparation any in the aforementioned claim, it is characterized in that described cyclodextrin derivative in advance enclose its can enclose described core material in medicine.

21. according to controlled release preparation any in the aforementioned claim, it is characterized in that described be insoluble to or polymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, the lacceroic acid cellulose, three Palmic acid celluloses, the disuccinic acid cellulose, two Palmic acid celluloses, polyvinylacetate, methacrylic acid (ester) polymer, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, Merlon, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, vinyl acetate-vinyl chloride copolymer, polrvinyl chloride, polyethylene, polyisobutylene, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride) and compositions.

22., it is characterized in that described be insoluble to or polymer water-soluble hardly and harmonization of the stomach intestinal digestion liquid is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), contains 80～95% polrvinyl chloride, the terpolymer of 0.5～19% polyvinylacetate and 0.5～10% polyvinyl alcohol and/or contain 50～100% polrvinyl chloride and 0～50% polyvinylacetate copolymer and compositions thereof according to controlled release preparation any in the aforementioned claim.

23., it is characterized in that the consumption of described cyclodextrin derivative in described clothing film is 0.5%～80% (weight ratio), based on the dry weight of clothing film component according to controlled release preparation any in the aforementioned claim.

24., it is characterized in that described nuclear core is selected from the sheet of rule or irregular form, granule, ball, crystal or medicine carrying resin according to controlled release preparation any in the aforementioned claim.

25., it is characterized in that described medicine is selected from central stimulants according to controlled release preparation any in the aforementioned claim, analgesic, antipyretic analgesic, anti-inflammation analgesia medicine, antigout drug, antiparkinsonian drug, psychosis, antianxiety drugs, antidepressant, antuepileptic, tranquilizer, hypnotic, anticonvulsant, the automonic thing, calcium antagonists, the medicine of treatment chronic cardiac insufficiency, anti-arrhythmic, control angina pectoris medicine, peripheral vasodilators, hypotensor, blood lipid regulation medicine and antiatherosclerotic, medicine for respiratory system, antacid and treatment peptic ulcer disease medicine, the gastrointestinal antispasmodic medicine, digestant, Bendectin, emetic and the intestines and stomach promote medicine, the liver and gall diseases adjuvant drug, medicine for urological system, influence the medicine of blood and hemopoietic system, antihistaminic, anaphylaxis medium sustained-release agent, adrenocortical hormone and thyroliberin, gonadal hormone and short gonadal hormone, pancreas hormone and other influence the medicine of blood glucose, thyroid hormones medicine and antithyroid drug, penicillins, cephalosporins, beta-lactamase inhibitor, aminoglycoside, Tetracyclines, Macrolide, antituberculotic, antifungal agent, antiviral agents, antitumor drug, influence the medicine of body's immunity, vitamin and Amitin, appetrol.

26., it is characterized in that described medicine is selected from LECOZOTAN (SRA-333) according to controlled release preparation any in the aforementioned claim, the amoxicillin, A Sidamo, piperazine ferulate, acyclovir, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, aceclofenac, isosorbide mononitrate, diazepam, famciclovir, felodipine, fenofibrate, fluvastatin sodium, quetiapine fumarate, Metoprolol fumarate, the fumaric acid emedastine, gliquidone, gliclazide, potassium citrate, Tamoxifen Citrate, Tamoxifen Citrate, the succinic acid desmethylvenlafaxine, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, Tolterodine tartrate, Zolpidemtar Trate, clarithromycin, kurarinone, ranolazine, ribavirin, benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, rosiglitazone, Roxithromycin, lovastatin, Trimebutine Maleate, mesalazine, medetofazone, mizolastine, naftopidil, naproxen sodium, Ni Ketating, nimesulide, nitrendipine, nisoldipine, Paliperidone, Perprazole, darifenacin hydrobromide, galanthamine hydrobromide, huperzine A, bicyclol, stavudine, gastrodine, ketoprofen, cefaclor, cefixime, vitamin C controlled-releasing vaginal sheet, vitamin E Nicotinate, urapidil, nicotinic acid, BUPROPIONE HCl, ambroxol hydrochloride, ditropan XL, Betahistine Hydrochloride, metformin hydrochloride, valaciclovir hydrochlordide, ciprofloxacin, labetalol hydrochloride, Licardipine Hydrochloride, paroxetine hydrochloride, minipress, propafenone hydrochloride, propranolol hydrochloride, dihydromorphinone hydrochloride, tramadol hydrochloride, Trimetazidine Hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, albuterol hydrochloride, levofloxacin hydrochloride, ofloxacin, etodolac, indapamide, guaifenesin, levodropropizine, bezafibrate, piribedil, theophylline, vincamine, dihydroergotoxine methanesulfonate, Carclura, spectinomycin hydrochloride, dihydrocodeine bitartrate, morphine sulfate, the sulphuric acid celebrating is mould greatly, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, diclofenac sodium, verapamil, dimension ferrum, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetacin, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, ibuprofen and codeine, Malotilate, naproxen, lithium carbonate, cefalexin, alfuzosin hydrochloride, Buflomedil Hydrochloride, the hydrochloric acid Ticlopidine, ibudilast, dextromethorphan, sinomenine, the single nitre Coronex of 5-, sodium valproate, Benserazide, chlorphenamine maleate, barnidipine, bunazosin, gallopamil, methylphenidate hydrochloride, oxycodone hydrochloride.

27. according to the preparation method of controlled release preparation any in the aforementioned claim, this method comprises:

1), preparation contains the core material of at least a medicine;

2), with contain described cyclodextrin derivative pharmaceutically acceptable be insoluble to or the aqueous dispersion of the polymer of water-soluble hardly and harmonization of the stomach intestinal digestion liquid to above-mentioned core material bag clothing film, wherein said cyclodextrin derivative all is dissolved in the aqueous dispersion of described polymer.