CN102018962B - Polymer intensifier in controlled release preparation - Google Patents

Abstract

The invention discloses application of a polymer intensifier in the production or the storage of a controlled release preparation, in particular to the controlled release preparation with zero order release. The invention also discloses the controlled release preparation with improved performance, in particular to the controlled release preparation with the zero order release. The controlled release preparation comprises a core material containing a bioactivator and a polymer controlled release coating which is coated on the core material, is provided with a plurality of medicine release micropores filled with air and contains the polymer intensifier, wherein the contact angle of a polymer and the polymer intensifier is less than 90 degrees, and the medicine release micropores are obtained by sublimating sublimable substances and/or degrading degradable harmless gases. The preparation has higher storage stability, higher production repeatability and better medicine release performance in the medicine release aspect; moreover, a controlled release membrane of the polymer intensifier has better mechanical behavior, therefore, the polymer intensifier has lower dosage pouring release possibility and higher administration safety.

Description

Polymer intensifier in controlled release preparation

Technical field

The present invention relates to a kind of polymer intensifier in the controlled release preparation particularly production of the controlled release preparation that discharges of zero level or the purposes in storage.It also relates to particularly controlled release preparation of discharging of zero level and preparation method thereof of a kind of controlled release preparation.More particularly, the controlled release preparation that it relates to a kind of performance improvement is the controlled release preparation that discharges of zero level particularly, this controlled release preparation comprises core material and the outer numerous release micropore and the polymer release-control clothing films that contain polymer intensifier that are filled with air of containing of above-mentioned core material that are overlying on that contain bioactive substance, wherein, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °, and above-mentioned release micropore obtains through the material that distil sublimable material and/or degraded can be biodegradable into innocuous gas.

Background technology

Some insoluble polymers are controlled drug release by coating at controlled release preparation in the controlled release preparation that particularly zero level discharges.Due to the water-insoluble of polymer, the permeability (permeability) that usually needs the micropore of clothing film to improve clothing film is 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 hour.

For example, prior art proposes some controlled release preparation preparation methoies, its by volatilization the method that volatile composition or the one-tenth that can be biodegradable into innocuous gas of degraded in thin film assigns to form micropore that has in thin film come controlled release drug to discharge.For example: EP0425023 (or US42561989, US5126146) has disclosed a kind of device that passes through osmotic pressure controlled release release medicine that contains the cellulosic films clothing of micropore, the average pore size of this micropore is 10 dusts-100 micron, accounts for the 5-95% of film-coat volume.In this patented technology embodiment, the inventor has mentioned a kind of by (solidifying, curing) produce gas in the processing procedure and make thin film form the method for micropore in thin film in the thin film healing.The method of described aerogenesis is volatilization having volatile composition or passing through the chemical reaction process gas in thin film.

In addition, the controlled release in non-water environment that US5798119 has disclosed a kind of film-coat that contains micropore and a release opening discharges the osmotic pumps device of effective ingredient, and this micropore is full of by gas, and its average pore size is the 0.1-30 micron, accounts for the 5-95% of film-coat volume.In this patented technology embodiment, the inventor has mentioned and has utilized the sublimable or degradable composition granule such as Mentholum, naphthalene, Camphora, phenol, ammonium acetate, ammonium carbonate to form the method for micropore in film-coat.

Above-mentioned two patented technologies of the mentioning method that composition (material) with volatilization (or distillation) property in thin film or the composition that can be biodegradable into innocuous gas (material) of degraded in thin film do not form micropore to the utilization volatilization is further described, and there is no so far this type of other correlation techniques simultaneously.The inventor does further deep research to the method, found that, the controlled release preparation fixture of making has some more serious problems, when after middle especially polymer plasticising, its vitrification point (Tg) is low.

For example, the stability of preparation has larger problem: after the controlled release preparation of this technology preparation is deposited a period of time, usually by a relatively large margin the decline of the speed of its Release Performance or release, and the medicament contg in preparation does not have to change substantially or amplitude of variation is relatively much smaller.With microscope, the product of these storages after certain hours observed, be found that the size of the micropore in its thin film has reduced even fully closed than initial period.The degree that micropore reduces is relevant with storage time, and the time, Yu was long, and it is large that the aperture dwindles Yu; The degree that micropore reduces is also relevant with original pore size, and former aperture Yu is large, and it is little that the aperture dwindles Yu, and former aperture Yu is little, and it is large that the aperture dwindles Yu.

For another example, relatively poor production repeatability: some batch drug release is relatively very fast sometimes, but does not mostly very slowly even discharge; Namely use the sublimable material grains of same batch (granular size is consistent) to prepare controlled release preparation system, the drug release rate of the controlled release preparation system that result is made difference between different batches is very large, in the very difficult control of actual production.With microscope, the product of above-mentioned different batches is observed, be found that the more former volatile composition granular size of size of the micropore in its thin film significantly reduces even fully closed; Average pore size difference is very large between different batches, although former volatile composition granule mean size is consistent.

and for example, the Release Performance of the controlled release preparation of this technology preparation or the speed of release usually obviously the water solublity in adopting the equal size in a footpath on the low side preferably material make the film controlled release preparation of porogen, and the micropore that adopts in theory the hollow (existing without porogen) of the equal size in a footpath come controlled release drug the film controlled release preparation should faster than or be not less than at least the film controlled release preparation of the porogen that contains the equal size in a footpath, because porogen need to be dissolved into micropore ability controlled release drug, and porogen need to dissolve and needs the regular hour, certain time stickiness can appear when making drug release.

In addition, the mechanical strength of the preparation that makes as stated above is usually unsatisfactory, when particularly the vitrification point of polymer clothing film (Tg) is higher, because of mechanical strength inadequate, clothing film may be broken by External Force Acting, thereby the dosage that may cause controlled release preparation inclines and releases (dose-dumping), affects drug safety.

Yet in reality, in most cases, art for coating is to carry out under the vitrification point of lower polymer (Tg), as ethyl cellulose (EC) commonly used ( With

) and acrylic resin (Eudragit) etc.Therefore, also need in reality to above-mentioned controlled release preparation particularly the controlled release preparation preparation method that discharges of zero level do further technological improvement.

Goal of the invention

One of main purpose of the present invention just is to provide a kind of polymer intensifier in the above-mentioned controlled release preparation purposes in the controlled release preparation that discharges of zero level particularly.

One of main purpose of the present invention just is to provide particularly controlled release preparation of discharging of zero level and preparation method thereof of a kind of above-mentioned controlled release preparation, and said preparation has relatively high storage-stable aspect release.

Main purpose of the present invention just is to provide particularly controlled release preparation of discharging of zero level and preparation method thereof of a kind of above-mentioned controlled release preparation, and said preparation has relatively high production repeatability aspect release.

Main purpose of the present invention just is to provide particularly controlled release preparation of discharging of zero level and preparation method thereof of a kind of above-mentioned controlled release preparation, and the performance of said preparation aspect release obtains relatively large improvement.

Another main purpose of the present invention just is to provide particularly controlled release preparation of discharging of zero level and preparation method thereof of a kind of above-mentioned controlled release preparation, the release-controlled film of said preparation has mechanical performance relatively preferably, has probability and higher drug safety that lower dosage inclines and releases.

Other purpose sees following description for details.

Summary of the invention

the invention provides the particularly purposes in the controlled release preparation that discharges of zero level of controlled release preparation that polymer release-control clothing films that a kind of polymer intensifier contained numerous release micropores that are filled with air outside coat, particularly above-mentioned release micropore be through distillation fall to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned polymer release-control clothing film and/or decompose be arranged in above-mentioned polymer release-control clothing film pharmaceutically acceptable can be biodegradable into innocuous gas material and, this polymer intensifier is used as delaying the above-mentioned minimizing of aperture in production process and/or storage that is filled with the release micropore of air, wherein, the contact angle of the polymer in above-mentioned polymer intensifier and above-mentioned polymer release-control clothing film is lower than 90 °.

the invention provides the particularly purposes in the controlled release preparation that discharges of zero level of controlled release preparation that polymer release-control clothing films that a kind of polymer intensifier contained numerous release micropores that are filled with air outside coat, particularly above-mentioned release micropore be through distillation fall to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned polymer release-control clothing film and/or decompose be arranged in above-mentioned polymer release-control clothing film pharmaceutically acceptable can be biodegradable into innocuous gas material and, this polymer intensifier is used as improving the stability of rate of releasing drug in storage of above-mentioned controlled release preparation, the contact angle of the polymer in above-mentioned polymer intensifier and above-mentioned polymer release-control clothing film is lower than 90 °.

the invention provides the particularly purposes in the controlled release preparation that discharges of zero level of controlled release preparation that polymer release-control clothing films that a kind of polymer intensifier contained numerous release micropores that are filled with air outside coat, particularly above-mentioned release micropore be through distillation fall to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned polymer release-control clothing film and/or decompose be arranged in above-mentioned polymer release-control clothing film pharmaceutically acceptable can be biodegradable into innocuous gas material and, this polymer intensifier is used as improving the rate of releasing drug repeatability in process of production of above-mentioned controlled release preparation, the contact angle of the polymer in above-mentioned polymer intensifier and above-mentioned polymer release-control clothing film is lower than 90 °.

the invention provides the particularly purposes in the controlled release preparation that discharges of zero level of controlled release preparation that polymer release-control clothing films that a kind of polymer intensifier contained numerous release micropores that are filled with air outside coat, particularly above-mentioned release micropore be through distillation fall to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned polymer release-control clothing film and/or decompose be arranged in above-mentioned polymer release-control clothing film pharmaceutically acceptable can be biodegradable into innocuous gas material and, this polymer intensifier is used as improving above-mentioned controlled release preparation Release Performance, as improve drug release rate, the contact angle of the polymer in above-mentioned polymer intensifier and above-mentioned polymer release-control clothing film is lower than 90 °.

1), contain the core material of at least a bioactive substance the controlled release preparation that the invention provides a kind of performance improvement is the controlled release preparation that discharges of zero level particularly, and this controlled release preparation comprises:, 2), be overlying on numerous clothing films that are filled with the release micropore of air of containing of above-mentioned core material outward, wherein, this clothing film includes pharmaceutically acceptable being insoluble to or polymer and the pharmaceutically acceptable polymer intensifier of water-soluble and Digestive system hardly, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °, above-mentioned release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned polymer release-control clothing film and/or decomposes the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned polymer release-control clothing film to obtain through distillation.

1), preparation contains the core material of at least a bioactive substance the outer quilt that the invention provides a kind of performance improvement contains the particularly preparation method of the controlled release preparation that discharges of zero level of controlled release preparation that numerous polymer release-control clothing films that are filled with the release micropore of air coat, and this preparation method comprises following several basic step:, 2), with contain pharmaceutically acceptable sublimable material grains and/or can be biodegradable into the material grains of innocuous gas and pharmaceutically acceptable polymer intensifier pharmaceutically acceptable is insoluble to or hardly the solution of the polymer of water-soluble and Digestive system or aqueous dispersions to above-mentioned core material coated polymer clothing film, wherein, above-mentioned sublimable material and/or can be biodegradable into the material of innocuous gas and solution or the aqueous dispersions that above-mentioned polymer intensifier was insoluble to or was dissolved in hardly above-mentioned polymer, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °, 3), distillation is fallen to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned polymer release-control clothing film and/or is decomposed the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned polymer release-control clothing film.

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

The term " polymer " reinforcing agent that the present invention uses " refer to be distributed in the polymer phase (continuous phase) in polymer clothing film and can improve or strengthen the pharmaceutically acceptable additive that polymer clothing film comprises the mechanical performance of machinery (mechanics) strength and stiffness with form (decentralized photo) independently.

When the polymer that the term " contact angle " that the present invention uses refers to be in the fluid attitude is positioned at the polymer intensifier surface of solids at liquid (polymer) Gu-formed angle during the balance of (polymer intensifier)-gas (air) tri-state junction; After the polymer that refers in particular to above-mentioned fluid attitude further solidifies and is cooled to 25 ℃ of room temperatures, at solid (polymer) Gu-formed angle during the balance of (polymer intensifier)-gas (air) tri-state junction.

Just one of the quantity that the term " numerous " that the present invention uses refers to the release micropore on outer polymer (controlled release) the clothing film that is overlying on preparation, have a plurality of, usually be not less than 20, usually be not less than 50, especially be not less than 100, more particularly be not less than 1000, particularly be not less than 5000.

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

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

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

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

The specific embodiment

The below introduces the main component in the polymer clothing film (clothing film) of above-mentioned controlled release preparation in detail.

The present invention adopt pharmaceutically acceptable sublimable material and/or can be biodegradable into innocuous gas material as the pore material in polymer clothing film (clothing film) (following pharmaceutically acceptable sublimable material and/or can be biodegradable into innocuous gas material be called the pore material), the composition with the voltinism of rising by distillation in polymer clothing film (clothing film) or the one-tenth that can be biodegradable into innocuous gas of degraded in thin film are assigned to form the release micropore and are come controlled release drug to discharge.

It is its fusing point and sublimable or degradable temperature, the dissolubility in coating solution and mean diameter thereof that above-mentioned pore material affects the key factor of performance of polymer clothing film (clothing film) and controlled release preparation important.Above-mentioned pore material the fusing point under 1 normal atmosphere (101.325ka) and under 1 normal atmosphere (101.325ka) beginning the distillation (sublimation point) or the degraded temperature usually above 40 ℃, preferably be not less than 60 ℃, more preferably be not less than 80 ℃, be not less than best 100 ℃; And above-mentioned pore material under 1 normal atmosphere (101.325ka) fusing point and begin distillation (sublimation point) or the temperature of degraded should be higher than the minimum film formation temperature of the mixing coating solution of above-mentioned polymer or the glass transition temperature of above-mentioned polymer clothing film, usually exceed (containing) 10 ℃, preferably exceed (containing) 20 ℃, goodly exceed (containing) 30 ℃, exceed best (containing) 40 ℃.The dissolubility (temperature 25 ℃, temperature when preferably for art for coating carrying out) of above-mentioned pore material in coating solution should be higher than 30mg/ml, preferably not higher than 10mg/ml, more preferably not higher than 1mg/ml, best not higher than 0.1mg/ml.The mean diameter of above-mentioned pore material should be 30～1200 μ m, is preferably 50～900 μ m, is more preferably 100～600 μ m, is 150～400 μ m best.Because the mean diameter of pore material is impact or the principal element that determines release micropore size in polymer clothing film (clothing film), therefore in the clothing film, release micropore mean size should be positioned at 30～1200 μ m substantially, preferably be positioned at 50～900 μ m, more preferably be positioned at 100～600 μ m, be positioned at best 150～400 μ m.

Too low fusing point, too low sublimable or degradable temperature are unfavorable for the formation of coating and release micropore, the material that also can make sublimable material and/or can be biodegradable into innocuous gas may distil in a large number and degrade in the coating process, lose from the clothing film too early, thereby affect Release Performance and the production repeatability of preparation.Too small release micropore may cause production repeatability and relatively poor etc. the problem of storage-stable in production, the more important thing is, too small release micropore will produce additional press (the Δ P) of larger micropore (because of Δ P=2 σ/r, wherein, Δ P represents the additional pressure of micropore, σ polymer-air surface tension force, r represents pore radius), and additional press (the Δ P) of larger micropore will make micropore slowly dwindle voluntarily in production or storage, it is stable not that thereby the drug release that makes the film controlled release preparation becomes, and the production repeatability is relatively poor.Through experiment confirm repeatedly, its stability is big or small relevant with the release-controlled film micropore size, and micropore size Yu is large, its stable Yu is good, micropore size Yu is little, and its stable Yu is poor, and the amplitude that its stability increases (or minimizing) is larger than the amplitude that micropore size increases (or minimizing).Therefore the present invention adopts relatively large release micropore to come controlled release drug to discharge, and improves the stability of the drug release of preparation with raising.But excessive release micropore also easily causes the problem of the relatively poor grade of production repeatability in production.

The consumption of pore material in coating solution thus in technical field the technical ability those skilled in the art determine according to the character of medicine and desired rate of releasing drug.The consumption of pore material is usually according to decisions such as the kind of its particle diameter, polymer and consumption thereof, the character of medicine, desirable rate of releasing drug, be generally 5%～95% (weight ratio or volume ratio), be preferably 25%～90%, be more preferably 40%～80%, this is based on gross weight or polymer clothing film (clothing film) volume done of polymer clothing film (clothing film) component.

The consumption of pore material is impact or the principal element that determines the porosity of polymer clothing film (clothing film), therefore, the porosity of polymer clothing film (clothing film) should be positioned at 5%～95% substantially, preferably is positioned at 25%～90%, more preferably is positioned at 40%～80%.Term used herein " porosity " refers to fling to the ratio that left space after pore material in polymer clothing film (clothing film) accounts for the volume of whole original copolymer clothing film (clothing film).

the component preferred embodiment that is fit to the sublimable component as the pore material of the present invention or can be biodegradable into innocuous gas includes but not limited to benzoic acid (mp121.5～123.5 ℃, 100 ℃ begin distillation (1atm)), benzoate and benzoate compounds are (as benzoic acid second fat, phenol benzoate, benzoic acid the third fat, benzyl benzoate, essence of Niobe, benzoate such as sodium salt), vanillin (mp81～83 ℃), ethyl vanillin (mp76～81 ℃, sterling mp77～78 ℃), natural or artificial camphor (natural camphor mp176～181 ℃, artificial camphor mp174～179 ℃), gum camphor (approximately 179.8 ℃ of mp, 204 ℃ begin distillation (1atm)), levo-camphor (approximately 178.6 ℃ of mp, 204 ℃ begin distillation (1atm)), raceme Mentholum (alcohol) (mp42～44 ℃), levorotatory menthol (mp41～45 ℃), natural or synthetic borneol (mp205-210 ℃), dextro Borneolum Syntheticum (approximately 208 ℃ of mp), L-Borneol (approximately 204 ℃ of mp), dextrorotation isoborneol (approximately 214 ℃ of mp), left-handed isoborneol (approximately 214 ℃ of mp), raceme isoborneol (approximately 212 ℃ of mp), dithiooxamide (dithio diamides) (approximately 41 ℃ of mp), 6-methyl-2-deracil (methylthiouracil) (approximately 330 ℃ of mp, 326～331 ℃ of decomposition), azulene sulfonate such as sodium salt, butylated hydroxyarisol (mp57～65 ℃), di-tert-butyl hydroxy-methylbenzene (2,6-d-tert-butyl-p-cresol) (mp69～71 ℃), salicylic acid (mp158 ℃, 76 ℃ begin distillation), aspirin, ethenzamide, the caffeine compounds is (as caffeine 1 hydrate (238 ° of mp, 178 ° of distillations), the caffeine anhydride, caffeine citrate, caffeine benzoate such as sodium salt), alanine, leucine, isoleucine, valine, phenylalanine, carbamide, urethane, ammonium halide such as ammonium chloride, ammonium bicarbonate, ammonium carbonate, ammonium acetate and composition thereof.

Be fit to coating polymer of the present invention can for pharmaceutically acceptable be insoluble to or hardly water-soluble and Digestive system block polymer or copolymer.Suitable polymer can be selected from but be not limited to be insoluble to or cellulose esters, acrylic acid (ester) base polymer, polyvinyl acetate, polyvinyl chloride and the compositions thereof of water-soluble and Digestive system hardly.the suitable examples of polymer 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, the vinyl chloride-ethylene acetate copolymer, polrvinyl chloride, polyethylene, polyisobutylene, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride).

Can adopt the commercial latex of supplying of above-mentioned polymer, pseudo-latex and emulsion to carry out coating, (EC) has as ethyl cellulose: With

Acrylic resin has:

RS30D,

RE30D reaches RL30D, acetate fiber rope (CA) has: CA398-10.

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

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

The ratio of coating polymer in drying is according to the kind of selected polymer, kind and the decisions such as consumption, the character of medicine, selected dosage form and desirable drug release mode thereof thereof of pore material, be generally 40%～95% weight ratio, 50%～90% weight ratio preferably, 55%～85% weight ratio more preferably, this is based on the gross weight of doing of polymer clothing film (clothing film) component.

For improving the quality of clothing film, add in the coating of 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, pliability and the intensity of enhancing clothing film are improved the clothing film to the coherent condition of substrate.Usually in general coating process, the glass transition temperature of polymer (Tg) adopts lower value, as 25-80 ℃.In the present invention, the glass transition temperature (Tg) of plasticising post polymerization thing is usually less demanding in 90 ℃, is not less than 15 ℃, is preferably 25～80 ℃, and more preferably 35～70 ℃, more preferably 45～65 ℃; The glass transition temperature (Tg) of polymer clothing film also should begin the temperature that distils or degrade lower than this sublimable material and/or the material that can be biodegradable into innocuous gas under 1 normal atmosphere (101.325ka), usually hang down 10 ℃, preferably hang down 20 ℃, goodly hang down 20 ℃, hang down best 40 ℃.Adopt lower glass transition temperature (Tg) in the present invention, thereby can adopt lower temperature in the coating process, be conducive to like this carrying out smoothly of art for coating, particularly be conducive to reduce distillation or the degraded of pore material work in-process, thereby be conducive to improve Release Performance, technology stability and the production repeatability of preparation.The glass transition temperature (Tg) of polymer clothing film should be too not high, will increase technology difficulty and cost because of higher.

Plasticizer be generally high boiling point, low volatility and can with the liquid substance of the micromolecule (Mr is about 150～800, is preferably 300～500) of Polymers Miscibility or the solid matter of low melting point.The example of accessible plasticizer such as physiology compatible by C ₆～C ₄₀(preferred C ₆～C ₃₀, C particularly preferably ₁₀～C ₁₆) aliphatic or aromatic series one is to tricarboxylic acid and C ₁～C ₈(preferred C ₂～C ₆, C particularly preferably 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 SA ester, Isosorbide Dinitrate, sucrose ester.The example of other accessible plasticizers such as glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini.

The consumption of plasticizer is according to the character of desired 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), 10～30% (weight ratios) particularly preferably, this is based on the gross weight of doing of polymer clothing film (clothing film) component.

It needs to be noted, polymer clothing film adopts lower glass transition temperature (Tg) usually can reduce preparation release storage-stable, the release production repeatability that makes, because of the glass transition temperature of polymer clothing film lower, polymer molecule freely ability or the trend of " flowing " or " slips " is stronger, the release micropore more easily produce and/or preserve (at term of the present invention " storage " when typically referring to preparation and finishing from producing process when being used by user (patient)) reduce even complete closure process; In addition, the space that still is improved of the function performance of above-mentioned polymer clothing film such as tensile property.In order to improve these performances of the preparation that makes, the present invention need to add the particular polymers reinforcing agent at coating solution.Specifically, add in coating solution or coating and the contact angle (θ) of the above-mentioned polymer polymer intensifier lower than 90 °, preferably above-mentioned contact angle (θ) is less than or equal to 60 °, more preferably less than or equal to 30 °, best less than or equal to 10 °." polymer intensifier " described herein refers to be distributed in the polymer phase (continuous phase) in polymer clothing film (clothing film) and can improve the pharmaceutically acceptable additive that polymer clothing film comprises the mechanical performance of machinery (mechanics) strength and stiffness with form (decentralized photo) independently.When the polymer that " polymer intensifier and polymer contact angle " described herein refers to be in the fluid attitude is positioned at the polymer intensifier surface of solids at liquid (polymer) Gu-formed angle during the balance of (polymer intensifier)-gas (air) tri-state junction; More preferably, after the polymer that refers to above-mentioned fluid attitude further solidifies, after particularly solidifying and being cooled to 25 ℃ of room temperatures, at solid (polymer) Gu-formed angle during the balance of (polymer intensifier)-gas (air) tri-state junction.In the present invention, typically refer to static (attitude) contact angle (θ).A kind of to can be used for static (attitude) contact angle of the present invention (θ) assay method example as follows: heating makes temperature greater than the rheological temperature T of polymer _fMake polymer be in the fluid attitude, drip polymer liquid and make it the contact angle that the static surface (being generally the clean, smooth horizontal plane) that is positioned at polymer intensifier records with proper method until (more preferably further solidify and be cooled to 25 ℃ of room temperatures after) after its form stable, for example, the contact angle of directly measuring with microscope or directly measuring on TV image or the photo.

Wish not exclusively to be subjected to the restriction of this principle, contact angle (θ) is commonly referred to be solid by the moistening quantification pointer of liquid, and Yu is little for contact angle (θ), and solid is large by moistening degree Yu of liquid, and compatibility Yu between both is good, the affinity Yu Qiang between both.When the contact angle of polymer and polymer intensifier lower than 90 °, more very less than or equal to 60 °, especially less than or equal to 30 °, during particularly less than or equal to 10 °, between polymer and polymer intensifier, the compatibility is better, stronger affinity is arranged both, " moistened surface " can occur even " expand ".At this moment, because of polymer and the mutual active force of polymer intensifier stronger, and polymer intensifier is with particulate matter (molecule aggregation body) or figuratively speaking be scattered in polymer with the form on " island ", the ability of polymer molecule free " flowing " or " slip " is aggregated the thing reinforcing agent and weakens, the freedom of polymer molecule " flows " or the scope of " slip " is aggregated in the scope that the thing reinforcing agent is limited in less, show " viscosity " on the polymer macroscopic view and rise, " mobility " descends.Thereby, above-mentioned polymer intensifier can weaken or delay produce and/or storage in (as distillation and/or decompose the above-mentioned sublimable material that is arranged in above-mentioned polymer clothing film and/or can be biodegradable into the material etc. of innocuous gas) established release micropore dwindle voluntarily or closed etc. variation tendency, the effect with stable release micropore size.Therefore, above-mentioned polymer intensifier can improve (or improve) preparation storage-stable and production repeatability, Release Performance etc., but also can increase the mechanical strength of clothing film, reduces the probability that the dosage of preparation inclines and releases, and improves drug safety.

Above-mentioned contact angle has reacted the compatibility or the affinity between polymer and polymer intensifier indirectly.The compatibility between polymer and polymer intensifier or affinity also can be used " similar compatibility " principle and estimate or predict, as polarity or nonpolar similarity.

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

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

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

Can be used for polymer intensifier of the present invention and include but not limited to the acceptable filler reinforcing agent of pharmacy, microfibre reinforcing agent and composition thereof.

Can be used for filler reinforcing agent of the present invention and can be the acceptable rigid inorganic particle of pharmacy and Rigid Organic Fillers.Can be used for the thin or ultra-fine grain that rigid inorganic particle of the present invention includes but not limited to carbonate, Sulfates, metal-oxide, metal powder, carbon element compound, silicon-containing compound (as Si oxide, silicate) and composition thereof.Can be used for the preferred example of rigid inorganic particle of the present invention and include but not limited to attapulgite, soap clay, calcium carbonate, calcium sulfate, barium sulfate, white carbon black, silicon dioxide, aluminium oxide, zinc oxide, titanium dioxide, kaolin, Muscovitum, Talcum, calcium phosphate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium trisilicate.being used for rigid inorganic particle of the present invention has preferably used surfactant (as higher fatty acids, higher fatty acid salt, high-grade aliphatic ester) or macromolecule dispersing agent (as polyolefin, polyester, polyacrylate or polyethers) adsorb the parcel processing or use organo silane coupling agent, titanate coupling agent, the zirconium aluminate coupling agent, the coupling agent treatment such as aluminate coupling agent or grafting or block polymerization or encapsulated polymerization or carried out surface modification with other suitable methods on particle surface.Can be used for the preferred example of Rigid Organic Fillers of the present invention and include but not limited to polymethyl methacrylate (PMMA), polystyrene (PS), methyl methacrylate/styrol copolymer (MMA/ST) and styrene/acrylonitrile copolymer (SAN).

The mean diameter of above-mentioned rigid particles (diameter) is not more than 1 μ m usually, preferably is not more than 400nm, more preferably is not more than 100nm, more more preferably is not more than 20nm, is not more than best 5nm.Nano level particle (being not more than 100nm) can improve intensity, toughness, impact resistance and release pore size stability to a greater degree simultaneously, thereby is preferred.

Can be used for microfibre reinforcing agent of the present invention and comprise inorganic microfibre, organic microfibre and metal microfibre.Inorganic microfibre is the chemical microfibre of making take mineral as raw material, available example such as glass microfiber, quartz glass microfibre, boron microfibre, ceramic microfibre and metal microfibre etc.Available organic microfibre example such as synthetic microfibril such as aramid fiber microfibre, Orlon microfibre, polyester microfiber, nylon microfibre, the little synthetic fibre fiber of dimension Buddhist nun, Polypropylene Tiny Fiber, polyimides microfibre etc.; Natural microfibre such as cotton microfibre, sisal hemp microfiber, wooden microfibre etc.The example of metal microfibre is as metal microfibres such as silver, copper, nickel.

This paper term as used herein " microfibre " refers to that the length-width ratio due to them can be described as the granular materials of fiber usually, and the length-width ratio that is used for the preferred microfibre of this paper is approximately 10: 1-approximately 500: 1, more preferably from about 25: 1-300: 1.The average diameter of above-mentioned fiber is not more than 1 μ m usually, preferably is not more than 400nm, more preferably is not more than 100nm, more more preferably is not more than 20nm, is not more than best 5nm.The average length of above-mentioned fiber is not more than 100 μ m usually, preferably is not more than 10 μ m, more preferably is not more than 1 μ m, is not more than best 100nm.

The rigid particles that is used for enhancing by polymer of the present invention particularly rigid polymer can also outer be overlying on the polymer toughening agent (" the polymer toughening agent " herein stated refers to have the acceptable composition of pharmacy that reduces clothing film fragility and raising clothing film shock resistance, lower same), thus form " duricrust-soft nuclear structure ".In above-mentioned " nucleocapsid structure ", " shell " can coat " core " wholly or in part; Can contain one or more " cores " in " shell "; Can also contain less " core " in " shell "; Shell " in " core " in also can comprise the component of " shell " or less " nucleocapsid structure "; Can also be more complicated hard/soft/hard three layers; The particle of soft/hard/soft/mode such as hard four layers.Above-mentioned " nucleocapsid structure " particle has enhancing and toughness reinforcing effect preferably simultaneously, and effect is better than simple polymer intensifier or polymer toughening agent, therefore be preferred.In above-mentioned " nucleocapsid structure ", " shell " accounts for the 0.5-50% of total volume usually, preferably 1-30%, more preferably 2-10%.

it is believed that, above-mentioned " nucleocapsid structure " particle also has to be increased the clothing membrane polymer " mobility " during higher than its glass transition temperature (Tg) reaches " ductility " in temperature, reduce " melt " inner tensions and can also keep higher " melt " intensity simultaneously, accelerate " melting ", promote " plasticizing ", improve " processability ", these are conducive to coating and the healing of polymer clothing film (clothing film), shorten the time that their machinings need, reduce volatilization or the degraded of above-mentioned porogen in the above-mentioned course of processing, thereby the effect with stronger stable release micropore size.Therefore, above-mentioned " nucleocapsid structure " particle in the present invention most preferably.

In suitable conduct " nucleocapsid structure ", the composition of " core " is that the polymer toughening agent comprises natural and synthetic elastomeric polymer, as natural rubber, synthetic rubber and thermoplastic elastomer (TPE).They are usually derived from various monomers, as alkene (as the ethylene in C2-C8 alkene, propylene, 1-butylene, 4-methyl-1-pentene), alkenyl aromatic monomer (as the styrene in the C2-C8 alkenyl aromatic monomer and α-methyl styrene), conjugated diene (as the butadiene in the C4-C8 conjugated diene, isoprene and chlorobutadiene) and vinyl carboxylic acid and derivant (as vinyl acetate, acrylic acid, alkyl acrylic, ethyl acrylate, methyl methacrylate, acrylonitrile) thereof.They can be homopolymer, can be also copolymers.

More particularly, comprise being not limited to all polymer rubber sills those as deriving from acrylic acid, MBS (MBS) type impact modifier; Siliceous rubber polymer and copolymer, as siloxanes, silicone etc.; Synthetic rubber, as butadiene rubber, SBR styrene butadiene rubbers (SBR), and isoprene, etc.; Contain flexible chain to reduce the polymer of glass transition temperature, as polyester; TPO; Vinyl aromatic hydrocarbons-diene block copolymers; Polyurethanes; The rubber-like polyethers, as the polymer of ethylene glycol and propylene glycol, etc.; And their blend, graft, and copolymer.

In suitable " nucleocapsid structure " of the present invention, the composition of " core " is that the polymer toughening agent can comprise polyolefin polymer, and it is C _nH _2nGeneral structure, comprise polyethylene, polypropylene and polyisobutylene, preferred homopolymer is polyethylene, ULDPE (ultra-low density polyethylene), LLDPE (linear low density polyethylene), HDPE (high density polyethylene (HDPE)) and MDPE (medium density polyethylene) and isotactic polypropylene.Vistanex of this general structure and preparation method thereof is well-known in the art, and sees and for example be set forth in U.S. Patent number 2933480,3093621,3211709,3646168,3790519,3884993,3894999,4059654,4166055 and 484334.

In suitable " nucleocapsid structure " of the present invention, the composition of " core " is that the polymer toughening agent also can comprise various polyolefinic copolymers, as the propylene of ethylene and alpha-olefines and the copolymer of 4-methyl-1-pentene.The copolymer (being referred to as the EPDM copolymer herein) of suitable example such as ethylene and C3-C10 monoolefine and non-conjugated diene.

In suitable " nucleocapsid structure ", the composition of " core " is that the polymer toughening agent can also comprise conjugated diene homopolymers and random copolymer.Its example comprises polybutadiene, BS, butadiene-propylene acid ester copolymer, isoprene-isobutylene copolymers, chloroprene polymer, butadiene acrylonitrile polymer, polyisoprene.

Suitable " nucleocapsid structure " particle example as mechanical performance improving agent (polymer intensifier) comprises AB (two-block), (AB) m-R (two-block) and ABA ' (three-block) block copolymer.Block A and A ' are generally alkenyl aromatic units, and B block is generally conjugated diene unit.For the block copolymer of formula (AB) m-R, integer m is at least 2, and R is the multifunctional coupling agent that is used for the block of structure AB.Suitable especially example such as polystyrene-poly butadiene (SBR), polystyrene-poly (ethylene-propylene), polystyrene-poly isoprene, poly-(α-methyl styrene)-polybutadiene, polystyrene-poly butadiene-polystyrene, polystyrene-poly (ethylene-propylene)-polystyrene, polystyrene-poly isoprene-polystyrene and poly-(α-methyl styrene)-polybutadiene-poly-(α-methyl styrene) with and selective hydration product etc.Also can use the mixture of aforementioned block copolymer.This analog copolymer can be available from multiple channel, as comprise commodity, the Shell Chemical Co. of the S OLPRENE by name of Phillips Petroleum, the commodity of commodity, Dexco VECTOR by name of KRATON by name and the commodity of the SEPTON by name of Kuraray.

Another suitable " nucleocapsid structure " particle example as mechanical performance improving agent (polymer intensifier) is as comprising the star block copolymer of vi-ny l aromatic monomers and conjugate diene monomer.The copolymer of the type generally comprises the polymerization of vinyl aromatic monomer of about 60% to 95% (weight) and the about polymerized conjugated diene monomer of 40% to 5% (weight).Described copolymer has at least 3 polymer chains that form the star configuration.The end of each chain is connected with the stiff segment of being essentially of elastomeric polymer segment on it.Sometimes these block copolymers are called " branching " polymer (described in U.S. Patent number 4097550), and its consumption is similar to other conjugated diene as the mechanical performance improving agent.

suitable " nucleocapsid structure " particle example as mechanical performance improving agent (polymer intensifier) also comprises but is confined to polyethylene-vinyl acetate (EVA), ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer (E-VA-CO), ethylene-C1～C8 (alkyl acrylic-carbonyl (carbon list oxide) trimer of preferred C1～C4), ethylene-C1～C8 (preferred C1～C4) alkyl acrylic copolymer and acrylic nitrile-butadiene-styrene (ABS).

The present invention's above-mentioned " nucleocapsid structure " particle used is stored in polymer clothing film (clothing film) as mechanical performance improving agent (polymer intensifier) with certain shape and big or small particle.About its shape, the particle that consists of described " nucleocapsid structure " typically is spherical.But they can have any suitable shape, and the particle of various shapes can be by the known method preparation of polymer particle technical field.The example of the shape of particle that other are fit to includes but not limited to: draw ratio greater than the ellipsoid particle of 1: 1, certain kind of berries shape particle, multi-petal shape particle, dumb-bell shape grain in, aggregated particle, bivalve shape particle and hollow ball particle etc.About its size, its mean diameter (diameter) is not more than 1 μ m usually.Preferably, its mean diameter is not more than 400nm, more preferably is not more than 100nm, more more preferably is not more than 20nm, is not more than best 5nm.Usually, less particle is conducive to improve shock strength.

Fusing point (or the crystal melting temperature of " nucleocapsid structure " particle of suitable mechanical performance improving agent of the present invention (polymer intensifier), Crystalline Melt Temperature) or/and Vickers softening point (Vicat Softening Point) is not less than the glass transition temperature (Tg) of the polymer in above-mentioned clothing film usually, preferably exceed its 5 ℃ (containing), more preferably exceed 10 ℃ (containing), exceed best 20 ℃ (containing); And its (center) vitrification point (Glass Transition Temperature) requires the glass transition temperature (Tg) lower than the polymer in above-mentioned clothing film usually, usually not higher than 15 ℃ of temperature, best not higher than 0 ℃ of temperature; In addition, above-mentioned " nucleocapsid structure " particle also should have mechanical performance preferably, as higher resistance to tension, has than high elongation at tear or fracture tensile strength.

Suitable other parameters of " nucleocapsid structure " particle as mechanical performance improving agent (polymer intensifier) are preferably as follows: fusing point (or crystal melting temperature, Crystalline Melt Temperature) (DSC, via ASTM D3418 ISO 3146) or/and Vickers softening point (Vicat Softening Point, via ASTM D1525 ISO 306) be preferably 60～2000 ℃, more preferably 80～1000 ℃, be particularly preferably 100～500 ℃; Vickers softening point (Vicat Softening Point, via ASTMD1525 ISO 306) is preferably 45～150 ℃, more preferably 45～100 ℃, is particularly preferably 50～80 ℃; Elongation at break (Tensile Elongation@Break) is preferably 200～5000% (via ASTM D638/ISO 527-2); Fracture tensile strength (Tensile Strength@Break) is preferably 1～50MPa (via ASTM D638/ISO 527-2); (center) vitrification point (Glass Transition Temperature) is preferably-10～-200 ℃ (via ASTM D5418loss modulus peak at 1hz); (190 ℃/2.16kg) be preferably 0.5～150g/10min (via ASTM D1238 ISO 1133), more preferably 1～100g/10min, be particularly preferably 2～50g/10min to melt flow rate (MFR) (Melt Flow Rate).

The common consumption 0.5～50% of polymer intensifier (weight ratio), 1%～30% (weight ratio) preferably, 2%～20% (weight ratio) more preferably, this is based on the gross weight of doing of polymer clothing film (clothing film) component.

the example of clothing membrane polymer and polymer intensifier use in conjunction is, the clothing membrane polymer is selected from being insoluble to of polar functionalities or the polymer of water-soluble and Digestive system hardly, as the cellulose esters base polymer, acrylic acid (ester) base polymer, polyvinyl acetate, and polymer intensifier is selected from the thin or ultra-fine grain (particle diameter preferably is not more than 100nm (diameter)) of the rigid inorganic particle of polarity, as carbonate, sulfate, metal-oxide, Si oxide, silicate and composition thereof, more preferably use polarity macromolecule dispersing agent (as polyacrylate) absorption parcel processing mode for it and carried out the thin or ultra-fine grain (particle diameter preferably is not more than 100nm (diameter)) of surface modification.The example of the cellulose esters base polymer of above-mentioned polar functionalities such as cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose.the acrylic acid of above-mentioned polar functionalities (ester) base polymer, but the application example of polyvinyl acetate includes but not limited to polyvinylacetate, methacrylic acid (ester) polymer, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, polyvinylacetate, ethyl acrylate-ethyl acrylate-chlorination trimethyl amino-ethyl Methyl metacrylate 99 polymer (poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride)).

the example of preferred clothing membrane polymer and polymer intensifier use in conjunction is, the clothing membrane polymer be selected from contain non-polar group be insoluble to or hardly the cellulose esters base polymer of water-soluble and Digestive system (as ethyl cellulose, the lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses), and polymer intensifier is selected from surfactant (as higher fatty acids, higher fatty acid salt, high-grade aliphatic ester) absorption parcel processing mode has been carried out the polarity rigid inorganic particle of surface modification, as carbonate, sulfate, metal-oxide, Si oxide, thin or the ultra-fine grain (particle diameter preferably is not more than 100nm (diameter)) of silicate and composition thereof, the nanometer grade calcium carbonate particle (particle diameter preferably is not more than 100nm (diameter)) that coated by stearic acid of surface particularly preferably.

the example of another preferred clothing membrane polymer and polymer intensifier use in conjunction is, the clothing membrane polymer is selected from and is insoluble to or the cellulose esters base polymer of water-soluble and Digestive system hardly, and the polymer intensifier particle is selected from the copolymer of methyl methacrylatestyrene (MMA-ST) that contains simultaneously polarity and non-polar group, SAN (SAN), styrene-butadiene-acrylonitrile trimer (ABS), MBS (MBS), ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer (E-VA-CO), ethylene-C1～C8 (alkyl acrylic-carbonyl (carbon list oxide) trimer of preferred C1～C4), ethylene-(((particle diameter preferably is not more than 400nm (diameter) for the alkyl acrylic copolymer of preferred C1～C4) or their mixture for C1～C8), more preferably no more than 100nm (diameter)), copolymer of methyl methacrylatestyrene (MMA-ST) wherein, MBS (MBS) is for more preferably.But the application example of above-mentioned cellulose esters base polymer includes but not limited to ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose and their mixture.

the example of another preferred clothing membrane polymer and polymer intensifier use in conjunction is, the clothing membrane polymer is selected from and is insoluble to or acrylic acid (ester) base polymer of water-soluble and Digestive system hardly, and the polymer intensifier particle is selected from polymethyl methacrylate (PMMA), copolymer of methyl methacrylatestyrene (MMA-ST), MBS (MBS), ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer (E-VA-CO), ethylene-C1～C8 (alkyl acrylic-carbonyl (carbon list oxide) trimer of preferred C1～C4), ethylene-C1～C8 (alkyl acrylic copolymer of preferred C1～C4), (particle diameter preferably is not more than 400nm (diameter) for crylic acid resin anti-impact modifier or their mixture, more preferably no more than 100nm (diameter)).But the application example of above-mentioned polymer includes but not limited to be insoluble to or methacrylic acid (ester) polymer, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, the ethyl acrylate-ethyl acrylate-chlorination trimethyl amino-ethyl Methyl metacrylate 99 polymer (poly (ethylacrylate of water-soluble and Digestive system hardly, methylmetacrylate, trimethylamonioethylmetacrylatchloride)) and their mixture.

the example of another preferred clothing membrane polymer and polymer intensifier use in conjunction is, the clothing membrane polymer is selected from and is insoluble to or the polyvinyl acetate of water-soluble and Digestive system hardly, and the polymer intensifier particle is selected from copolymer of methyl methacrylatestyrene (MMA-ST), SAN (SAN), styrene-butadiene-acrylonitrile trimer (ABS), MBS (MBS), ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer (E-VA-CO), ethylene-C1～C8 (alkyl acrylic-carbonyl (carbon list oxide) trimer of preferred C1～C4), ((particle diameter preferably is not more than 400nm (diameter) to ethylene-C1～C8 for the alkyl acrylic copolymer of preferred C1～C4) and their mixture, more preferably no more than 100nm (diameter)).But the application example of above-mentioned polymer includes but not limited to terpolymer, vinyl chloride-vinyl acetate copolymer and their mixture of polyvinylacetate, vinyl chloride-ethylene alcohol-vinylacetate.

the example of another preferred clothing membrane polymer and polymer intensifier use in conjunction is, the clothing membrane polymer is selected from polrvinyl chloride, and the polymer intensifier particle is selected from copolymer of methyl methacrylatestyrene (MMA-ST), SAN (SAN), styrene-butadiene-acrylonitrile trimer (ABS), MBS (MBS), ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer (E-VA-CO), ethylene-C1～C8 (alkyl acrylic-carbonyl (carbon list oxide) trimer of preferred C1～C4), ((particle diameter preferably is not more than 400nm (diameter) to ethylene-C1～C8 for the alkyl acrylic copolymer of preferred C1～C4) or their mixture, more preferably no more than 100nm (diameter)).

((commodity of the had listing of alkyl acrylic copolymer of preferred C1～C4) are as DuPont company for alkyl acrylic-carbonyl (the carbon list oxide) trimer of preferred C1～C4), ethylene-C1～C8 for above-mentioned ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer (E-VA-CO), ethylene-C1～C8

Series of products (as Elvaloy AC 1,2,3 series, Elvaloy HP series).The crylic acid resin anti-impact modifier can have the commodity of listing such as the nanoscale product P ARALOID BP series of products that Rohm and Haas company produces.

Can add clothing film universal additive material in the coating solution that invention relates to.The addition of clothing film 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 affect the permeability of clothing layer, and this equally can be as additional adjusting parameter.

Being described below of the additive that some are commonly used.

Antitack agent (separating medium)

Separating medium is generally useful hydrophobic material, generally adds to spray in suspension.They stop the gathering of core between film forming stage.The preferred Talcum that uses, magnesium stearate or calcium stearate, the silicic acid of porphyrize, Kaolin or HLB value are 3～8 nonionic emulsifier.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 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 interface active agent is arranged, and aqueous dispersion is played Stabilization.suitable stabilizing agent example is if any diethanolamine, monoethanolamine, triethanolamine, fatty acid, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), nonoxynolum, octoxinol, oleic acid, poloxamer, polyoxyethylene 50 stearate, polyethylene glycol fatty acid class (Polyoxyl fatty acid), polyethylene glycol alkyl ether (Polyoxyl hydrocarbon ether), polysorbate (Tween), sorbitan ester (Span), fatty acid salt, polyvidone, sodium lauryl sulfate, cetyl stearyl sodium sulfate, sucrose stearate fat, Spheron MD 30/70 and composition thereof.The content of stabilizing agent is 1～15% (weight ratio), preferred 5～10% (weight ratios), and this is based on the wet weight of aqueous dispersion coating solution component.

Pigment

Seldom add with the solubility pigment form.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 the pigment binding ability is high, addition also can be as high as 100% (weight ratio).

Defoamer

Defoamer is typically dimethicone.

In 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.The consumption of requirement when being manufactured in polymeric layer accounts for 0.1～2% of pharmaceutical dosage form weight.

In the clothing film, the material of all uses must be pharmaceutically acceptable, nontoxic in principle, in medicine to patient without danger.

The below explains the present invention's core material used.

Can be used for of the present inventionly being included but not limited to rule or irregular form sheet, granule, (little) ball, crystal, medicine carrying resin by the core material of coating (carrier).The size of granule, (little) ball or crystal is generally 0.01～2.5mm, and the size of sheet is usually at 2.5～30mm.The bioactive substance (active substance) that they usually contain and be up to 95% (weight ratio, below without specifying herewith) and other pharmacy auxiliary agent that is up to 99.9%.

Be used for bioactive substance of the present invention (active substance) except those are degraded because of heat effect in preparation process, volatilization, inactivation cause that drug effect loses, just there is no other restriction, if but use that certain method (as cyclodextrin inclusion compound, microencapsulation technology) can prevent that bioactive substance from degrading in preparation process, volatilization, inactivation, these bioactive substances also can be used for the present invention.

As the present invention's active component used, can be above-mentioned any pharmaceutically or the threpsology on have material therapeutical effect or preventive effect.The present invention can with the active component example be 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, isopropyl 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.

-adjusting blood fat 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:

-drugs for antiacid and peptic ulcer diseases: 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.

-affect 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 affect 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.

-affect 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 are fragrant, fluorine Lamine, oxazimedrine, fenproporex, phentermine, furfenorex.

-other drug: finasteride, Alendronate sodium, alosetron, orlistat, epristeride, epalrestat, tolterodine, tolrestat, Chinese herbal medicine extract.

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, emedastine difumarate, 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 GENTAMICIN is mould, 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, ticlopidine, ibudilast, dextromethorphan, ZHENGQINGFENGTONGNING, the 5-isosorbide-mononitrate, sodium valproate, Benserazide, gentamycin sulfate-zirconium dioxide compound recipe, chlorphenamine maleate, barnidipine, bunazosin, gallopamil, methylphenidate hydrochloride, oxycodone hydrochloride, Chinese herbal medicine extract.

Due to, the controlled release preparation that the present invention relates to particularly osmotic pump type controlled release preparation can synchronously be released preparation to the various compositions in Chinese herbal medicine extract, do not exist the active component that occurs because constitutive property is different to discharge nonsynchronous problem, therefore, the controlled release preparation that the present invention relates to particularly osmotic pump type controlled release preparation need to be specially adapted to the controlled release Chinese herbal medicine extract.

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

Core material can also contain other pharmacy auxiliary agent except bioactive substance, as bases such 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 (permeation-promoter).In addition, can also comprise solubilizing agent, suspending agent, sweeting agent, aromatic, pigment, absorbent and surfactant (as playing the 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 below elaborates with regard to each basic step in the preparation method of controlled release preparation.

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

The preparation method that is used for core material of the present invention is bright without particular limitation at this.Usually; the core material preparation method can adopt direct pressing method; do, the pressing method of wet or sintered particles; extrude and rounding method subsequently; wet or dry state pelletize or directly make ball (for example on disk) method; perhaps adopt powder (powder bed) to be bonded to the ball (particle) of non-activity material or to contain method on the granule of active substance, perhaps adopt in a certain way as make the method for tablet, perhaps mix the use said method.

2), coating steps: with contain sublimable material and/or can be biodegradable into the material grains of innocuous gas and polymer intensifier be insoluble to or solution or the aqueous dispersions of the polymer of water-soluble and Digestive system coat the clothing film to above-mentioned core material hardly, this sublimable material and/or the material that can be biodegradable into innocuous gas are insoluble to or are dissolved in hardly solution or the aqueous dispersions of this polymer, and the contact angle of this polymer and polymer intensifier is lower than 90 °.

In the present invention, the step that the core material that contains at least a bioactive substance is coated the clothing film also comprises the following step (process) in more detail usually.

A), with sublimable material and/or can be biodegradable into the material grains of innocuous gas and polymer intensifier disperses and suspendible or be dissolved in is insoluble to or hardly in the solution or (water) dispersion suspension of the polymer of water-soluble and Digestive system, in case of necessity, also can add other polymer clothing film (clothing film) universal additive such as polymeric plasticizers, even can also add bioactive substance, mix homogeneously must mix coating solution.What need particularly point out is, above-mentioned sublimable material and/or the material that can be biodegradable into innocuous gas are insoluble to or are dissolved in hardly solution or the aqueous dispersions of above-mentioned polymer, and the contact angle of above-mentioned polymer and polymer intensifier is lower than 90 °.The solvent of above-mentioned polymer or dispersant are pharmaceutically acceptable organic solvent and water or their mixture.When above-mentioned sublimable material and/or the material that can be biodegradable into innocuous gas are insoluble to or are dissolved in hardly certain pharmaceutically acceptable organic solvent, and this organic solvent can select this organic solvent as the solvent of above-mentioned polymer can dissolve above-mentioned polymer the time; When above-mentioned sublimable material and/or the material that can be biodegradable into innocuous gas is insoluble to or when water-soluble hardly, preferably select water as the dispersant of this polymer, namely select the aqueous dispersion of polymer.Available organic solvent of the present invention includes but not limited to ethanol, propylene glycol, oxolane, n-butyl alcohol, 2-butanols, butanone, propyl acetate, isopropyl acetate, Ethyl formate, pentane, normal propyl alcohol, 2-propanol, dichloromethane, acetone, ether, ethyl methyl ether, ethyl acetate, methyl acetate and their mixture.The content of above-mentioned polymer in organic solution is generally 0.5～12%, and preferably 1～8%, more preferably 2～5%.The content of above-mentioned polymer in the aqueous dispersion suspension is generally 5～30%, and preferably 8～20%, more preferably 10～15%.

B), utilize the mixing coating solution of above-mentioned gained by coating processes such as melting, casting, brushing or sprayings, the above-mentioned core material that makes to be prepared the clothing layer.Preferably adopt spraying method to carry out.Film forming procedure does not rely on coating process and is undertaken by energy input.This can complete by convection current (heat), radiation (infrared or microwave) or conduction.Thus will be for organic solvent or the water of coating as solvent or suspending agent use evaporate, necessary words also may be used vacuum and accelerate evaporation.The higher drying efficiency of this process need, so the present invention often adopts high efficiency coating equipment in sugar production line (as fluid bed, high-efficiency coating pot).

Before the core material coating, also can be according to reality to core material bag sealing coat clothing, this helps: 1. avoid medicine to migrate to the clothing film with solvent or dispersant (water); 2. improve the core material friability, avoid the Fragmentation Phenomena in the coating process; 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. avoid the water sensitivity medicine to be hydrolyzed in the coating process.According to practical situation, can select water-soluble polymer (as Gonak and hydroxypropyl fibrinolytic liquid) 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.

during coating, the core material surface temperature should (minimum film formation temperature refers to the minimum temperature of polymer formation seriality clothing film higher than the minimum film formation temperature (MFT) of polymer, below minimum film formation temperature, polymer particle can not be out of shape and merge and film forming), usually exceed 10～20 ℃ of minimum film formation temperature, thereby but the core material surface temperature is should be high fully softening or melt the clothing film is sticked together to some materials that make the coating material, and should do not softened fully or melt or degrade by high some compositions in core material yet, the core material surface temperature is especially answered height to the sublimable material that makes the coating material and/or be can be biodegradable into a large amount of distillations of material of innocuous gas and degrade, therefore, the core material surface temperature is preferably lower than sublimable material and/or can be biodegradable into the fusing point of material of innocuous gas or at least 10 ℃ of its sublimable or degradable temperature, more preferably 20 ℃, 30 ℃ best.The core material surface temperature can not be too low in the present invention, makes because the core material surface temperature is too low that the clothing film is easily crisp the crack may occur, affects the preparation drug release feature; Simultaneously, the core material surface temperature can not be too high, because of the too high too softening polymer of core material surface temperature, causes the clothing film coalescence, but also can make sublimable material and/or can be biodegradable into a large amount of distillations of material of innocuous gas and degrade, and loses from the clothing film too early.

During coating, (when adopting polymer organic solution, this temperature is relatively low for the common preheating of core material, when adopting aqueous polymer dispersion, this temperature is relatively high) to 20～70 ℃, preferably 30～60 ℃, more preferably 30～50 ℃, first with low hydrojet speed coating, after having coated skim clothing film to the core material surface, improve hydrojet speed to coating again and finish, this operation can be avoided solvent, and especially dispersant (water) infiltration core material is inner, causes storage process core material character to change.

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

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

3), fling to the pore material

In the present invention, the pore material demand in preparation clothing film flings to obtain the satisfied clothing film of rate of releasing drug control of certain porosity.

The pore material is flung to, usually carry out under lower than clothing film glass transition temperature and normal pressure, decompression or vacuum, preferably carry out at lower than the temperature of clothing film glass transition temperature below 5 ℃, carry out at lower than the temperature of clothing film glass transition temperature below 10 ℃ best.Too high temperature may make established release micropore dwindle even fully healing, and severe patient causes the clothing film coalescence.

4), healing (curing) is processed

The present invention is for the stability of the drug release that improves preparation, preferably in step 2) in (coating) process and/or step 2) after (coating) finish, and step 3) (flinging to the pore material) is front, the above-mentioned clothing film of healing processing produces numerous minimum micropores and forms fine and close clothing film to eliminate in the coating process in the clothing film, to guarantee the relatively stable of drug release.

After coating finished, the solvent of polymer or dispersant volatilized substantially in the clothing film, leave many minimum micropores in the clothing film, and in the clothing film, polymer particle does not often merge fully.It is believed that, under the additional pressure of micropore (Δ P) effect that the interfacial tension between polymer-air produces, these minimum micropores slowly dwindle automatically, deposit fusion phenomenon occurs in process, make the permeability of clothing film occur constantly to change, thereby make the drug release behavior of preparation become unstable.According to additional formula (the Δ P=2 σ/r that presses (Δ P) of micropore, wherein, Δ P represents the additional pressure of micropore, σ polymer-air surface tension force, r represents pore radius) can push away, the interfacial tension size between, polymer-air big or small with the membrane micropore footpath etc. is relevant usually to merge required time.Polymer-air surface tension force one timing, the membrane micropore footpath is less, and the additional pressure of micropore is larger, merges required time shorter, and the membrane micropore footpath is larger, and the additional pressure of micropore is less, merges required time longer.Just because of this, the present invention adopts relatively large micropore to come controlled release drug to discharge, and eliminates in the coating process the numerous minimum micropore that produces because of solvent or dispersant volatilization.

The present invention assigns to form the release of micropore controlled release drug by the composition with the voltinism of rising or the one-tenth that can be biodegradable into innocuous gas of degraded in thin film that distil in thin film, and these relatively large micropores still can produce additional press (the Δ P) of certain micropore in the healing processing process, make micropore dwindle to a certain extent (as micropore less than 30 μ m time, during particularly less than 1 μ m).For the relatively large micropore that controlled release drug discharges that is used for that prevents or delay that these have produced dwindles at healing processing, improve stability (relevant to Release Performance) and the production repeatability of the transparent performance of clothing film, stability and the production repeatability of the aspects such as raising clothing film mechanical performance, in the present invention, clothing film healing processing process best be used for relatively large micropore that controlled release drug discharges form before (before namely flinging to the pore material) complete.

The healing processing process is completed before flinging to the pore material and is flung to the pore material and healing processing carries out simultaneously and healing processing is completed many incomparable advantages after flinging to the pore material.Healing processing with fling to that the pore material carries out simultaneously and healing processing carries out or complete the healing processing terminal point that can't reach expection after flinging to the pore material; although perhaps healing is reached home; but very slowly not release even substantially of drug release; because of in the healing processing process; establishedly comprise micropore that controlled release drug discharges and also constantly dwindling even until fully closed, and make the transparent performance of clothing film or drug release feature, mechanical performance etc. be difficult to stable and reappear.The healing processing process complete before flinging to the pore material can so that the pore material that can distil and/or degrade all the time clean amount of solid be arranged in unchangeably the clothing film, avoid being dwindled in clothing film agglutination by the release micropore that the pore material produces, the clothing film is healed fully, can eliminate the numerous minimum micropore that is produced by solvent evaporates in the clothing film fully and form fine and close clothing film in the coating process, thus transparent performance or Release Performance, mechanical performance etc. stable, that reappear and improve the clothing film.

in the present invention, healing processing (curing treating) comprises following process: after in above-mentioned clothing film, solvent or dispersant (water) evaporate substantially, in enclosed environment, the core material of the above-mentioned clothing of coated polymer film is placed in higher than the long enough time at the temperature of the glass transition temperature of above-mentioned clothing film until terminal point, polymer particle in above-mentioned preparation clothing film is merged completely or almost completely, eliminate or substantially eliminate the minimum micropore that forms in the coating process and form complete densification or the clothing film of substantially complete densification, the permeance property of above-mentioned clothing film Release Performance in other words reaches stable state substantially constant state in other words.More particularly, exactly at higher than the temperature of the vitrifying point of above-mentioned clothing film the above-mentioned coated preparation of healing processing until preparation for example approximately the temperature of 40 ± 2 ℃ and be not less than 50% and not higher than above-mentioned sublimable material grains and/or can be biodegradable into place under accelerated storage condition under the relative humidity of (moisture absorption) critical relative humidity of material of innocuous gas 3 months and/or 6 months or longer as 9 months or 12 months its dissolution characteristics basically unaffected till.Perhaps in other words, with the In Vitro Dissolution of the bioactive substance after firm healing processing with approximately 40 ± 2 ℃ temperature and be not less than 50% and not higher than above-mentioned sublimable material grains and/or the In Vitro Dissolution that can be biodegradable into the bioactive substance that is placed 3 months and/or 6 months or longer as 9 months or 12 months under accelerated storage condition under the relative humidity of (moisture absorption) critical relative humidity of material of innocuous gas compare, the coated preparation of healing processing has stable dissolution characteristic.The meaning of term " stable " finishes, solidifies the dissolution characteristic comparison of coated preparation with firm curing in addition, its In Vitro Dissolution is in acceptable limit, acceptable limit is by administrative organization, determines as Chinese drug and food management supervision office, U.S. food and drug administration etc.Substantially be not subjected to the stable dissolution characteristic of accelerated storage condition influence.That above-mentioned dissolution test preferably adopts all the components that contains in above-mentioned controlled release polymer clothing film (but do not comprise above-mentioned water miscible pore material (being above-mentioned sublimable material grains and/or the material grains that can be biodegradable into innocuous gas), be because of its stripping pore of needs) here and above-mentioned all the components is saturated release medium (dissolution medium) all.Adopt the saturated solution of all the components in above-mentioned controlled release polymer clothing film can make in above-mentioned dissolution test, the clean stripping quantity of all the components in above-mentioned controlled release polymer clothing film was 0 (not comprising the stripping of above-mentioned water miscible pore material), thereby the medicine that is conducive to judge stripping is stripping in stripping from former controlled release polymer clothing membrane micropore rather than micropore that produce because of wherein composition stripping, because of from being conducive to more to judge that above-mentioned controlled release polymer clothing film has healed fully or state or healing state substantially fully or substantially to terminal to terminal.

In the present invention, it is even longer that the required time of healing processing is generally tens of hours.The selected temperature of healing processing should be higher than clothing film glass transition temperature, preferably higher than clothing film glass transition temperature more than 10 ℃, more preferably higher than 20～30 ℃ of clothing film glass transition temperatures, the selected temperature of healing processing and should be not make the fully softening or fusing of composition in the coating material or the clothing film coalescence not occur as degree.Preferably use certain humidity during healing processing, under the effect of moisture or dampness, its glass transition temperature can significantly descend because of clothing film, processes thereby be conducive to healing acceleration.Selected humidity is not less than relative humidity 50% usually, preferably is not less than relative humidity 60%, more preferably is not less than relative humidity 70%, and selected humidity is usually too not low, because the too low meeting of humidity makes the time of healing processing longer.but selected humidity usually usually should and/or not can be biodegradable into (moisture absorption) critical relative humidity of the material of innocuous gas higher than above-mentioned sublimable material grains, because of higher than above-mentioned sublimable material grains and/or after can be biodegradable into (moisture absorption) critical relative humidity of material of innocuous gas, above-mentioned sublimable material grains and/or can be biodegradable into the material of innocuous gas can remarkable moisture absorption, water miscible sublimable material grains and/or can be biodegradable into the material of innocuous gas particularly, significantly after moisture absorption, part or whole dissolution-crystallization phenomenons will appear in above-mentioned sublimable material grains and/or the material that can be biodegradable into innocuous gas, thereby may separate out from the clothing film, " scum " phenomenon appears, and then the release micropore is dwindled in agglutination, affect release stability.

In above-mentioned healing processing process and under above-mentioned accelerated storage condition in put procedure, the clean amount of solid that requires to be arranged in the above-mentioned sublimable material of above-mentioned polymer clothing film and/or can be biodegradable into the pore material of innocuous gas does not reduce.in order to prevent to distil or degradability pore material is not flung to or lost before the clothing film merges fully, prevent that micropore is less than what expect, the clean amount of solid that makes in other words above-mentioned sublimable material and/or can be biodegradable into the pore material of innocuous gas does not reduce, thereby prevent further the difference between batch opposite sex that micropore also can occur with the porogen of same batch, improve the production repeatability of preparation, stability and rate of releasing drug, usually but the healing processing process is being carried out more than or equal to the equilibrium partial pressure of the sublimability pore material at condition of living in such as temperature and/or under more than or equal to the equilibrium partial pressure of all catabolites of the degradability pore material at condition of living in such as temperature or at the temperature lower than the minimum degradation temperature of the degradability pore material under condition of living in such as pressure, in this process, the clean amount of solid that is arranged in the above-mentioned sublimable of above-mentioned polymer clothing film and/or can be biodegradable into the pore material of innocuous gas can not reduce.The equilibrium partial pressure of pore material (or its catabolite) refers in enclosed environment under uniform temperature, and when the pore material in the pore material in gas phase (or its all catabolites) and solid phase thereof is in poised state, the solid of pore material has a net increase of or the dividing potential drop of clean decrement when being zero.but in order to obtain the equilibrium partial pressure more than or equal to sublimability or degradability pore material, common way be blow in airtight environment (as airtight casing) (filling) but but enter more than or equal to the sublimability pore material gas of the equilibrium partial pressure of sublimability pore material and/or enter all catabolite gases more than or equal to the equilibrium partial pressure of the catabolite of degradability pore material, perhaps put in airtight environment (or casing) excessive (namely usually total some surplus solid exists) but sublimability or degradability pore material, but but rising temperature certain hour makes the catabolite of sublimability pore material in gas phase or degradability pore material and the sublimability pore material in solid phase or degradability pore material be in poised state.

Healing processing can carry out with heat treatment modes such as baking oven and fluid beds.The characteristics such as the fluid bed heat processing has efficiently, saves time can be completed coating and heat treatment operation in same equipment, the industrialization suitability is higher.Elevation system temperature after coating finishes, material is dry in same fluid unit relaying afterflowization, can promote film healing balance 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 is relatively low.Therefore the present invention preferably adopts the baking oven heat treatment mode.

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

Can wrap skim water solublity coating material with the surface integral that improves preparation or prevent that in storage process preparation mutually bonds or prevents or delay that the release micropore changes in storage process with the preparation of above-mentioned either 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 be fully thin and be water miscible, with the Release Performance of obstruction free preparation.After wrapping this thin layer, the partially enclosed release micropore (occupying former part air) of flinging to the pore material and staying of water-soluble coating material meeting is therefore have (size) Stabilization to established release micropore.

Pharmaceutical dosage form with above-mentioned either method preparation can directly use basically, as directly oral.Pack into as in gelatine capsule, bag (sachet) or suitable many measuring containers with granule, ball or the granule of above-mentioned preparation also available measuring equipment.Obtain by compacting after mixing with other auxiliary agent if possible, preparation decomposes after taking, and most of junior unit that coats discharges.Can consider equally aggregation is embedded in Polyethylene Glycol or lipid with preparation inspection agent or vagina medicinal agent type.The tablet that coats is packed with hemispherical container or multi-dose container, and clothes for patients is with front direct taking-up.

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

Embodiment

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

Embodiment 1 and reference examples 1

1, Preparation Example 1 sample

1), prepare label by following prescription and technique:

With diltiazem hydrochloride, lactose, hyprolose and polyvidone mix homogeneously, carry out pelletize with ethanol; Wet granular material was forced to pass 18 purpose sieves also dry 24 hours; After granulate, add the magnesium stearate mixing, with the circular punch die compressed tablet of the spill of the standard of a 12mm, press power used is 1200～2000kg, press time 2s.Hardness is 6～10kg.

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

Coating fluid prescription:

※, the calcium carbonate that the surface is coated by stearic acid

Solvay company produces, and is determined as 21 ° with the contact angle θ of coating polymer.

With label coating on the Hicoater/Fruend seed-coating machine.Coating conditions parameter: inlet temperature, 50～60 ℃; Outlet temperature, 40～42 ℃; 40 ℃ of label temperature; Label weightening finish 16%.

Wrap state clothing film before the bag one water-soluble film clothing.The coating material that bag water-soluble film clothing is used is for containing 4.5% hydroxypropyl emthylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and the aqueous solution of 1.5% micronized Talcum.Coating conditions parameter inlet temperature, 55 ℃; Outlet temperature, 30 ℃.The weightening finish of water-soluble film clothing coating is about 1%.

3), healing clothing film

Healing processing carries out in airtight baking oven.The salicylic acid of the built-in capacity of baking oven (the remaining amount of solid of Retained is namely always arranged).Be filled with the hot-air of 65 ℃ of the temperature of the salicylic acid gas that contains saturation capacity before healing processing.The healing temperature is 50 ℃, and healing time is 56 hours.

4), fling to porogen

Salicylic acid take out the clothing film under the condition of 20 ℃ of temperature and near vacuum in.

2, preparation reference examples 1 sample

Surface in coating fluid prescription is removed by the calcium carbonate that stearic acid coats, and other are constant, prepare reference examples 1 according to embodiment 1 method.

Embodiment 2 and reference examples 2

1, Preparation Example 2 samples

1), preparation label:

With glipizide, polyethylene glycol oxide and sodium chloride mixing, then mix the label that rear mold is pressed into 502mg with magnesium stearate, with the circular punch die compressed tablet of the spill of the standard of a 12mm, press power used is 1200～1800kg, press time 1～2s, 6～8kg.

2), preparation coating solution:

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

3), coating:

Before the clothing film coating, bag is every wet protective finish.The coating material of using every wet protective finish is for containing 4.5% hydroxypropyl emthylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and the suspension of 1.5% micronized Talcum.Coating conditions parameter: spraying time approximately 20 seconds, blasting time approximately 30～40 seconds, 50～55 ℃ of blast temperatures, 30～40 ℃ of label temperature.Be about 1% every wet protective finish coating weightening finish.

The nano aluminium oxide dispersion pulp that adds ethyl vanillin (60～80 order), polyacrylate to coat in the above-mentioned cellulose acetate that makes adds aqueous dispersion (is on average expected footpath 10nm, be determined as 70 ° with the contact angle θ of coating polymer) and be used as the diacetine of plasticizer, cellulose acetate wherein: ethyl vanillin: nano aluminium oxide (take dry weight basis): diacetine is 1: 2: 0.06: 1 (weight ratio) is diluted with water to and contains 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 18%.

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

4), healing clothing film

Healing processing carries out in airtight baking oven.The ethyl vanillin of the built-in capacity of baking oven (the remaining amount of solid of Retained is namely always arranged).Be filled with the hot-air of the temperature 70 C of the ethyl vanillin gas that contains saturation capacity before healing processing.The healing temperature is 65 ℃, and healing time is 64 hours.

5), fling to porogen

Ethyl vanillin take out the clothing film under the condition of 35 ℃ of temperature and near vacuum in.

2, preparation reference examples 2 samples

Nano aluminium oxide in coating fluid prescription is removed, and other are constant, prepare reference examples 2 according to embodiment 2 methods.

Embodiment 3 and reference examples 3

1, Preparation Example 3 samples

1), prepare label by following prescription and technique:

With diltiazem hydrochloride, monobasic sodium citrate and polyvidone mix homogeneously, carry out pelletize with ethanol solution; Wet granular material was forced to pass 18 purpose sieves also dry 24 hours; After granulate, add the magnesium stearate mixing, with the circular punch die compressed tablet of the spill of the standard of a 12mm, press power used is 1200～2000kg, press time 2s.Hardness is 6～10kg.

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

Coating fluid prescription (1000 consumptions):

※, methyl methacrylate/styrol copolymer (MMA/ST), wherein methyl methacrylate content approximately 52%, and styrene approximately 48% is determined as 12 ° with the contact angle θ of coating polymer.

With label coating on the Hicoater/Fruend seed-coating machine.Coating conditions parameter: inlet temperature, 50～60 ℃; Outlet temperature, 35～37 ℃; 36～38 ℃ of label temperature; Label weightening finish 12.6%.

3), healing clothing film

Healing processing carries out in airtight baking oven.The benzoic acid of the built-in capacity of baking oven (the remaining amount of solid of Retained is namely always arranged).Be filled with the hot-air of the temperature 50 C of the benzoic acid gas that contains saturation capacity before healing processing.The healing temperature is 45 ℃, and healing time is 48 hours.

4), fling to porogen

Benzoic acid take out the clothing film under the condition of 20 ℃ of temperature and near vacuum in.

2, preparation reference examples 3 samples

Methyl methacrylate/styrol copolymer in coating fluid prescription (MMA/ST) is removed, and other are constant, prepare reference examples 3 samples according to embodiment 3 methods.

Embodiment 4 and reference examples 4

1, Preparation Example 4 samples

1), prescription and the technique by embodiment 3 prepares label

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

Coating fluid prescription (1000 consumptions):

※, PARALOID BPM-500 are the nanoscale crylic acid resin duricrust produced of Rohm and Haas company-soft nuclear structure type anti-impact modifier, are determined as 7 ° with the contact angle θ of coating polymer.

With label coating on the Hicoater/Fruend seed-coating machine.Coating conditions parameter: inlet temperature, 50～60 ℃; Outlet temperature, 30～35 ℃; 31～36 ℃ of label temperature; Label weightening finish 12.6%.

3), healing clothing film

Healing processing carries out in airtight baking oven.The butylated hydroxyarisol of the built-in capacity of baking oven (the remaining amount of solid of Retained is namely always arranged).Be filled with the hot-air of the temperature 50 C of the butylated hydroxyarisol gas that contains saturation capacity before healing processing.The healing temperature is 45 ℃, and healing time is 60 hours.

4), fling to porogen

Butylated hydroxyarisol take out the clothing film under the condition of 10 ℃ of temperature and near vacuum in.

2, preparation reference examples sample 4.

PARALOID BPM-500 in coating fluid prescription is removed, and other are constant, prepare reference examples 4 samples according to embodiment 4 methods.

Embodiment 5 and reference examples 5

1, Preparation Example 5 samples

1), prescription and the technique by embodiment 1 prepares label

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

Coating fluid prescription:

※, MBS (MBS), wherein polybutadiene content approximately 70%, and styrene-content approximately 20%, methyl methacrylate content approximately 10% is determined as 47 ° with the contact angle θ of coating polymer.

With label coating on the Hicoater/Fruend seed-coating machine.Coating conditions parameter: inlet temperature, 50～60 ℃; Outlet temperature, 40～42 ℃; 40 ℃ of label temperature; Label weightening finish 16%.

Wrap state clothing film before the bag one water-soluble film clothing.The coating material that bag water-soluble film clothing is used is for containing 4.5% hydroxypropyl emthylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and the aqueous solution of 1.5% micronized Talcum.Coating conditions parameter inlet temperature, 55 ℃; Outlet temperature, 30 ℃.The weightening finish of water-soluble film clothing coating is about 1%.

3), fling to porogen

Di-tert-butyl hydroxy-methylbenzene take out the clothing film under the condition of 15 ℃ of temperature and near vacuum in.

2, preparation reference examples sample 4.

MBS in coating fluid prescription (MBS) is removed, and other are constant, prepare reference examples 5 samples according to embodiment 5 methods.

Embodiment 6 and reference examples 6

1, Preparation Example 6 samples

1), preparation label:

With simvastatin, carbopol, the sodium citrate that grinds and cross 200 mesh sieves, lactose and polyvinylpyrrolidone mix homogeneously, and carry out pelletize with the alcoholic solution (containing required BHA) of moisture 10% (by weight).Wet stock is crossed 18 mesh sieves and drying whole night, and granulate adds magnesium stearate to lubricate mixing, and with the uniform mixture of spill circular tool compacting of the standard of 1/4 inch, press power used is 1000 pounds.After compacting, the thickness of tablet is 3.89mm, and hardness is 8-10kg.

2), to label bag water-soluble film clothing

With timing automatic film coating machine coating to above-mentioned label bag one water-soluble film clothing.The coating material that bag water-soluble film clothing is used is for containing 4.5% hydroxypropyl emthylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and the aqueous solution of 1.5% micronized Talcum.The weightening finish of water-soluble film clothing coating is about 2%.

3), bag water-soluble film garment piece core is pressed following prescription and technique bag controlled release clothing:

Controlled release coat liquid prescription

※, MBS (MBS), wherein butadiene content approximately 70%, and styrene-content approximately 15%, methyl methacrylate content approximately 15% is determined as 16 ° with the contact angle θ of coating polymer.

((8 inches dishes), coating a thickness to tablet is the coating of 200 microns to adopt a miniature high-performance coating machine of Freand type HCT.

Annotate: ※, the vitrification point (Tg) that is adjusted to according to need clothing film (doing) is 50 ℃ of required amounts.

4), fling to porogen

Carbamide take out the clothing film under the condition of 30 ℃ of temperature and near vacuum in.

2, preparation reference examples 6 samples

Polymethyl methacrylate in coating fluid prescription (PMMA) is removed, and other are constant, prepare reference examples 6 samples according to embodiment 6 methods.

Embodiment 7

The nano aluminium oxide dispersion pulp that polyacrylate in embodiment 2 is coated changes the methyl methacrylate/styrene copolymer latices that waits weight (dry weight) into, and (mean diameter is 15nm approximately, wherein, methyl methacrylate content approximately 60%, styrene-content approximately 40% is determined as 39 ° with the contact angle θ of coating polymer) with the standby embodiment 7 of legal system.

Embodiment 8

The nano aluminium oxide dispersion pulp that only polyacrylate in embodiment 2 is coated changes into and waits weight (dry weight)

HP662 latex (ethylene/butane group acrylic acid/carbonyl (carbon list oxide) trimer, mean diameter is 60nm approximately, is determined as 30 ° with the contact angle θ of coating polymer) is with the standby embodiment 8 of legal system.

Embodiment 9

Methyl methacrylate/styrol copolymer in embodiment 3 is changed etc. into heavy (dry weight)

AC 2618 latex (ethylene/ethyl propylene acid copolymer), mean diameter is 200nm approximately, is determined as 5 ° with the contact angle θ of coating polymer) with the standby embodiment 9 of legal system.

Embodiment 10

Methyl methacrylate/styrol copolymer in embodiment 3 into such as is changed at the MBS latex of heavy (dry weight), and (mean diameter is 100nm approximately, wherein, butadiene content approximately 70%, styrene-content approximately 15%, methyl methacrylate content approximately 15% is determined as 12 ° with the contact angle θ of coating polymer) with the standby embodiment 10 of legal system.

Embodiment 11

The methyl methacrylate latex (mean diameter is 4nm approximately, is determined as 4 ° with the contact angle θ of coating polymer) that PARALOID BPM-500 in embodiment 4 is changed etc. into heavy (dry weight) is with the standby embodiment 11 of legal system.

Embodiment 12

PARALOID BPM-500 in embodiment 4 into such as is changed at the methyl methacrylate/styrene copolymer latices of heavy (dry weight), and (mean diameter is 55nm approximately, wherein, methyl methacrylate content approximately 70%, styrene-content approximately 30% is determined as 21 ° with the contact angle θ of coating polymer) with the standby embodiment 12 of legal system.

Embodiment 13

MBS in embodiment 6 (MBS) is changed etc. into the DuPont of heavy (dry weight) ^TM

HP4051 latex (mean diameter is 150nm approximately, is determined as 14 ° with the contact angle θ of coating polymer) is with the standby embodiment 13 of legal system.

Embodiment 14

MBS in embodiment 6 (MBS) is changed etc. into the DuPont of heavy (dry weight) ^TM

HP441 latex (mean diameter is 150nm approximately, is determined as 28 ° with the contact angle θ of coating polymer) is with the standby embodiment 14 of legal system.

Test example 1 release in vitro (release) test

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

Diltiazem hydrochloride release method of testing: adopt Chinese Pharmacopoeia version oar method in 2005 to measure.Rotating speed is 100r/min, and temperature is (37 ± 1) ℃, and mediator is with simulated gastric fluid (pH1.2 hydrochloric acid solution) and each 1000mL of simulated intestinal fluid (pH7.5 phosphate buffer).Embodiment and contrast are directly dropped into respectively in stripping rotor with sample, the 5mL that takes a sample at regular intervals, and replenish with volume stripping mediator.Measure diltiazem hydrochloride with the HPLC method and enter amount in dissolution medium, calculate every in the release of different dissolution times.

Glipizide release method of testing: sample thief, shine drug release determination method (Chinese Pharmacopoeia version appendix XD first method in 2005) under 37 ℃, take Tris buffer (0.004M Tris, pH8.7) 1000ml as solvent, rotating speed is per minute 100 to turn, in accordance with the law operation.The 5mL that takes a sample at regular intervals, and replenish with volume stripping mediator.Measure glipizide with the HPLC method and enter amount in dissolution medium.Calculate the release of each dissolution time of glipizide.

Simvastatin release method of testing: under 37 ℃, turn by per minute 50 with USP 2 type devices and carry out being 7.4, containing the test that discharges medicine in the phosphate buffered solution 1000ml of sodium lauryl sulphate 0.4% to pH value under laboratory condition after every sub-sampling.The 5mL that takes a sample at regular intervals, and replenish with volume stripping mediator.Measure simvastatin with the HPLC method and enter amount in dissolution medium.Calculate the release of each dissolution time of simvastatin.Test result sees Table 1-6.

Table 1 embodiment 1 and reference examples 1 example pharmaceuticals rate of release test result thereof

(n=9)

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

(n=9)

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

(n=9)

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

(n=9)

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

(n=9)

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

(n=9)

The result of the test demonstration of embodiment 1-6 and reference examples 1-6, embodiment pharmaceutical preparation Release Performance and production repeatability are than reference examples good (rate of releasing drug is relatively large, and relative deviation Sr is relatively less)

Test example 2 preparation medicines discharge stability test

Working sample: in the 1st crowd of embodiment 1-6 and reference examples 1-6 sample.

Detection method: sample is 25 ℃ of temperature, place (wherein under the same environment of relative humidity 60%, embodiment 2,6 and reference examples 2,6 insert 42 ℃ of temperature, under the acceleration environment of relative humidity 80%), regularly take a sample and measure preparation and do not carry out medicament contg and the drug release rate of drug release when testing and (measure 12, in meansigma methods), wherein, drug release rate (%)=stripping enters medication amount in medication amount/preparation in dissolution medium * 100%.Stripping enters the method for testing of the medication amount in dissolution medium: referring to test example 1; Medication amount method of testing in preparation: medicine is measured with the HPLC method after extracting in preparation fully.Test result sees Table 7-12.

Table 7 embodiment 1 and its reference examples 1 sample release amount of medicine test result of 8 hours

Table 8 embodiment 2 and its reference examples 2 sample release amount of medicine test result of 4 hours

Table 9 embodiment 3 and its reference examples 3 sample release amount of medicine test result of 8 hours

Table 10 embodiment 4 and its reference examples 4 sample release amount of medicine test result of 4 hours

Table 11 embodiment 5 and its reference examples 5 sample release amount of medicine test result of 6 hours

Table 12 embodiment 6 and its reference examples 6 sample release amount of medicine test result of 4 hours

Annotate ※, the percentage (%) that expression is compared with 0 month original vol.

The test result demonstration of embodiment and reference examples thereof, embodiment pharmaceutical preparation release stability is excellent to reference examples.

Test example 3 preparation clothing film measuring mechanical properties

Get after the test of embodiment 1-6 in test example 1 tablets in vitro (release) testing experiment and reference examples 1-6 thereof half wet residue (clothing film that namely directly takes out from dissolution fluid) and second half at the temperature dried residue that vacuum drying gets during lower than 0 ℃, measure its maximum pull during tension power effect fracture and the percentage ratio (elongation at break) of extended length and original length when being broken thereof when 25 ℃ of temperature.Test result sees Table 13.

Table 13 embodiment 1-6 and reference examples 1-6 preparation clothing film measuring mechanical property result thereof

Its reference examples test result of embodiment shows: the mechanical performance of embodiment preparation clothing film is excellent than reference examples.This residence shows that the embodiment preparation has the performance that better antiradiation drug inclines and releases, higher drug safety.

Test example 4 polymer clothing film release micropore average pore size tests

Method: get 0 month sample (sample that has just prepared) and 25 ℃ of temperature first batch of formulation samples, place the sample of 24 and 36 months under the same environment of relative humidity 60%, separate and strip polymer clothing film, with IM4000 type picture conceptual analyzer (Analytical Imaging Concepts, IM4000) measure average (orientation) aperture of release micropore (arithmetic) of clothing film according to micro-picture, the results are shown in Table 14.

Table 14 polymer clothing film release micropore average pore size test result (μ m)

Result shows, adds effective polymer intensifier and be conducive to the drug loosed time micropore and reduce in production process and storage in polymer clothing film.

Claims (48)

1. a polymer intensifier is contained outside be used as the purposes that reduce in the aperture that delays described release micropore in the controlled release preparation that numerous polymer release-control clothing films that are filled with the release micropore of air coat in production process and/or storage, wherein, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °, above-mentioned release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned clothing film and/or decomposes the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned clothing film to obtain through distillation, but before distillation and/or decomposing the material of above-mentioned sublimability and/or can be biodegradable into the material formation release micropore of innocuous gas, the core material of the above-mentioned clothing film of coated polymer is placed in higher than healing processing at the temperature of the glass transition temperature of above-mentioned polymer release-control clothing film, until this coating core material has stable dissolution characteristic, the coating core material of healing processing terminal point by more just finishing healing processing with the temperature of 40 ± 2 ℃ and be not less than 50% and the dissolution characteristic of placing the coating core material of 3 months and/or 6 months not higher than above-mentioned sublimable material grains and/or in can be biodegradable into accelerated storage condition under the relative humidity of moisture absorption critical relative humidity of material of innocuous gas determine, in above-mentioned healing processing process and in above-mentioned accelerated storage condition in put procedure, the clean amount of solid that is arranged in the above-mentioned sublimable material of above-mentioned polymer clothing film and can be biodegradable into the material of innocuous gas does not reduce, above-mentioned sublimable material grains and/or the material grains that can be biodegradable into innocuous gas are selected from benzoic acid, vanillin, ethyl vanillin, natural or artificial camphor, the raceme Mentholum, levorotatory menthol, natural or synthetic borneol, dextro Borneolum Syntheticum, L-Borneol, the dextrorotation isoborneol, left-handed isoborneol, the raceme isoborneol, dithiooxamide, 6-methyl-2-deracil, butylated hydroxyarisol, the di-tert-butyl hydroxy-methylbenzene, salicylic acid, aspirin, ethenzamide, caffeine 1 hydrate, the caffeine anhydride, caffeine citrate, the caffeine benzoate, alanine, leucine, isoleucine, valine, phenylalanine, carbamide, urethane, ammonium halide, ammonium bicarbonate, ammonium carbonate, ammonium acetate or their mixture, above-mentioned controlled release preparation comprises:

1) core material that, contains at least a bioactive substance;

2), being overlying on containing of above-mentioned core material numerous porositys that are filled with the release micropore of air outward is 5%～95% clothing film, it is being insoluble to of 55%～85% weight ratio or water-soluble and polymer and pharmaceutically acceptable consumption Digestive system are the polymer intensifier of 1%～30% weight ratio hardly that this clothing film comprises the plasticizer that consumption is 10%～40% weight ratio, pharmaceutically acceptable consumption, above-mentioned consumption is all based on the gross weight of doing of polymer release-control clothing membrane component

Wherein, above-mentioned plasticizer be selected from the physiology compatible by C ₆～C ₄₀Aliphatic or aromatic series one are to tricarboxylic acid and C ₁～C ₈Lipophilic ester, glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini that aliphatic alcohol forms,

above-mentioned polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, the disuccinic acid cellulose, polyvinylacetate, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride), above-mentioned polymer intensifier is selected from the thin or ultra-fine grain that has carried out the polarity rigid inorganic particle of surface modification with polyacrylate absorption parcel processing mode

Perhaps

Above-mentioned polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, above-mentioned polymer intensifier is selected from the polarity rigid inorganic particle that has carried out surface modification with surfactant absorption parcel processing mode

Perhaps

above-mentioned polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

above-mentioned polymer is selected from and is insoluble to or poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride) of water-soluble and Digestive system hardly, above-mentioned polymer intensifier is selected from polymethyl methacrylate, copolymer of methyl methacrylatestyrene, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer, crylic acid resin anti-impact modifier or their mixture

Perhaps

above-mentioned polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble and Digestive system hardly, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl chloride-ethylene acetate copolymer or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

Above-mentioned polymer is selected from polrvinyl chloride, and above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer and their mixture.

2. a polymer intensifier is contained outside in the controlled release preparation that numerous polymer release-control clothing films that are filled with the release micropore of air coat and is used for improving its rate of releasing drug in the purposes of the stability of storage, wherein, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °, above-mentioned release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned clothing film and/or decomposes the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned clothing film to obtain through distillation, but before distillation and/or decomposing the material of above-mentioned sublimability and/or can be biodegradable into the material formation release micropore of innocuous gas, the core material of the above-mentioned clothing film of coated polymer is placed in higher than healing processing at the temperature of the glass transition temperature of above-mentioned polymer release-control clothing film, until this coating core material has stable dissolution characteristic, the coating core material of healing processing terminal point by more just finishing healing processing with the temperature of 40 ± 2 ℃ and be not less than 50% and the dissolution characteristic of placing the coating core material of 3 months and/or 6 months not higher than above-mentioned sublimable material grains and/or in can be biodegradable into accelerated storage condition under the relative humidity of moisture absorption critical relative humidity of material of innocuous gas determine, in above-mentioned healing processing process and in above-mentioned accelerated storage condition in put procedure, the clean amount of solid that is arranged in the above-mentioned sublimable material of above-mentioned polymer clothing film and can be biodegradable into the material of innocuous gas does not reduce, above-mentioned sublimable material grains and/or the material grains that can be biodegradable into innocuous gas are selected from benzoic acid, vanillin, ethyl vanillin, natural or artificial camphor, the raceme Mentholum, levorotatory menthol, natural or synthetic borneol, dextro Borneolum Syntheticum, L-Borneol, the dextrorotation isoborneol, left-handed isoborneol, the raceme isoborneol, dithiooxamide, 6-methyl-2-deracil, butylated hydroxyarisol, the di-tert-butyl hydroxy-methylbenzene, salicylic acid, aspirin, ethenzamide, caffeine 1 hydrate, the caffeine anhydride, caffeine citrate, the caffeine benzoate, alanine, leucine, isoleucine, valine, phenylalanine, carbamide, urethane, ammonium halide, ammonium bicarbonate, ammonium carbonate, ammonium acetate or their mixture, above-mentioned controlled release preparation comprises:

1) core material that, contains at least a bioactive substance;

2), being overlying on containing of above-mentioned core material numerous porositys that are filled with the release micropore of air outward is 5%～95% clothing film, it is being insoluble to of 55%～85% weight ratio or water-soluble and polymer and pharmaceutically acceptable consumption Digestive system are the polymer intensifier of 1%～30% weight ratio hardly that this clothing film comprises the plasticizer that consumption is 10%～40% weight ratio, pharmaceutically acceptable consumption, above-mentioned consumption is all based on the gross weight of doing of polymer release-control clothing membrane component

Wherein, above-mentioned plasticizer be selected from the physiology compatible by C ₆～C ₄₀Aliphatic or aromatic series one are to tricarboxylic acid and C ₁～C ₈Lipophilic ester, glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini that aliphatic alcohol forms,

above-mentioned polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, the disuccinic acid cellulose, polyvinylacetate, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride), above-mentioned polymer intensifier is selected from the thin or ultra-fine grain that has carried out the polarity rigid inorganic particle of surface modification with polyacrylate absorption parcel processing mode

Perhaps

Above-mentioned polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, above-mentioned polymer intensifier is selected from the polarity rigid inorganic particle that has carried out surface modification with surfactant absorption parcel processing mode

Perhaps

above-mentioned polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

above-mentioned polymer is selected from and is insoluble to or poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride) of water-soluble and Digestive system hardly, above-mentioned polymer intensifier is selected from polymethyl methacrylate, copolymer of methyl methacrylatestyrene, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer, crylic acid resin anti-impact modifier or their mixture

Perhaps

above-mentioned polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble and Digestive system hardly, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl chloride-ethylene acetate copolymer or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

Above-mentioned polymer is selected from polrvinyl chloride, and above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer and their mixture.

3. a polymer intensifier is contained outside in the controlled release preparation that numerous polymer release-control clothing films that are filled with the release micropore of air coat and is used for improving its rate of releasing drug reproducible purposes in process of production, wherein, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °, above-mentioned release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned clothing film and/or decomposes the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned clothing film to obtain through distillation, but before distillation and/or decomposing the material of above-mentioned sublimability and/or can be biodegradable into the material formation release micropore of innocuous gas, the core material of the above-mentioned clothing film of coated polymer is placed in higher than healing processing at the temperature of the glass transition temperature of above-mentioned polymer release-control clothing film, until this coating core material has stable dissolution characteristic, the coating core material of healing processing terminal point by more just finishing healing processing with the temperature of 40 ± 2 ℃ and be not less than 50% and the dissolution characteristic of placing the coating core material of 3 months and/or 6 months not higher than above-mentioned sublimable material grains and/or in can be biodegradable into accelerated storage condition under the relative humidity of moisture absorption critical relative humidity of material of innocuous gas determine, in above-mentioned healing processing process and in above-mentioned accelerated storage condition in put procedure, the clean amount of solid that is arranged in the above-mentioned sublimable material of above-mentioned polymer clothing film and can be biodegradable into the material of innocuous gas does not reduce, above-mentioned sublimable material grains and/or the material grains that can be biodegradable into innocuous gas are selected from benzoic acid, vanillin, ethyl vanillin, natural or artificial camphor, the raceme Mentholum, levorotatory menthol, natural or synthetic borneol, dextro Borneolum Syntheticum, L-Borneol, the dextrorotation isoborneol, left-handed isoborneol, the raceme isoborneol, dithiooxamide, 6-methyl-2-deracil, butylated hydroxyarisol, the di-tert-butyl hydroxy-methylbenzene, salicylic acid, aspirin, ethenzamide, caffeine 1 hydrate, the caffeine anhydride, caffeine citrate, the caffeine benzoate, alanine, leucine, isoleucine, valine, phenylalanine, carbamide, urethane, ammonium halide, ammonium bicarbonate, ammonium carbonate, ammonium acetate or their mixture, above-mentioned controlled release preparation comprises:

1) core material that, contains at least a bioactive substance;

2), being overlying on containing of above-mentioned core material numerous porositys that are filled with the release micropore of air outward is 5%～95% clothing film, it is being insoluble to of 55%～85% weight ratio or water-soluble and polymer and pharmaceutically acceptable consumption Digestive system are the polymer intensifier of 1%～30% weight ratio hardly that this clothing film comprises the plasticizer that consumption is 10%～40% weight ratio, pharmaceutically acceptable consumption, above-mentioned consumption is all based on the gross weight of doing of polymer release-control clothing membrane component

Wherein, above-mentioned plasticizer be selected from the physiology compatible by C ₆～C ₄₀Aliphatic or aromatic series one are to tricarboxylic acid and C ₁～C ₈Lipophilic ester, glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini that aliphatic alcohol forms,

above-mentioned polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, the disuccinic acid cellulose, polyvinylacetate, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride), above-mentioned polymer intensifier is selected from the thin or ultra-fine grain that has carried out the polarity rigid inorganic particle of surface modification with polyacrylate absorption parcel processing mode

Perhaps

Above-mentioned polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, above-mentioned polymer intensifier is selected from the polarity rigid inorganic particle that has carried out surface modification with surfactant absorption parcel processing mode

Perhaps

above-mentioned polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

above-mentioned polymer is selected from and is insoluble to or poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride) of water-soluble and Digestive system hardly, above-mentioned polymer intensifier is selected from polymethyl methacrylate, copolymer of methyl methacrylatestyrene, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer, crylic acid resin anti-impact modifier or their mixture

Perhaps

above-mentioned polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble and Digestive system hardly, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl chloride-ethylene acetate copolymer or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

Above-mentioned polymer is selected from polrvinyl chloride, and above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer and their mixture.

4. a polymer intensifier is contained the purposes that is used for improving its Release Performance in the controlled release preparation that numerous polymer release-control clothing films that are filled with the release micropore of air coat outside, wherein, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °, above-mentioned release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned clothing film and/or decomposes the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned clothing film to obtain through distillation, but before distillation and/or decomposing the material of above-mentioned sublimability and/or can be biodegradable into the material formation release micropore of innocuous gas, the core material of the above-mentioned clothing film of coated polymer is placed in higher than healing processing at the temperature of the glass transition temperature of above-mentioned polymer release-control clothing film, until this coating core material has stable dissolution characteristic, the coating core material of healing processing terminal point by more just finishing healing processing with the temperature of 40 ± 2 ℃ and be not less than 50% and the dissolution characteristic of placing the coating core material of 3 months and/or 6 months not higher than above-mentioned sublimable material grains and/or in can be biodegradable into accelerated storage condition under the relative humidity of moisture absorption critical relative humidity of material of innocuous gas determine, in above-mentioned healing processing process and in above-mentioned accelerated storage condition in put procedure, the clean amount of solid that is arranged in the above-mentioned sublimable material of above-mentioned polymer clothing film and can be biodegradable into the material of innocuous gas does not reduce, above-mentioned sublimable material grains and/or the material grains that can be biodegradable into innocuous gas are selected from benzoic acid, vanillin, ethyl vanillin, natural or artificial camphor, the raceme Mentholum, levorotatory menthol, natural or synthetic borneol, dextro Borneolum Syntheticum, L-Borneol, the dextrorotation isoborneol, left-handed isoborneol, the raceme isoborneol, dithiooxamide, 6-methyl-2-deracil, butylated hydroxyarisol, the di-tert-butyl hydroxy-methylbenzene, salicylic acid, aspirin, ethenzamide, caffeine 1 hydrate, the caffeine anhydride, caffeine citrate, the caffeine benzoate, alanine, leucine, isoleucine, valine, phenylalanine, carbamide, urethane, ammonium halide, ammonium bicarbonate, ammonium carbonate, ammonium acetate or their mixture, above-mentioned controlled release preparation comprises:

1) core material that, contains at least a bioactive substance;

2), being overlying on containing of above-mentioned core material numerous porositys that are filled with the release micropore of air outward is 5%～95% clothing film, it is being insoluble to of 55%～85% weight ratio or water-soluble and polymer and pharmaceutically acceptable consumption Digestive system are the polymer intensifier of 1%～30% weight ratio hardly that this clothing film comprises the plasticizer that consumption is 10%～40% weight ratio, pharmaceutically acceptable consumption, above-mentioned consumption is all based on the gross weight of doing of polymer release-control clothing membrane component

Wherein, above-mentioned plasticizer be selected from the physiology compatible by C ₆～C ₄₀Aliphatic or aromatic series one are to tricarboxylic acid and C ₁～C ₈Lipophilic ester, glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini that aliphatic alcohol forms,

above-mentioned polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, the disuccinic acid cellulose, polyvinylacetate, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride), above-mentioned polymer intensifier is selected from the thin or ultra-fine grain that has carried out the polarity rigid inorganic particle of surface modification with polyacrylate absorption parcel processing mode

Perhaps

Above-mentioned polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, above-mentioned polymer intensifier is selected from the polarity rigid inorganic particle that has carried out surface modification with surfactant absorption parcel processing mode

Perhaps

above-mentioned polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

above-mentioned polymer is selected from and is insoluble to or poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride) of water-soluble and Digestive system hardly, above-mentioned polymer intensifier is selected from polymethyl methacrylate, copolymer of methyl methacrylatestyrene, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer, crylic acid resin anti-impact modifier or their mixture

Perhaps

above-mentioned polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble and Digestive system hardly, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl chloride-ethylene acetate copolymer or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

Above-mentioned polymer is selected from polrvinyl chloride, and above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer and their mixture.

5. the purposes of any one according to claim 1 to 4, wherein said polymer intensifier has " duricrust-soft core " structure.

6. according to claim 5 purposes, the fusing point of wherein said polymer intensifier is or/and the Vickers softening point is not less than the glass transition temperature of the polymer in described clothing film, and its center vitrification point is not higher than 0 ℃.

7. according to claim 5 purposes, the fusing point of wherein said polymer intensifier is or/and the Vickers softening point exceeds the glass transition temperature of 10 ℃ of polymer in described clothing film, and its center vitrification point is-10～-200 ℃.

8. according to claim 5 purposes, the elongation at break of described polymer intensifier is 200～5000%.

9. the purposes of any one according to claim 1 to 4, wherein said polymer is selected from ethyl cellulose, and described polymer intensifier is selected from the calcium carbonate particle that the surface is coated by stearic acid.

10. the purposes of any one according to claim 1 to 4, wherein said polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate or their mixture, and described polymer intensifier is selected from copolymer of methyl methacrylatestyrene, MBS, ethylene-C1～C4 alkyl acrylic-carbonyl trimer or their mixture.

11. the purposes of any one according to claim 1 to 4, wherein said polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate or their mixture, and described polymer intensifier is selected from copolymer of methyl methacrylatestyrene, MBS or their mixture.

12. the purposes of any one according to claim 1 to 4, wherein said polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble and Digestive system hardly, and described polymer intensifier is selected from copolymer of methyl methacrylatestyrene, MBS, ethylene-C1～C4 alkyl acrylic copolymer or their mixture.

13. the purposes of any one according to claim 1 to 4, the mean diameter of wherein said polymer intensifier is not more than 400nm.

14. the purposes of any one according to claim 1 to 4, the mean diameter of wherein said polymer intensifier is not more than 100nm.

15. the purposes of any one according to claim 1 to 4, the mean diameter of wherein said polymer intensifier is not more than 20nm.

16. the purposes of any one according to claim 1 to 4, the mean diameter of wherein said polymer intensifier is not more than 5nm.

17. the purposes of any one according to claim 1 to 4, the glass transition temperature of wherein said polymer release-control clothing film is 25～80 ℃.

18. the purposes of any one according to claim 1 to 4, the consumption of wherein said polymer intensifier are 2%～20%(weight ratio), this is based on the gross weight of doing of polymer release-control clothing membrane component.

19. a performance improvement outer containing of the core material numerous porositys that are filled with the release micropore of air of being overlying on are arranged is the preparation method of the controlled release preparation of 5%～95% clothing film, this preparation method comprises:

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

2), be the sublimable material grains of 5%～95% volume ratio and/or the material grains that can be biodegradable into innocuous gas with containing pharmaceutically acceptable consumption in coating solution, plasticizer and pharmaceutically acceptable polymer intensifier pharmaceutically acceptable be insoluble to or hardly the solution of the polymer of water-soluble and Digestive system or aqueous dispersions to above-mentioned core material coated polymer clothing film, above-mentioned sublimable material grains and/or the consumption of material grains that can be biodegradable into innocuous gas be based on the volume of above-mentioned polymer release-control clothing film, and above-mentioned sublimable material grains and/or the material grains that can be biodegradable into innocuous gas are selected from benzoic acid, vanillin, ethyl vanillin, natural or artificial camphor, the raceme Mentholum, levorotatory menthol, natural or synthetic borneol, dextro Borneolum Syntheticum, L-Borneol, the dextrorotation isoborneol, left-handed isoborneol, the raceme isoborneol, dithiooxamide, 6-methyl-2-deracil, butylated hydroxyarisol, the di-tert-butyl hydroxy-methylbenzene, salicylic acid, aspirin, ethenzamide, caffeine 1 hydrate, the caffeine anhydride, caffeine citrate, the caffeine benzoate, alanine, leucine, isoleucine, valine, phenylalanine, carbamide, urethane, ammonium halide, ammonium bicarbonate, ammonium carbonate, ammonium acetate or their mixture, wherein, above-mentioned sublimable material and/or can be biodegradable into the material of innocuous gas and solution or the aqueous dispersions that above-mentioned polymer intensifier was insoluble to or was dissolved in hardly above-mentioned polymer, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °

Above-mentioned plasticizer be selected from the physiology compatible by C ₆～C ₄₀Aliphatic or aromatic series one are to tricarboxylic acid and C ₁～C ₈Lipophilic ester, glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini that aliphatic alcohol forms,

above-mentioned polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, the disuccinic acid cellulose, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, polyvinylacetate, poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride), above-mentioned polymer intensifier is selected from the thin or ultra-fine grain that has carried out the polarity rigid inorganic particle of surface modification with polyacrylate absorption parcel processing mode

Perhaps

Above-mentioned polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, above-mentioned polymer intensifier is selected from the polarity rigid inorganic particle that has carried out surface modification with surfactant absorption parcel processing mode

Perhaps

above-mentioned polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

above-mentioned polymer is selected from and is insoluble to or poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride) of water-soluble and Digestive system hardly, above-mentioned polymer intensifier is selected from polymethyl methacrylate, copolymer of methyl methacrylatestyrene, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer, crylic acid resin anti-impact modifier or their mixture

Perhaps

above-mentioned polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble and Digestive system hardly, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl chloride-ethylene acetate copolymer or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

Above-mentioned polymer is selected from polrvinyl chloride, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer and their mixture

Above-mentioned clothing film comprises the above-mentioned polymer intensifier that above-mentioned plasticizer that consumption is 10%～40% weight ratio, above-mentioned polymer that consumption is 55%～85% weight ratio and consumption are 1%～30% weight ratio, and above-mentioned consumption is all based on the gross weight of doing of polymer release-control clothing membrane component;

3), but before distillation and/or decomposing the material of above-mentioned sublimability and/or can be biodegradable into the material formation release micropore of innocuous gas, the core material of the above-mentioned clothing film of coated polymer is placed in higher than healing processing at the temperature of the glass transition temperature of above-mentioned polymer release-control clothing film, until this coating core material has stable dissolution characteristic, the coating core material of healing processing terminal point by more just finishing healing processing with the temperature of 40 ± 2 ℃ and be not less than 50% and the dissolution characteristic of placing the coating core material of 3 months and/or 6 months not higher than above-mentioned sublimable material grains and/or in can be biodegradable into accelerated storage condition under the relative humidity of moisture absorption critical relative humidity of material of innocuous gas determine, in above-mentioned healing processing process and in above-mentioned accelerated storage condition in put procedure, the clean amount of solid that is arranged in the above-mentioned sublimable material of above-mentioned polymer clothing film and can be biodegradable into the material of innocuous gas does not reduce,

4), distillation is fallen to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned polymer release-control clothing film and/or is decomposed the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned polymer release-control clothing film.

20. preparation method according to claim 19, wherein said polymer intensifier have " duricrust-soft core " structure.

21. preparation method according to claim 20, the fusing point of wherein said polymer intensifier are or/and the Vickers softening point is not less than the glass transition temperature of the polymer in described clothing film, and its center vitrification point is not higher than 0 ℃.

22. preparation method according to claim 20, the fusing point of wherein said polymer intensifier are or/and the Vickers softening point exceeds the glass transition temperature of 10 ℃ of polymer in described clothing film, and its center vitrification point is-10～-200 ℃.

23. preparation method according to claim 20, the elongation at break of described polymer intensifier are 200～5000%.

24. preparation method according to claim 19, wherein said polymer is selected from ethyl cellulose, and described polymer intensifier is selected from the calcium carbonate particle that the surface is coated by stearic acid.

25. preparation method according to claim 19, wherein said polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate or their mixture, and described polymer intensifier is selected from copolymer of methyl methacrylatestyrene, MBS, ethylene-propylene acid butyl ester-carbonyl trimer or their mixture.

26. preparation method according to claim 19, wherein said polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate or their mixture, and described polymer intensifier is selected from copolymer of methyl methacrylatestyrene, MBS or their mixture.

27. preparation method according to claim 19, wherein said polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble and Digestive system hardly, and described polymer intensifier is selected from copolymer of methyl methacrylatestyrene, MBS, ethylene-C1～C4 alkyl acrylic copolymer or their mixture.

28. according to claim 19 to the preparation method of any one in 27, the mean diameter of wherein said polymer intensifier is not more than 400nm.

29. according to claim 19 to the preparation method of any one in 27, the mean diameter of wherein said polymer intensifier is not more than 100nm.

30. according to claim 19 to the preparation method of any one in 27, the mean diameter of wherein said polymer intensifier is not more than 20nm.

31. according to claim 19 to the preparation method of any one in 27, the mean diameter of wherein said polymer intensifier is not more than 5nm.

32. according to claim 19 to the preparation method of any one in 27, wherein said release micropore mean size is 50～900 μ m.

33. according to claim 19 to the preparation method of any one in 27, wherein said release micropore mean size is 100～600 μ m.

34. according to claim 19 to the preparation method of any one in 27, the glass transition temperature of wherein said polymer release-control clothing film is 25～80 ℃.

35. according to claim 19 to the preparation method of any one in 27, the porosity of wherein said polymer release-control clothing film is 40%～80%.

36. according to claim 19 to the preparation method of any one in 27, the consumption of wherein said polymer intensifier is 2%～20%(weight ratio), this is based on the gross weight of doing of polymer release-control clothing membrane component.

37. according to claim 19 to the preparation method of any one in 27, wherein said core material is sheet, granule, ball, crystal or the medicine carrying resin of rule or irregular form.

38. according to claim 19 to the preparation method of any one in 27, wherein said bioactive substance is selected from central stimulants, analgesic, antigout drug, antiparkinsonian drug, psychosis, antianxiety drugs, antidepressant, antuepileptic, tranquilizer, hypnotic, anticonvulsant, the automonic thing, the medicine for the treatment of chronic cardiac insufficiency, anti-arrhythmic, control angina pectoris medicine, hypotensor, regulate blood fat medicine and antiatherosclerotic, medicine for respiratory system, drugs for antiacid and peptic ulcer diseases, 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, antihistaminic, anaphylaxis medium sustained-release agent, adrenocortical hormone and thyroliberin, gonadal hormone and short gonadal hormone, pancreas hormone, thyroid hormones medicine and antithyroid drug, beta-lactamase inhibitor, aminoglycoside, Tetracyclines, Macrolide, antituberculotic, antifungal agent, antiviral agents, antitumor drug, Amitin, appetrol and their mixture.

39. according to claim 19 to the preparation method of any one in 27, wherein said bioactive substance is selected from central stimulants, antipyretic analgesic, anti-inflammation analgesia medicine, antigout drug, antiparkinsonian drug, psychosis, antianxiety drugs, antidepressant, antuepileptic, tranquilizer, hypnotic, anticonvulsant, the automonic thing, the medicine for the treatment of chronic cardiac insufficiency, anti-arrhythmic, control angina pectoris medicine, peripheral vasodilators, regulate blood fat medicine and antiatherosclerotic, medicine for respiratory system, drugs for antiacid and peptic ulcer diseases, 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, antihistaminic, anaphylaxis medium sustained-release agent, adrenocortical hormone and thyroliberin, gonadal hormone and short gonadal hormone, pancreas hormone, thyroid hormones medicine and antithyroid drug, penicillins, cephalosporins, aminoglycoside, Tetracyclines, Macrolide, antituberculotic, antifungal agent, antiviral agents, antitumor drug, vitamin, appetrol and their mixture.

40. according to claim 19 to the preparation method of any one in 27, wherein said bioactive substance is selected from SRA-333, the amoxicillin, A Sidamo, piperazine ferulate, acyclovir, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, aceclofenac, isosorbide mononitrate, diazepam, famciclovir, felodipine, fenofibrate, fluvastatin sodium, acipimox, vitamin B6, quetiapine fumarate, Metoprolol fumarate, emedastine difumarate, gliquidone, gliclazide, potassium 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, 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, gentamycin sulfate, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, diclofenac sodium, verapamil, dimension ferrum, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, indomethacin, acemetacin, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, ibuprofen and codeine, Malotilate, naproxen, lithium carbonate, cefalexin, alfuzosin hydrochloride, Buflomedil Hydrochloride, ticlopidine, ibudilast, dextromethorphan, sinomenine, sodium valproate, Benserazide, chlorphenamine maleate, barnidipine, bunazosin, gallopamil, methylphenidate hydrochloride, oxycodone hydrochloride.

41. according to claim 19 to the preparation method of any one in 27, wherein said bioactive substance is selected from the amoxycillin with clavulanate potassium compound recipe, aspirin-ligustrazine phosphate compound recipe, aspirin-dipyridamole compound recipe, acetaminophen-pseudoephedrine hydrochloride-dexbrompheniramine maleate compound recipe, isosorbide mononitrate-aspirin compound recipe, metformin-rosiglitazone compound recipe, fexofenadine hydrochloride-pseudoephedrine hydrochloride compound recipe, felodipine-spectinomycin hydrochloride compound recipe, lovastatin-nicotinic acid compound recipe, cetirizine-pseudoephedrine hydrochloride compound recipe, fexofenadine hydrochloride-pseudoephedrine hydrochloride compound recipe, guaifenesin-pseudoephedrine-dextromethorphan compound recipe, glipizide-metformin hydrochloride compound recipe, glimepiride-metformin compound recipe, loratadine-acetaminophen-pseudoephedrine compound recipe, loratadine-pseudoephedrine compound recipe, enalapril maleate-felodipine compound recipe, pseudoephedrine-naproxen sodium compound, nicotinic acid-simvastatin compound recipe, guaifenesin-pseudoephedrine hydrochloride compound recipe, the carbidopa and levodopa compound recipe, theophylline-albuterol compound recipe, gentamycin sulfate-zirconium dioxide compound recipe.

42. according to claim 19 to the preparation method of any one in 27, the fusing point that wherein said sublimable material and/or the material that can be biodegradable into innocuous gas are depressed at 1 standard atmosphere and the temperature that begins to distil or degrade thereof exceed 10 ℃ in the minimum film formation temperature of the mixing coating solution of described polymer or the glass transition temperature of described polymer release-control clothing film.

43. according to claim 19 to the preparation method of any one in 27, the fusing point that wherein said sublimable material and/or the material that can be biodegradable into innocuous gas are depressed at 1 standard atmosphere and the temperature that begins to distil or degrade thereof exceed 20 ℃ in the minimum film formation temperature of the mixing coating solution of described polymer or the glass transition temperature of described polymer release-control clothing film.

44. according to claim 19 to the preparation method of any one in 27, wherein said sublimable material and/or the material that can be biodegradable into innocuous gas are selected from benzoic acid, salicylic acid or their mixture.

45. according to claim 19 to the preparation method of any one in 27, the equilibrium partial pressure of wherein said healing processing described sublimable material at temperature when carrying out more than or equal to described healing processing and/or when carrying out more than or equal to described healing processing described at temperature can be biodegradable under the equilibrium partial pressure of all catabolites of material of innocuous gas or carry out at the temperature of the minimum degradation temperature of the described degradable material under pressure when carrying out lower than described healing processing.

46. according to claim 19 to the preparation method of any one in 27, but the material of the described sublimability that wherein distils and/or to decompose the described material that can be biodegradable into innocuous gas be under decompression or vacuum and carry out at lower than the temperature of clothing film glass transition temperature below 5 ℃.

47. according to claim 19 to the preparation method of any one in 27, the outer water solublity clothing film that further coats of described polymer release-control clothing film.

48. the controlled release preparation of a performance improvement, this controlled release preparation comprises:

1) core material that, contains at least a bioactive substance;

2), being overlying on containing of above-mentioned core material numerous porositys that are filled with the release micropore of air outward is 5%～95% clothing film, it is being insoluble to of 55%～85% weight ratio or the polymer of water-soluble and Digestive system hardly that this clothing film comprises pharmaceutically acceptable consumption, consumption is that plasticizer and the pharmaceutically acceptable consumption of 10%～40% weight ratio is the polymer intensifier of 1%～30% weight ratio, above-mentioned consumption is all based on the gross weight of doing of polymer release-control clothing membrane component, the contact angle of above-mentioned polymer and above-mentioned polymer intensifier is lower than 90 °

Wherein, above-mentioned plasticizer be selected from the physiology compatible by C ₆～C ₄₀Aliphatic or aromatic series one are to tricarboxylic acid and C ₁～C ₈Lipophilic ester, glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini that aliphatic alcohol forms,

above-mentioned polymer is selected from cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, the disuccinic acid cellulose, polyvinylacetate, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride), above-mentioned polymer intensifier is selected from the thin or ultra-fine grain that has carried out the polarity rigid inorganic particle of surface modification with polyacrylate absorption parcel processing mode

Perhaps

Above-mentioned polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, above-mentioned polymer intensifier is selected from the polarity rigid inorganic particle that has carried out surface modification with surfactant absorption parcel processing mode

Perhaps

above-mentioned polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate, celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

above-mentioned polymer is selected from and is insoluble to or poly-(ethyl acrylate-methyl methacrylate-trimethyl amino methyl ethyl acrylate chloride) of water-soluble and Digestive system hardly, above-mentioned polymer intensifier is selected from polymethyl methacrylate, copolymer of methyl methacrylatestyrene, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer, crylic acid resin anti-impact modifier or their mixture

Perhaps

above-mentioned polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble and Digestive system hardly, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl chloride-ethylene acetate copolymer or their mixture, above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture,

Perhaps

Above-mentioned polymer is selected from polrvinyl chloride, and above-mentioned polymer intensifier is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, MBS, ethylene-vinyl acetic acid-carbonyl trimer, ethylene-C1～C4 alkyl acrylic-carbonyl trimer, ethylene-C1～C4 alkyl acrylic copolymer and their mixture;

wherein, above-mentioned release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned clothing film and/or decomposes the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned clothing film to obtain through distillation, but before distillation and/or decomposing the material of above-mentioned sublimability and/or can be biodegradable into the material formation release micropore of innocuous gas, the core material of the above-mentioned clothing film of coated polymer is placed in higher than healing processing at the temperature of the glass transition temperature of above-mentioned polymer release-control clothing film, until this coating core material has stable dissolution characteristic, the coating core material of healing processing terminal point by more just finishing healing processing with the temperature of 40 ± 2 ℃ and be not less than 50% and the dissolution characteristic of placing the coating core material of 3 months and/or 6 months not higher than above-mentioned sublimable material grains and/or in can be biodegradable into accelerated storage condition under the relative humidity of moisture absorption critical relative humidity of material of innocuous gas determine, in above-mentioned healing processing process and in above-mentioned accelerated storage condition in put procedure, the clean amount of solid that is arranged in the above-mentioned sublimable material of above-mentioned polymer clothing film and can be biodegradable into the material of innocuous gas does not reduce, above-mentioned sublimable material grains and/or the material grains that can be biodegradable into innocuous gas are selected from benzoic acid, vanillin, ethyl vanillin, natural or artificial camphor, the raceme Mentholum, levorotatory menthol, natural or synthetic borneol, dextro Borneolum Syntheticum, L-Borneol, the dextrorotation isoborneol, left-handed isoborneol, the raceme isoborneol, dithiooxamide, 6-methyl-2-deracil, butylated hydroxyarisol, the di-tert-butyl hydroxy-methylbenzene, salicylic acid, aspirin, ethenzamide, caffeine 1 hydrate, the caffeine anhydride, caffeine citrate, the caffeine benzoate, alanine, leucine, isoleucine, valine, phenylalanine, carbamide, urethane, ammonium halide, ammonium bicarbonate, ammonium carbonate, ammonium acetate or their mixture.