CN102018962A - 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 reinforcing agent in controlled release preparation

Technical field

The present invention relates to a kind of polymer reinforcing agent in the controlled release preparation particularly production of the controlled release preparation that discharges of zero level or the purposes in the 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 polymer release-control clothing films release micropore and that contain the polymer reinforcing agent 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 reinforcing agent 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 particularly pass through the coating control drug release in the controlled release preparation that zero level discharges at controlled release preparation.Because the water-insoluble of polymer, 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, and it comes controlled release drug to discharge by 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 of volatilization in thin film.For example: EP0425023 (or US42561989, US5126146) has disclosed a kind of device that the osmotic pressure controlled release discharges medicine that passes through of the cellulosic films clothing that contains micropore, and 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 an 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 that sublimable or degradable composition granules such as utilizing Mentholum, naphthalene, Camphora, phenol, ammonium acetate, ammonium carbonate forms the method for micropore in film-coat.

To utilizing composition (material) with volatilization (or distillation) property or degraded the composition that can be biodegradable into innocuous gas (material) in thin film the method that form micropore of volatilization in thin film to be further described, the while does not have this type of other correlation techniques to above-mentioned two patented technologies of mentioning so far.The inventor does further deep research to the method, found that the controlled release preparation fixture of making has some more serious problems, when its vitrification point (Tg) is low after the middle especially polymer plasticising.

For example, stability of formulation has bigger 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 the preparation does not have to change substantially or amplitude of variation is much smaller relatively.With microscope the product of these storages behind certain hours observed, the size that found that the micropore in its thin film reduces than initial period even is closed fully.The degree that micropore reduces is relevant with storage time, and the time, Yu was long, and it is big that the aperture dwindles Yu; The degree that micropore reduces is also relevant with original pore size, and former aperture Yu is big, and it is little that the aperture dwindles Yu, and former aperture Yu is little, and it is big that the aperture dwindles Yu.

For another example, relatively poor production repeatability: some batch drug release is very fast relatively sometimes, but does not mostly very slowly even discharge; Promptly use the sublimable material grains of same batch (granular size unanimity) to prepare controlled release preparation system, the drug release rate of the controlled release preparation system that the result makes is very big at the different batches differences, 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 complete closure; Average pore size difference is very big between different batches, although former volatile composition granule mean size unanimity.

And for example, the Release Performance of the controlled release preparation of this technology preparation or the speed of release are usually obviously on the low side in the water solublity that adopts the equal size in a footpath preferably material make the film controlled release preparation of porogen, and the micropore that adopts the hollow (no porogen exists) of the equal size in a footpath in theory come controlled release drug the film controlled release preparation should faster than or be not less than the film controlled release preparation that contains the equal big or small porogen in a footpath at least, because porogen need be dissolved into micropore ability controlled release drug, and porogen need dissolve and need the regular hour, can occur certain time stickiness 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 not enough, clothing film may be broken by the external force effect, thereby the dosage that may cause controlled release preparation inclines and releases (dose-dumping), influences drug safety.

Yet in most cases, art for coating is to carry out under the vitrification point of lower polymer (Tg) in the reality, as ethyl cellulose (EC) commonly used ( With ) and acrylic resin (Eudragit) etc.Therefore, also need in the 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 provides a kind of polymer reinforcing agent 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 provides 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 higher relatively storage-stable aspect release.

Main purpose of the present invention just provides 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 higher relatively production repeatability aspect release.

Main purpose of the present invention just provides 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 provides 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 lower dosage the incline probability released and higher drug safety.

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 reinforcing agent 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 reinforcing agent is used as and delays 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 reinforcing agent and the 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 reinforcing agent 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 reinforcing agent is used as the stability of rate of releasing drug in storage that improves above-mentioned controlled release preparation, and the contact angle of the polymer in above-mentioned polymer reinforcing agent and the 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 reinforcing agent 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 reinforcing agent is used as the rate of releasing drug repeatability in process of production that improves above-mentioned controlled release preparation, and the contact angle of the polymer in above-mentioned polymer reinforcing agent and the 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 reinforcing agent 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 reinforcing agent is used as the above-mentioned controlled release preparation Release Performance of improvement, as improving drug release rate, the contact angle of the polymer in above-mentioned polymer reinforcing agent and the 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 the polymer and the pharmaceutically acceptable polymer reinforcing agent of water-soluble hardly and Digestive system, the contact angle of above-mentioned polymer and above-mentioned polymer reinforcing agent is lower than 90 °, and above-mentioned release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned polymer release-control clothing film and/or decompose 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 reinforcing agent pharmaceutically acceptable is insoluble to or the solution of the polymer of water-soluble hardly 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 reinforcing agent was insoluble to or was dissolved in hardly above-mentioned polymer, the contact angle of above-mentioned polymer and above-mentioned polymer reinforcing agent 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 is meant the hydrophobicity that contains q.s (polymer) material on the nuclear core outer surface that is coated on controlled release preparation and have sufficient mechanical strength and keep controlled release preparation its contained medicine or be in harmony the treatment activating agent when placing the not disruptive coating membrane of aqueous solution drug release process, this coating membrane can delay to discharge above-mentioned controlled release preparation to be placed in aqueous solution.

The term " polymer " reinforcing agent that the present invention uses " be meant with form (decentralized photo) independently and be distributed in the polymer phase (continuous phase) in the 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.

The term " contact angle " that the present invention uses be meant when the polymer that is in the fluid attitude is positioned at the polymer reinforcing agent surface of solids at liquid (polymer) Gu-formed angle during the balance of the ternary junction of (polymer reinforcing agent)-gas (air); 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 the ternary junction of (polymer reinforcing agent)-gas (air).

The term " numerous " that the present invention uses is meant that the quantity of the release micropore on polymer (controlled release) the clothing film that is overlying on preparation outward is not one, have a plurality of, one 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 is meant that any material has detectable biological effect and comprises any physiological, diagnosis, preventative or pharmacological effect when it bestows live body.This term is intended to include but not limited to material any pharmacy, therapeutic, preventative, the threpsology.

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

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

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

The specific embodiment

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

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

The key factor of the performance of above-mentioned pore material impact polymer clothing film (clothing film) and controlled release preparation is important to be its fusing point and sublimable or degradable temperature, the dissolubility in coating solution and mean diameter thereof.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 100 ℃ best; 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 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 (containing) 40 ℃ best.The dissolubility (temperature 25 ℃, temperature when preferably for art for coating carrying out) of above-mentioned pore material in coating solution should not be higher than 30mg/ml, preferably is not higher than 10mg/ml, more preferably is not higher than 1mg/ml, is not higher than 0.1mg/ml best.The mean diameter of above-mentioned pore material should be 30～1200 μ m, preferably is 50～900 μ m, more preferably is 100～600 μ m, is 150～400 μ m best.Because the mean diameter of pore material is the principal element of release micropore size in influence or the decision polymer clothing film (clothing film), so release micropore mean size should be positioned at 30～1200 μ m substantially in the clothing film, preferably be positioned at 50～900 μ m, more preferably be positioned at 100～600 μ m, be positioned at 150～400 μ m best.

Cross low fusing point, cross the formation that low sublimable or degradable temperature is unfavorable for coating and release micropore, the material that also can make sublimable material and/or can be biodegradable into innocuous gas may distil and degrade in the coating process in a large number, from the clothing film, lose too early, thereby influence the Release Performance and the production repeatability of preparation.Too small release micropore may cause the problem that production repeatability and storage-stable are relatively poor etc. in production, the more important thing is, too small release micropore will produce additional press (the Δ P) of bigger 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 bigger micropore will make micropore slowly dwindle voluntarily in production or storage, it is stable inadequately 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 big, 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 bigger than the amplitude that micropore size increases (or minimizing).So 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 the technical field technical ability those skilled in the art according to the character of medicine and desired rate of releasing drug decision.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), preferably be 25%～90%, more preferably be 40%～80%, this is based on the gross weight or polymer clothing film (clothing film) volume done of polymer clothing film (clothing film) component.

The consumption of pore material is the principal element of the porosity of influence or decision 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 " is meant that left space behind the pore material of flinging in the polymer clothing film (clothing film) accounts for the ratio of the volume of whole original copolymer clothing film (clothing film).

Be fit to sublimable component or the component preferred embodiment that can be biodegradable into innocuous gas as the pore material of the present invention and include 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 third fat, benzyl benzoate, essence of Niobe, benzoate such as sodium salt), vanillin (mp81～83 ℃), ethyl vanillin (mp76～81 ℃, pure product mp77～78 ℃), natural or artificial camphor (natural camphor mp176～181 ℃, artificial camphor mp174～179 ℃), gum camphor (about 179.8 ℃ of mp, 204 ℃ begin distillation (1atm)), left-handed Camphora (about 178.6 ℃ of mp, 204 ℃ begin distillation (1atm)), raceme Mentholum (alcohol) (mp42～44 ℃), left-handed menthol (mp41～45 ℃), natural or synthetic borneol (mp205-210 ℃), dextro Borneolum Syntheticum (about 208 ℃ of mp), left-handed Borneolum Syntheticum (about 204 ℃ of mp), dextrorotation isoborneol (about 214 ℃ of mp), left-handed isoborneol (about 214 ℃ of mp), raceme isoborneol (about 212 ℃ of mp), dithiooxamide (dithio diamides) (about 41 ℃ of mp), 6-methyl-2-deracil (methylthiouracil) (about 330 ℃ of mp, 326～331 ℃ of decomposition), azulene sulfonate such as sodium salt, butylated hydroxyarisol (mp57～65 ℃), di-tert-butyl hydroxy-methylbenzene (2, the 6-d-tert-butyl-p-cresol) (mp69～71 ℃), (mp158 ℃ of salicylic acid, 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 water-soluble hardly and Digestive system block polymer or copolymer.Suitable polymers can be selected from but be not limited to be insoluble to or cellulose esters, acrylic acid (ester) base polymer, polyvinyl acetate esters, polyvinyl chloride and the compositions thereof of water-soluble hardly and Digestive system.The suitable polymers example of preferred example includes but not limited to ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, the lacceroic acid cellulose, three Palmic acid celluloses, the disuccinic acid cellulose, two Palmic acid celluloses, polyvinylacetate, methacrylic acid (ester) polymer, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, Merlon, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, 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.

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

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

The ratio of coating polymer in drying is according to the kind of selected polymer, the kind and the decisions such as consumption, the character of medicine, selected dosage form and desirable release pattern thereof thereof of 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 the being everlasting prescription plasticizer with the glass transition temperature (Tg) that reduces polymer to suitable scope, and the film forming ability of raising coating material, the pliability and the intensity of enhancing clothing film are improved the coherent condition of clothing film to substrate.Usually in one 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 less demanding in 90 ℃ usually, is not less than 15 ℃, is preferably 25～80 ℃, and more preferably 35～70 ℃, more preferably 45～65 ℃; Glass transition temperature (the T of polymer clothing film _g) material that also should be lower than this sublimable material and/or can be biodegradable into innocuous gas begins the temperature that distils or degrade under 1 normal atmosphere (101.325ka), hang down 10 ℃ usually, preferably hangs down 20 ℃, goodly hangs down 20 ℃, hangs down 40 ℃ best.Adopt lower glass transition temperature (Tg) in the present invention, thereby can in the coating process, adopt lower temperature, help carrying out smoothly of art for coating like this, particularly help reducing the distillation or the degraded of pore material work in-process, thereby help improving Release Performance, technology stability and the production repeatability of preparation.Glass transition temperature (the T of polymer clothing film _g) should be too not high, will increase technology difficulty and cost because of higher.

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

Plasticizer dosage is according to the character of desired clothing film, as glass transition temperature, mechanical performance etc., the kind of plasticizer, the kind of film former (being the water-insoluble film forming polymer), consumption etc. and decide, usually consumption is 5～50% (weight ratios), preferred 10～40% (weight ratios), preferred especially 10～30% (weight ratios), this is based on the 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) can reduce preparation release storage-stable, the release production repeatability that makes usually, because of the glass transition temperature of polymer clothing film lower, the polymer molecule freedom " flow " or the ability or the trend of " slip " stronger, the release micropore is more easily produced and/or is preserved and reduces (at term of the present invention " storage " typically refer to preparation process when being used by user (patient) when produce finishing) process even closure fully; In addition, the function performance of above-mentioned polymer clothing film such as the tensile property space that still has improvement.In order to improve these performances of the preparation that makes, the present invention need add the particular polymers reinforcing agent at coating solution.Specifically, the contact angle (θ) that adds in coating solution or coating with above-mentioned polymer is lower than 90 ° polymer reinforcing agent, preferably above-mentioned contact angle (θ) is less than or equal to 60 °, more preferably is less than or equal to 30 °, is less than or equal to 10 ° best." polymer reinforcing agent " described herein is meant with form (decentralized photo) independently and is distributed in the polymer phase (continuous phase) in the polymer clothing film (clothing film) and can improves the pharmaceutically acceptable additive that polymer clothing film comprises the mechanical performance of machinery (mechanics) strength and stiffness." polymer reinforcing agent and polymer contact angle " described herein be meant when the polymer that is in the fluid attitude is positioned at the polymer reinforcing agent surface of solids at liquid (polymer) Gu-formed angle during the balance of the ternary junction of (polymer reinforcing agent)-gas (air); More preferably, after the polymer that is meant 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 the ternary junction of (polymer reinforcing agent)-gas (air).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 the rheology temperature T of temperature greater than polymer _fMake polymer be in the fluid attitude, drip polymer liquid and make it the static surface (being generally the clean, smooth horizontal plane) that is positioned at the polymer reinforcing agent after treating its form stable the contact angle that (more preferably further solidify and be cooled to 25 ℃ of room temperatures after) records with proper method, 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 big by moistening degree Yu of liquid, and compatibility Yu of the two is good, the affinity Yu Qiang of the two.When the contact angle of polymer and polymer reinforcing agent is lower than 90 °, more very be less than or equal to 60 °, especially be less than or equal to 30 °, when particularly being less than or equal to 10 °, the compatibility is better between polymer and polymer reinforcing agent, the two has stronger affinity, and " moistened surface " even " expanding " can take place.At this moment, because of polymer and the mutual active force of polymer reinforcing agent stronger, and the polymer reinforcing agent is with particulate matter (molecule aggregation body) or figuratively speaking be scattered in the polymer with the form on " island ", the polymer molecule freedom " flows " or the ability of " slip " then is aggregated the thing reinforcing agent and weakens, the freedom of polymer molecule " flows " or the scope of " slip " is aggregated the thing reinforcing agent and is limited in the relative small range, show " viscosity " on the polymer macroscopic view and rise, " flowability " descends.Thereby, above-mentioned polymer reinforcing agent 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 or the variation tendency of closure etc. effect voluntarily with stable release micropore size.Therefore, above-mentioned polymer reinforcing agent 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 reinforcing agent indirectly.The compatibility between polymer and polymer reinforcing agent or affinity also can be used " similar compatibility " principle and estimate or predict, as polarity or nonpolar similarity.

When the polymer reinforcing agent 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 reinforcing agent.Generally, especially for nonpolar amorphous polymer blend, when the difference of the solubility parameters of two polymer less than 0.5 or the difference of the solubility parameters of polymer and organic solvent less than 1.5 the time, the two just can be with the arbitrary proportion mixing, the two has the good compatibility.When having very strong polarity and can form hydrogen bond for the co-mixing system that contains crystalline polymer or polymer molecule, can adopt two dimension or three-dimensional solubility parameter to judge that the compatibility of system is (referring to Shaw M.T., J 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 with in a kind of solvent, mix mutually then, judge the polymer-polymer miscibility size according to two solution mixing situations.2), microscopic method, but with the phase contrast microscope method particularly its mixed phase of electron microscope method direct observation hold degree.3), the solution viscosity method, the viscosity of solution can disclose the compatibility of polymer blend solution, and is to the percentage composition of polymer mapping, linear as its relation with viscosity under different polymer concentrations, shows to reach the compatible fully of molecular level between polymer; Being tied to form non-linearly as its pass, then is that part is compatible; When being complete incompatible co-mixing system, then it concerns S-type curve.4), by the use of thermal means and dynamic mechanical analysis method (surveying vitrification point Tg), three kinds of Tg variation tendencies can appear in special recommendation the method for the present invention, polymer alloy system, suppose that the Tg of two kinds of polymer in the bianry alloy system is respectively Tg ₁And Tg ₂(Tg ₁＜Tg ₂), (1), complete compatible system: a Tg only occurs, Tg ₁＜Tg＜Tg ₂(2), complete incompatible system: two Tg occur, be respectively Tg ₁And Tg ₂(3), the compatible system of part: two Tg occur ₁', Tg ₂', Tg ₁＜Tg ₁'＜Tg ₂'＜Tg ₂

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

Can be used for polymer reinforcing agent 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 acceptable rigid inorganic particle of pharmacy and rigidity organic filler.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 chemical compound, silicon-containing compound (as Si oxide, silicate) and composition thereof.Can be used for rigid inorganic particle preferred examples 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) absorption parcel to handle or with coupling agent treatment such as organo silane coupling agent, titanate coupling agent, zirconium aluminate coupling agent, 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 rigidity organic filler preferred examples 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 5nm best.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 to be the chemical microfibre that raw material is made with the mineral, 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, Folium Agaves Sisalanae microfibre, wooden microfibre etc.The example of metal microfibre is as metal microfibres such as silver, copper, nickel.

This paper term as used herein " microfibre " is meant that the length-width ratio that is used for the preferred microfibre of this paper is about 10 because their length-width ratio can be described as the granular materials of fiber usually: about 500: 1 of 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 5nm best.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 100nm best.

Be used for the enhanced rigid particles of polymer of the present invention particularly rigid polymer can also outer be overlying on the polymer toughening agent (" the polymer toughening agent " herein stated is meant to have the acceptable composition of pharmacy that reduces clothing film fragility and improve clothing film shock resistance, together following), thus form " duricrust-soft nuclear structure ".In above-mentioned " nucleocapsid structure ", " shell " can coat " nuclear " wholly or in part; Can contain one or more " nuclears " in " shell "; Can also contain littler " nuclear " in " shell "; Shell " in " nuclear " in also can comprise the component of " shell " or littler " 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 pure polymers reinforcing agent or polymer toughening agent, so 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 the clothing of increasing membrane polymer and is higher than its glass transition temperature (T in temperature _g) time " flowability " reach " ductility ", reduce " melt " inner tensions and can also keep higher " melt " intensity simultaneously, accelerate " fusion ", promote " plasticizing ", improve " processability ", these help the coating and the healing of polymer clothing film (clothing film), shorten their required time of processing, reduce volatilization or the degraded of above-mentioned porogen in the above-mentioned course of processing, thereby have the effect of stronger stable release micropore size.Therefore, above-mentioned " nucleocapsid structure " particle in the present invention most preferably.

Suitable composition as " nuclear " in " nucleocapsid structure " 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 the C2-C8 alkene, propylene, 1-butylene, 4-methyl-1-pentene), alkenyl aromatic monomer (as styrene in the C2-C8 alkenyl aromatic monomer and α-Jia Jibenyixi), 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, also can be copolymers.

More particularly, comprise being not limited to all polymer rubber sills, as from acrylic acid, methyl methacrylate-butadiene-styrene (MBS) type impact modifier deutero-those; Siliceous rubber polymer and copolymer, as siloxanes, silicone or the like; Synthetic rubber, as butadiene rubber, SBR styrene butadiene rubbers (SBR), and isoprene, or the like; 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 type, or the like; And their blend, graft, and copolymer.

The composition of " nuclear " is that the polymer toughening agent can comprise polyolefin polymer in suitable " nucleocapsid structure " of the present invention, and it is C _nH _2nOne 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 one structure and preparation method thereof is well-known in the art, and sees and for example be set forth in the U.S. Patent number 2933480,3093621,3211709,3646168,3790519,3884993,3894999,4059654,4166055 and 484334.

The composition of " nuclear " is that the polymer toughening agent also can comprise various polyolefinic copolymers in suitable " nucleocapsid structure " of the present invention, 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.

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

Suitable " nucleocapsid structure " particle example as mechanical performance improving agent (polymer reinforcing agent) 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.Shi Yi example such as polystyrene-poly butadiene (SBR) especially, polystyrene-poly (ethylene-propylene), polystyrene-poly isoprene, poly-(α-Jia Jibenyixi)-polybutadiene, polystyrene-poly butadiene-polystyrene, polystyrene-poly (ethylene-propylene)-polystyrene, polystyrene-poly isoprene-polystyrene and poly-(α-Jia Jibenyixi)-polybutadiene-poly-(α-Jia Jibenyixi) 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 reinforcing agent) is as comprising the star block copolymer of vi-ny l aromatic monomers and conjugate diene monomer.One comprises the polymerization of vinyl aromatic monomer of about 60% to 95% (weight) and the polymerized conjugated diene monomer of about 40% to 5% (weight) copolymer of the type.Described copolymer has at least 3 polymer chains that form the star configuration.Elastomeric polymer is segmental to be essentially stiff segment to the end of each chain in order to be connected with 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 reinforcing agent) 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 (the carbon list oxide) trimer of preferred C1～C4), ethylene-C1～C8 (preferred C1～C4) alkyl acrylic copolymer and polyacrylonitrile-butadiene-styrene (ABS).

Used above-mentioned " nucleocapsid structure " particle of the present invention is stored in the polymer clothing film (clothing film) as mechanical performance improving agent (polymer reinforcing agent) with certain shape and big or small particle.About its shape, the particle that constitutes described " nucleocapsid structure " typically is sphere.But they can have any suitable shape, and the particle of different shape 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 1: 1 ellipsoid particle, 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 5nm best.One ground, less particle helps improving shock strength.

Fusing point (or the crystal melting temperature of " nucleocapsid structure " particle of suitable mechanical performance improving agent of the present invention (polymer reinforcing agent), Crystalline Melt Temperature) or/and Vickers softening point (Vicat Softening Point) is not less than the glass transition temperature (Tg) of the polymer in the above-mentioned clothing film usually, preferably exceed its 5 ℃ (containing), more preferably exceed 10 ℃ (containing), exceed 20 ℃ (containing) best; And its (center) vitrification point (Glass TransitionTemperature) requires to be lower than the glass transition temperature (Tg) of the polymer in the above-mentioned clothing film usually, is not higher than 15 ℃ of temperature usually, is not higher than 0 ℃ of temperature best; 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 as follows: fusing point (or crystal melting temperature as other parametric optimizations of " nucleocapsid structure " particle of mechanical performance improving agent (polymer reinforcing agent), Crystalline Melt Temperature) (DSC, via ASTM D3418 ISO 3146) or/and Vickers softening point (Vicat Softening Point, via ASTM D1525 ISO 306) is preferably 60～2000 ℃, more preferably 80～1000 ℃, be preferably 100～500 ℃ especially; Vickers softening point (Vicat Softening Point, via ASTMD1525 ISO 306) is preferably 45～150 ℃, more preferably 45～100 ℃, is preferably 50～80 ℃ especially; 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 is preferably 2～50g/10min to melt flow rate (MFR) (Melt Flow Rate) especially.

The common consumption 0.5～50% of polymer reinforcing agent (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 reinforcing agent use in conjunction is, the clothing membrane polymer is selected from the polymer of being insoluble to of polar functionalities or water-soluble hardly and Digestive system, as the cellulose esters base polymer, acrylic acid (ester) base polymer, the polyvinyl acetate esters, and the polymer reinforcing agent is selected from the thin or ultra-fine grain (particle diameter preferably is not more than 100nm (diameter)) of polar rigid inorganic particle, as carbonate, sulfate, metal-oxide, Si oxide, silicate and composition thereof has more preferably been used polarity macromolecule dispersing agent (as polyacrylate) absorption parcel processing mode for it and has been 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 esters 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 reinforcing agent use in conjunction is, the clothing membrane polymer be selected from contain non-polar group be insoluble to or the cellulose esters base polymer of water-soluble hardly and Digestive system (as ethyl cellulose, the lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses), and the polymer reinforcing agent 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 special preferred surface is coated by stearic acid.

The example of another preferred clothing membrane polymer and polymer reinforcing agent use in conjunction is, the clothing membrane polymer is selected from and is insoluble to or the cellulose esters base polymer of water-soluble hardly and Digestive system, and polymer reinforcing agent particle is selected from the copolymer of methyl methacrylatestyrene (MMA-ST) that contains polarity and non-polar group simultaneously, SAN (SAN), styrene-butadiene-acrylonitrile trimer (ABS), methyl methacrylate-butadiene-styrene trimer (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 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, methyl methacrylate-butadiene-styrene trimer (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 reinforcing agent use in conjunction is, the clothing membrane polymer is selected from and is insoluble to or acrylic acid (ester) base polymer of water-soluble hardly and Digestive system, and polymer reinforcing agent particle is selected from polymethyl methacrylate (PMMA), copolymer of methyl methacrylatestyrene (MMA-ST), methyl methacrylate-butadiene-styrene trimer (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), crylic acid resin anti-impact modifier or their mixture (particle diameter preferably is not more than 400nm (diameter), 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 hardly and Digestive system, methylmetacrylate, trimethylamonioethylmetacrylatchloride)) and their mixture.

The example of another preferred clothing membrane polymer and polymer reinforcing agent use in conjunction is, the clothing membrane polymer is selected from and is insoluble to or the polyvinyl acetate esters of water-soluble hardly and Digestive system, and polymer reinforcing agent particle is selected from copolymer of methyl methacrylatestyrene (MMA-ST), SAN (SAN), styrene-butadiene-acrylonitrile trimer (ABS), methyl methacrylate-butadiene-styrene trimer (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 (preferred C1～C4) alkyl acrylic copolymer and their mixture (particle diameter preferably is not more than 400nm (diameter), 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 reinforcing agent use in conjunction is, the clothing membrane polymer is selected from polrvinyl chloride, and polymer reinforcing agent particle is selected from copolymer of methyl methacrylatestyrene (MMA-ST), SAN (SAN), styrene-butadiene-acrylonitrile trimer (ABS), methyl methacrylate-butadiene-styrene trimer (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 (preferred C1～C4) alkyl acrylic copolymer or their mixture (particle diameter preferably is not more than 400nm (diameter), 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.

In the coating solution that invention relates to, can add clothing film universal additive material.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 influence the permeability of clothing layer, and this can be used as additional adjusting parameter equally.

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

Antitack agent (separating medium)

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

Stabilizing agent

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

Pigment

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

Defoamer

One ground of defoamer is dimethicone.

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

The material of all uses must be pharmaceutically acceptable, nontoxic in principle in the clothing film, in medicine patient is not had danger.

Below the used core material of the present invention is explained.

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).Granule, (little) ball or crystalline size are generally 0.01～2.5mm, and the size of sheet is usually at 2.5～30mm.They contain the bioactive substance (active substance) that is up to 95% (weight ratio does not below have special instruction herewith) and other pharmacy auxiliary agent that is up to 99.9% usually.

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 the drug effect loss, just there is not 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 used active component of the present invention, can be above-mentioned any pharmaceutically or the threpsology on have material therapeutical effect or preventive effect.The available active component example of the present invention is listed below:

-medicine for central nervous system:

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

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

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

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

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

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

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

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

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

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

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

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

-circulatory system drug:

-calcium is picked up drug resistance: anipamil, barnidipine, benidipine, bepridil, devapamil, falipamil, cinnarizine, lacidipine, Manidipine, tiapamil, verapamil, dexverapamil.

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

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

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

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

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

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

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

-medicine for digestive system:

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

-gastrointestinal antispasmodic medicine: adiphenine.

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

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

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

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

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

-allergy preparations:

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

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

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

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

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

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

-antimicrobial agents/antibiotic:

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

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

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

-aminoglycoside: paromomycin, kanamycin, gentamycin, neomycin.

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

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

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

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

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

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

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

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

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

-nucleotide.

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

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

-other drug: finasteride, Alendronate sodium, alosetron, orlistat, epristeride, epalrestat, tolterodine, tolrestat, 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, the fumaric acid emedastine, glipizide-metformin hydrochloride compound recipe, gliquidone, glimepiride-metformin compound recipe, gliclazide, potassium citrate, Tamoxifen Citrate, Tamoxifen Citrate, the succinic acid desmethylvenlafaxine, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, Tolterodine tartrate, Zolpidemtar Trate, clarithromycin, kurarinone, ranolazine, ribavirin, benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, loratadine-acetaminophen-pseudoephedrine compound recipe, loratadine-pseudoephedrine compound recipe, rosiglitazone, Roxithromycin, lovastatin, Trimebutine Maleate, enalapril maleate-felodipine compound recipe, mesalazine, medetofazone, mizolastine, naftopidil, naproxen sodium, Ni Ketating, nimesulide, nitrendipine, nisoldipine, Paliperidone, Perprazole, darifenacin hydrobromide, galanthamine hydrobromide, huperzine A, bicyclol, stavudine, gastrodine, ketoprofen, cefaclor, cefixime, vitamin C controlled-releasing vaginal sheet, vitamin E Nicotinate, pseudoephedrine-naproxen sodium compound, urapidil, nicotinic acid, nicotinic acid-simvastatin compound recipe, BUPROPIONE HCl, ambroxol hydrochloride, ditropan XL, Betahistine Hydrochloride, metformin hydrochloride, valaciclovir hydrochlordide, ciprofloxacin, labetalol hydrochloride, Licardipine Hydrochloride, paroxetine hydrochloride, minipress, propafenone hydrochloride, propranolol hydrochloride, dihydromorphinone hydrochloride, tramadol hydrochloride, Trimetazidine Hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, albuterol hydrochloride, levofloxacin hydrochloride, ofloxacin, etodolac, indapamide, guaifenesin, guaifenesin-pseudoephedrine hydrochloride compound recipe, levodropropizine, bezafibrate, piribedil, theophylline, vincamine, dihydroergotoxine methanesulfonate, Carclura, spectinomycin hydrochloride, dihydrocodeine bitartrate, the carbidopa and levodopa compound recipe, morphine sulfate, the sulphuric acid celebrating is mould greatly, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, diclofenac sodium, verapamil, dimension ferrum, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetacin, theophylline-albuterol compound recipe, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, ibuprofen and codeine, Malotilate, naproxen, lithium carbonate, cefalexin, alfuzosin hydrochloride, Buflomedil Hydrochloride, the hydrochloric acid Ticlopidine, ibudilast, dextromethorphan, ZHENGQINGFENGTONGNING, the single nitre Coronex of 5-, sodium valproate, Benserazide, gentamycin sulfate-zirconium dioxide compound recipe, chlorphenamine maleate, barnidipine, bunazosin, gallopamil, methylphenidate hydrochloride, oxycodone hydrochloride, Chinese herbal medicine extract.

Because, 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 the Chinese herbal medicine extract, do not exist the active component that occurs because of 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 its pharmaceutically available salt form of following active component, free acid form, free alkali form, hydrate, various crystal formation and optical isomer.

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

Elaborate with regard to each basic step in the preparation method of controlled release preparation below.

1), preparation contains the core material of at least a 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 the polymer reinforcing agent be insoluble to or the solution or the aqueous dispersions of the polymer of water-soluble hardly and Digestive system coat the clothing film to above-mentioned core material, this sublimable material and/or the material that can be biodegradable into innocuous gas are insoluble to or are dissolved in hardly the solution or the aqueous dispersions of this polymer, and the contact angle of this polymer and polymer reinforcing agent 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 the polymer reinforcing agent disperses and suspendible or be dissolved in is insoluble to or the solution or (water) dispersion suspension of the polymer of water-soluble hardly and Digestive system in, 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 the solution or the aqueous dispersions of above-mentioned polymer, and the contact angle of above-mentioned polymer and polymer reinforcing agent 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 certain pharmaceutically acceptable organic solvent hardly, and this organic solvent can be selected the solvent of this organic solvent as above-mentioned polymer for use can dissolve above-mentioned polymer the time; When above-mentioned sublimable material and/or the material that can be biodegradable into innocuous gas are insoluble to or are water-soluble hardly, preferably select the dispersant of water for use as this polymer, promptly select the aqueous dispersion of polymer for use.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 the above-mentioned core material that makes to be prepared the clothing layer by coating processes such as fusion, casting, brushing or sprayings.Preferably adopt spraying method to carry out.Film forming procedure does not rely on coating process and is undertaken by energy input.This can finish by convection current (heat), radiation (infrared or microwave) or conduction.Thus will be for the organic solvent or the water of coating as solvent or suspending agent use evaporate, necessary words also may be used the vacuum accelerated evaporation.The higher drying efficiency of this process need, so the present invention often adopts high efficiency coating equipment (as fluid bed, high-efficiency coating pot).

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 broken phenomenon 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 hydrolysis in the coating process of water sensitivity medicine.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.

The core material surface temperature should be higher than the minimum film formation temperature (MFT) of polymer (minimum film formation temperature is meant the minimum temperature of polymer formation seriality clothing film during coating, 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 softening fully or melt the clothing film is sticked together to some materials that make the coating material, and should do not softened fully or fusing or degraded by high some compositions in core material yet, the core material surface temperature especially should be high to the sublimable material that makes the coating material and/or can be biodegradable into a large amount of distillations of material of innocuous gas and degrade, therefore, the core material surface temperature preferably is 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 low excessively in the present invention, makes because of the core material surface temperature is low excessively that the clothing film is easily crisp the crack may to occur, influences the preparation drug release feature; Simultaneously, the core material surface temperature can not be too high, because of the too high then 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 and the degraded of innocuous gas, loses from the clothing film too early.

During coating, (this temperature is relatively low when adopting polymer organic solution for the common preheating of core material, this temperature is higher relatively when adopting aqueous polymer dispersion) to 20～70 ℃, preferably 30～60 ℃, more preferably 30～50 ℃, earlier 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 especially dispersant (water) infiltration core material inside of solvent, causes storage process core material character to change.

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

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

3), fling to the pore material

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

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

4), healing (curing) is handled

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 preceding, healing is handled above-mentioned clothing film and is produced numerous minimum micropores in the clothing film and form fine and close clothing film in the coating process to eliminate, 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 polymer particle does not often merge fully in the clothing film.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 takes place in the process, make the permeability of clothing film take place 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, merge that required time is big or small with the membrane micropore footpath usually, the interfacial tension size between polymer-air etc. is relevant.Polymer-air surface tension force one regularly, the membrane micropore footpath is more little, micropore is additional presses greatly more, it is short more to merge required time, the membrane micropore footpath is big more, micropore is additional presses more for a short time, it is long more to merge required time.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 of distillation in thin film, and these relatively large micropores still can produce additional press (the Δ P) of certain micropore in the healing processing procedure, make micropore dwindle (as micropore less than 30 μ m time, during) to a certain extent particularly less than 1 μ m.In order to prevent or being used for of delaying that these have produced the relatively large micropore that controlled release drug discharges is handled in healing and dwindled, improve the stability (relevant) and the production repeatability of the transparent performance of clothing film with Release Performance, the stability and the production repeatability of aspects such as raising clothing film mechanical performance, in the present invention, clothing film healing processing procedure best be used for relatively large micropore that controlled release drug discharges form before (before promptly flinging to the pore material) finish.

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

In the present invention, healing is handled (curing treating) and is comprised following process: after solvent or dispersant (water) evaporate substantially in the above-mentioned clothing film, in enclosed environment, the core material of the above-mentioned clothing of coated polymer film is placed under the temperature of the glass transition temperature that is higher than above-mentioned clothing film the long enough time until terminal point, polymer particle in the above-mentioned preparation clothing film is merged completely or almost completely, eliminate or eliminate the minimum micropore that forms in the coating process substantially and form complete densification or the clothing film of complete substantially densification, the permeance property of above-mentioned clothing film Release Performance in other words reaches the constant substantially in other words state of stable status.More particularly, exactly healing under the temperature of the vitrifying point that is higher than above-mentioned clothing film handle above-mentioned coated preparation until preparation for example about 40 ± 2 ℃ temperature and be not less than 50% and be not higher than above-mentioned sublimable material grains and/or can be biodegradable into place under the relative humidity acceleration storage requirement down 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 unaffected basically till.Perhaps in other words, the external stripping of the bioactive substance after handling just healing with about 40 ± 2 ℃ temperature and be not less than 50% and the external stripping that is not higher than above-mentioned sublimable material grains and/or 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 the relative humidity acceleration storage requirement down of (moisture absorption) critical relative humidity of material of innocuous gas compare, the coated preparation of the processing of healing has stable dissolution characteristic.The meaning of term " stable " finishes, solidifies the dissolution characteristic comparison of coated preparation with firm curing in addition, its external stripping is in the 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 do not quickened the stable dissolution characteristic that storage requirement influences.Above-mentioned dissolution test preferably adopts all the components that contains in the 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 release medium (dissolution medium) that above-mentioned all the components is all saturated.Adopt the saturated solution of all the components in the above-mentioned controlled release polymer clothing film can make in above-mentioned dissolution test, the clean stripping quantity of all the components in the above-mentioned controlled release polymer clothing film was 0 (not comprising the stripping of above-mentioned water miscible pore material), thereby the medicine that helps judging stripping is stripping in micropore stripping rather than that produce because of wherein composition stripping from former controlled release polymer clothing membrane micropore, because of from helping more judging 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, the healing required time of processing is generally tens of hours even is longer.The temperature that the healing treatment of selected is selected should be higher than clothing film glass transition temperature, preferably be higher than clothing film glass transition temperature more than 10 ℃, more preferably be higher than 20～30 ℃ of clothing film glass transition temperatures, the healing treatment of selected temperature of selecting and should be not make the softening fully or fusing of composition in the coating material or clothing film coalescence degree of being does not take place.Preferably use certain humidity when healing is handled, because of clothing film under the effect of moisture or dampness, its glass transition temperature can significantly descend, and handles thereby help 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 too low usually, because of the too low meeting of humidity makes the time of healing processing longer.But selected humidity should not be higher than above-mentioned sublimable material grains usually and/or can be biodegradable into (moisture absorption) critical relative humidity of the material of innocuous gas, after being higher than above-mentioned sublimable material grains and/or 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, particularly water miscible sublimable material grains and/or can be biodegradable into the material of innocuous gas, significantly 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 after the moisture absorption, thereby may from the clothing film, separate out, " scum " phenomenon appears, and then the release micropore is dwindled in agglutination, influence release stability.

In above-mentioned healing processing procedure and under the above-mentioned acceleration storage requirement in the 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 littler than what expect, the clean amount of solid that makes above-mentioned sublimable material in other words and/or can be biodegradable into the pore material of innocuous gas does not reduce, thereby prevent the difference between batch opposite sex that micropore also can occur with same batch porogen further, improve the production repeatability of preparation, stability and rate of releasing drug, usually but the healing processing procedure is more than or equal to the equilibrium partial pressure of the sublimability pore material under condition of living in such as the temperature and/or under more than or equal to the equilibrium partial pressure of all catabolites of the degradability pore material under condition of living in such as the temperature or be lower than under the temperature of minimum degradation temperature of the degradability pore material under condition of living in such as the pressure and carry out, 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) is meant in the enclosed environment under the uniform temperature, and the solid of pore material had a net increase of or the dividing potential drop of clean decrement when being zero when the pore material in pore material in the gas phase (or its all catabolites) and the solid phase thereof was in poised state.But in order to obtain equilibrium partial pressure more than or equal to sublimability or degradability pore material, common way be in airtight environment (as airtight casing), blow (filling) but but go into more than or equal to the sublimability pore material gas of the equilibrium partial pressure of sublimability pore material and/or go into all catabolite gases more than or equal to the equilibrium partial pressure of the catabolite of degradability pore material, perhaps in airtight environment (or casing), put into excessive (promptly usually total some surplus solid exists) but sublimability or degradability pore material, but but the elevated temperature certain hour makes the catabolite of sublimability pore material in the gas phase or degradability pore material and the sublimability pore material in the solid phase or degradability pore material be in poised state.

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

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

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

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

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

Embodiment

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 embodiment 1 sample

1), by following prescription and prepared label:

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

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

Coating fluid prescription:

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

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

With label coating on Hicoater/Fruend 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 for contain 4.5% hydroxypropyl emthylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized steatitic aqueous solution.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 is handled and is carried out in airtight baking oven.The salicylic acid of the built-in capacity of baking oven (the surplus amount of solid of Retained is promptly always arranged).Before handling, healing charges into the hot-air of 65 ℃ of the temperature of the salicylic acid gas that contains saturation capacity.The healing temperature is 50 ℃, and healing time is 56 hours.

4), fling to porogen

Under the condition of 20 ℃ of temperature and near vacuum, take out the salicylic acid in the clothing film.

2, preparation reference examples 1 sample

Surface in the 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 embodiment 2 samples

1), preparation label:

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

2), preparation coating solution:

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

3), coating:

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

Adding the nano aluminium oxide that adds ethyl vanillin (60～80 order), polyacrylate coating in the aqueous dispersion at the above-mentioned cellulose acetate that makes disperses slurry (on average to expect directly 10nm, be determined as 70 ° with the contact angle θ of coating polymer) and the diacetine used as plasticizer, cellulose acetate wherein: ethyl vanillin: nano aluminium oxide (with 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: about 20 seconds of spraying time, about 30～40 seconds of blasting time, 50～70 ℃ of blast temperatures, 45～50 ℃ of label temperature.

4), healing clothing film

Healing is handled and is carried out in airtight baking oven.The ethyl vanillin of the built-in capacity of baking oven (the surplus amount of solid of Retained is promptly always arranged).Before handling, healing charges into the hot-air of 70 ℃ of the temperature of the ethyl vanillin gas that contains saturation capacity.The healing temperature is 65 ℃, and healing time is 64 hours.

5), fling to porogen

Under the condition of 35 ℃ of temperature and near vacuum, take out the ethyl vanillin in the clothing film.

2, preparation reference examples 2 samples

Nano aluminium oxide in the 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 embodiment 3 samples

1), by following prescription and prepared label:

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

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

Coating fluid prescription (1000 consumptions):

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

With label coating on Hicoater/Fruend 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 is handled and is carried out in airtight baking oven.The benzoic acid of the built-in capacity of baking oven (the surplus amount of solid of Retained is promptly always arranged).Before handling, healing charges into the hot-air of 50 ℃ of the temperature of the benzoic acid gas that contains saturation capacity.The healing temperature is 45 ℃, and healing time is 48 hours.

4), fling to porogen

Under the condition of 20 ℃ of temperature and near vacuum, take out the benzoic acid in the clothing film.

2, preparation reference examples 3 samples

(MMA/ST) removes the methyl methacrylate/styrol copolymer in the coating fluid prescription, and other are constant, prepares reference examples 3 samples according to embodiment 3 methods.

Embodiment 4 and reference examples 4

1, preparation embodiment 4 samples

1), presses prescription and the prepared label of embodiment 3

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

Coating fluid prescription (1000 consumptions):

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

With label coating on Hicoater/Fruend 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 is handled and is carried out in airtight baking oven.The butylated hydroxyarisol of the built-in capacity of baking oven (the surplus amount of solid of Retained is promptly always arranged).Before handling, healing charges into the hot-air of 50 ℃ of the temperature of the butylated hydroxyarisol gas that contains saturation capacity.The healing temperature is 45 ℃, and healing time is 60 hours.

4), fling to porogen

Under the condition of 10 ℃ of temperature and near vacuum, take out the butylated hydroxyarisol in the clothing film.

2, preparation reference examples sample 4.

PARALOID BPM-500 in the 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 embodiment 5 samples

1), presses prescription and the prepared label of embodiment 1

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

Coating fluid prescription:

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

With label coating on Hicoater/Fruend 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 for contain 4.5% hydroxypropyl emthylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized steatitic aqueous solution.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

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

2, preparation reference examples sample 4.

(MBS) removes the methyl methacrylate-butadiene-styrene in the coating fluid prescription, and other are constant, prepares reference examples 5 samples according to embodiment 5 methods.

Embodiment 6 and reference examples 6

1, preparation embodiment 6 samples

1), preparation label:

With simvastatin, carbopol, grind and cross sodium citrate, lactose and the polyvinylpyrrolidone mix homogeneously of 200 mesh sieves, 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 the lubricated mixing of magnesium stearate, suppresses uniform mixture with the spill circular tool of one 1/4 inch standard, and used press power is 1000 pounds.The thickness of compacting back 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 for contain 4.5% hydroxypropyl emthylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized steatitic aqueous solution.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 technology bag controlled release clothing:

Controlled release coat liquid prescription

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

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

Annotate: ※ is adjusted to the vitrification point (T of clothing film (doing) according to need _g) be 50 ℃ of required amounts.

4), fling to porogen

Under the condition of 30 ℃ of temperature and near vacuum, take out the carbamide in the clothing film.

2, preparation reference examples 6 samples

(PMMA) removes the polymethyl methacrylate in the coating fluid prescription, and other are constant, prepares reference examples 6 samples according to embodiment 6 methods.

Embodiment 7

Methyl methacrylate/styrene copolymer latices (the about 15nm of mean diameter that the nano aluminium oxide of the coating of the polyacrylate among the embodiment 2 is disperseed to starch weights (dry weight) such as changing into, wherein, methyl methacrylate content about 60%, styrene-content is about 40%, is determined as 39 ° with the contact angle θ of coating polymer) be equipped with embodiment 7 with legal system.

Embodiment 8

Only weights (dry weight) such as changing into is starched in the nano aluminium oxide dispersion that the polyacrylate among the embodiment 2 is coated

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

Embodiment 9

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

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

Embodiment 10

Methyl methacrylate/styrol copolymer among the embodiment 3 is changed etc. into methyl methacrylate-butadiene-styrene trimer latex (about 100nm of mean diameter of heavy (dry weight), wherein, butadiene content about 70%, styrene-content about 15%, methyl methacrylate content is about 15%, is determined as 12 ° with the contact angle θ of coating polymer) be equipped with embodiment 10 with legal system.

Embodiment 11

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

Embodiment 12

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

Embodiment 13

Methyl methacrylate-butadiene-styrene among the embodiment 6 (MBS) is changed etc. into the DuPont of heavy (dry weight) ^TM HP4051 latex (the about 150nm of mean diameter is determined as 14 ° with the contact angle θ of coating polymer) is equipped with embodiment 13 with legal system.

Embodiment 14

Methyl methacrylate-butadiene-styrene among the embodiment 6 (MBS) is changed etc. into the DuPont of heavy (dry weight) ^TM

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

The test of test example 1 external Release Performance (release)

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

Diltiazem hydrochloride release method of testing: adopt Chinese Pharmacopoeia version oar in 2005 method 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 the 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 the dissolution medium, calculate every release at different dissolution times.

Glipizide release method of testing: sample thief, 37 ℃ down according to drug release determination methods (Chinese Pharmacopoeia version appendix in 2005 XD first method), with the Tris buffer (0.004M Tris, pH8.7) 1000ml is a solvent, rotating speed is that per minute 100 changes, operation in accordance with the law.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 the dissolution medium.Calculate the release of each dissolution time of glipizide.

Simvastatin release method of testing: each sampling back is changeed carrying out under the laboratory condition by per minute 50 with USP 2 type devices and to be 7.4, to contain the test of release medicine among the phosphate buffered solution 1000ml of sodium lauryl sulphate 0.4% to pH value under 37 ℃.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 the 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 of embodiment 1-6 and reference examples 1-6 shows, good (rate of releasing drug is relatively large, relative deviation S than reference examples for embodiment pharmaceutical preparation Release Performance and production repeatability _rLess relatively)

Test example 2 preparation medicines discharge stability test

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

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

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

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

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

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

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

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

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

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

Test example 3 preparation clothing film measuring mechanical properties

Get half wet residue (i.e. the clothing film that directly takes out from dissolution fluid) and the dried residue that gets of second half vacuum drying when temperature is lower than 0 ℃ after the test of embodiment 1-6 in test example 1 external release (release) testing experiment and reference examples 1-6 thereof, maximum pull when measuring it fracture taking place the effect of tension power when 25 ℃ of temperature and the percentage ratio (elongation at break) of extended length and original length when being broken thereof.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.

The test of test example 4 polymer clothing film release micropore average pore sizes

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

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

The result shows, adds effective polymer reinforcing agent and help delaying the release micropore and reduce in production process and storage in polymer clothing film.

Claims (65)

1. a polymer reinforcing agent is contained outside be used as the purposes that reduce in the aperture that delays described release micropore in the controlled release preparation controlled release preparation that particularly zero level discharges 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 described polymer reinforcing agent and described polymer is lower than 90.

2. a polymer reinforcing agent is contained outside in the controlled release preparation controlled release preparation that particularly zero level discharges that numerous polymer release-control clothing films that are filled with the release micropore of air coat and is used for improving the purposes of the rate of releasing drug of described controlled release preparation in the stability of storage, wherein, the contact angle of described polymer reinforcing agent and described polymer is lower than 90.

3. a polymer reinforcing agent is contained the rate of releasing drug reproducible purposes in process of production that is used to improve described controlled release preparation in the controlled release preparation controlled release preparation that particularly zero level discharges that numerous polymer release-control clothing films that are filled with the release micropore of air coat outside, wherein, the contact angle of described polymer reinforcing agent and described polymer is lower than 90.

4. a polymer reinforcing agent is contained the Release Performance that is used to improve described controlled release preparation in the controlled release preparation controlled release preparation that particularly zero level discharges that numerous polymer release-control clothing films that are filled with the release micropore of air coat outside, as improve the purposes of drug release rate, wherein, the contact angle of described polymer reinforcing agent and described polymer is lower than 90.

5. according to purposes any in the aforementioned claim, wherein said contact angle is less than or equal to 60 °.

6. according to purposes any in the aforementioned claim, wherein said contact angle is less than or equal to 30 °.

7. according to purposes any in the aforementioned claim, wherein said contact angle is less than or equal to 10 °.

8. according to purposes any in the aforementioned claim, wherein said release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of described polymer release-control clothing film and/or decomposes the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in described polymer release-control clothing film to obtain through distillation.

9. according to purposes any in the aforementioned claim, wherein said polymer reinforcing agent has " duricrust-soft nuclear " structure.

10. according to the purposes of claim 9, the fusing point of wherein said polymer reinforcing agent (or crystal melting temperature) is or/and Vickers softening point (Vicat Softening Point) is not less than the glass transition temperature (Tg) of the polymer in the described clothing film, and its center vitrification point is not higher than 0 ℃.

11. purposes according to claim 9, the fusing point of wherein said polymer reinforcing agent (or crystal melting temperature) is or/and Vickers softening point (Vicat Softening Point) exceeds the glass transition temperature (Tg) of 10 ℃ of (containing) polymer in described clothing film, and its center vitrification point is-10～-200 ℃.

12. according to the purposes of claim 9, the elongation at break of described polymer reinforcing agent is 200～5000%.

13. according to purposes any in the claim 1 to 4, wherein said polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, and described polymer reinforcing agent is selected from the polarity rigid inorganic particle that has carried out surface modification with surfactant absorption parcel processing mode.

14. according to purposes any in the claim 1 to 4, wherein said polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, and described polymer reinforcing agent is selected from the calcium carbonate particle that the surface is coated by stearic acid.

15. according to purposes any in the claim 1 to 4, wherein said polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, described polymer reinforcing agent is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, methyl methacrylate-butadiene-styrene trimer, ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture.

16. according to purposes any in the claim 1 to 4, wherein said polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, and described polymer reinforcing agent is selected from copolymer of methyl methacrylatestyrene, methyl methacrylate-butadiene-styrene trimer or their mixture.

17. according to purposes any in the claim 1 to 4, wherein said polymer is selected from and is insoluble to or methacrylic acid (ester) polymer of water-soluble hardly and Digestive system, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride) or their mixture, described polymer reinforcing agent is selected from polymethyl methacrylate, copolymer of methyl methacrylatestyrene, methyl methacrylate-butadiene-styrene trimer, ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic copolymer, crylic acid resin anti-impact modifier or their mixture.

18. according to purposes any in the claim 1 to 4, wherein said polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble hardly and Digestive system, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl chloride-ethylene acetate copolymer or their mixture, described polymer reinforcing agent is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, methyl methacrylate-butadiene-styrene trimer, ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture.

19. according to purposes any in the claim 1 to 4, wherein said polymer is selected from polrvinyl chloride, and described polymer reinforcing agent is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, methyl methacrylate-butadiene-styrene trimer, ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic copolymer and their mixture.

20. according to purposes any in the aforementioned claim, the mean diameter of wherein said polymer reinforcing agent (diameter) is not more than 400nm.

21. according to purposes any in the aforementioned claim, the mean diameter of wherein said polymer reinforcing agent (diameter) is not more than 100nm.

22. according to purposes any in the aforementioned claim, the mean diameter of wherein said polymer reinforcing agent (diameter) is not more than 20nm.

23. according to purposes any in the aforementioned claim, the mean diameter of wherein said polymer reinforcing agent (diameter) is not more than 5nm.

24. according to purposes any in the aforementioned claim, the glass transition temperature (Tg) of wherein said polymer release-control clothing film is 25～80 ℃.

25. according to purposes any in the aforementioned claim, the consumption of wherein said polymer reinforcing agent is 1%～30% (weight ratio), this is based on the gross weight of doing of polymer release-control clothing membrane component.

26. the controlled release preparation of a performance improvement is the preparation method of the controlled release preparation of zero level release particularly, this preparation method comprises:

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

2), with contain pharmaceutically acceptable sublimable material grains and/or can be biodegradable into the material grains of innocuous gas and pharmaceutically acceptable polymer reinforcing agent pharmaceutically acceptable is insoluble to or the solution of the polymer of water-soluble hardly 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 reinforcing agent was insoluble to or was dissolved in hardly above-mentioned polymer, the contact angle of above-mentioned polymer and above-mentioned polymer reinforcing agent 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.

27. according to the preparation method of claim 26, wherein said contact angle is less than or equal to 60 °.

28. according to the preparation method of claim 26, wherein said contact angle is less than or equal to 30 °.

29. according to the preparation method of claim 26, wherein said contact angle is less than or equal to 10 °.

30. according to preparation method any in the claim 26 to 29, wherein said polymer reinforcing agent has " duricrust-soft nuclear " structure.

31. preparation method according to claim 30, the fusing point of wherein said polymer reinforcing agent (or crystal melting temperature) is or/and Vickers softening point (Vicat Softening Point) is not less than the glass transition temperature (Tg) of the polymer in the described clothing film, and its center vitrification point is not higher than 0 ℃.

32. preparation method according to claim 30, the fusing point of wherein said polymer reinforcing agent (or crystal melting temperature) is or/and Vickers softening point (Vicat Softening Point) exceeds the glass transition temperature (Tg) of 10 ℃ of (containing) polymer in described clothing film, and its center vitrification point is-10～-200 ℃.

33. according to the preparation method of claim 30, the elongation at break of described polymer reinforcing agent is 200～5000%.

34. preparation method according to claim 26, wherein said polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, and described polymer reinforcing agent is selected from the polarity rigid inorganic particle that has carried out surface modification with surfactant absorption parcel processing mode.

35. preparation method according to claim 26, wherein said polymer is selected from ethyl cellulose, lacceroic acid cellulose, three Palmic acid celluloses, two Palmic acid celluloses or their mixture, and described polymer reinforcing agent is selected from the calcium carbonate particle that the surface is coated by stearic acid.

36. preparation method according to claim 26, wherein said polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, described polymer reinforcing agent is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, methyl methacrylate-butadiene-styrene trimer, ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture.

37. preparation method according to claim 26, wherein said polymer is selected from ethyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate propionate (cellulose acetate propionate), celluloid, three cellulose valerates, disuccinic acid cellulose or their mixture, and described polymer reinforcing agent is selected from copolymer of methyl methacrylatestyrene, methyl methacrylate-butadiene-styrene trimer or their mixture.

38. preparation method according to claim 26, wherein said polymer is selected from and is insoluble to or methacrylic acid (ester) polymer of water-soluble hardly and Digestive system, polymethyl methacrylate, ethyl acrylate-Methyl metacrylate 99 polymer, poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride) or their mixture, described polymer reinforcing agent is selected from polymethyl methacrylate, copolymer of methyl methacrylatestyrene, methyl methacrylate-butadiene-styrene trimer, ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic copolymer, crylic acid resin anti-impact modifier or their mixture.

39. preparation method according to claim 26, wherein said polymer is selected from and is insoluble to or the polyvinylacetate of water-soluble hardly and Digestive system, the terpolymer of vinyl chloride-ethylene alcohol-vinylacetate, vinyl chloride-ethylene acetate copolymer or their mixture, described polymer reinforcing agent is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, methyl methacrylate-butadiene-styrene trimer, ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic copolymer or their mixture.

40. preparation method according to claim 26, wherein said polymer is selected from polrvinyl chloride, and described polymer reinforcing agent is selected from copolymer of methyl methacrylatestyrene, SAN, styrene-butadiene-acrylonitrile trimer, methyl methacrylate-butadiene-styrene trimer, ethylene-vinyl acetic acid-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic-carbonyl (carbon list oxide) trimer, ethylene-C1～C4 alkyl acrylic copolymer and their mixture.

41. according to preparation method any in the claim 26 to 40, the mean diameter of wherein said polymer reinforcing agent (diameter) is not more than 400nm.

42. according to preparation method any in the claim 26 to 40, the mean diameter of wherein said polymer reinforcing agent (diameter) is not more than 100nm.

43. according to preparation method any in the claim 26 to 40, the mean diameter of wherein said polymer reinforcing agent (diameter) is not more than 20nm.

44. according to preparation method any in the claim 26 to 40, the mean diameter of wherein said polymer reinforcing agent (diameter) is not more than 5nm.

45. according to preparation method any in the claim 26 to 44, wherein said release micropore mean size is 50～900 μ m.

46. according to preparation method any in the claim 26 to 44, wherein said release micropore mean size is 100～600 μ m.

47. according to preparation method any in the claim 26 to 46, the glass transition temperature (Tg) of wherein said polymer release-control clothing film is 25～80 ℃.

48. according to preparation method any in the claim 26 to 47, the porosity of wherein said polymer release-control clothing film is 5%～95%.

49. according to preparation method any in the claim 26 to 48, the consumption of wherein said polymer reinforcing agent is 1%～30% (weight ratio), this is based on the gross weight of doing of polymer release-control clothing membrane component.

50. according to preparation method any in the claim 26 to 49, wherein said core material is sheet, granule, ball, crystal or the medicine carrying resin of rule or irregular form.

51. according to preparation method any in the claim 26 to 50, wherein said bioactive substance is selected from central stimulants, analgesic, antipyretic analgesic, anti-inflammation analgesia medicine, antigout drug, antiparkinsonian drug, psychosis, antianxiety drugs, antidepressant, antuepileptic, tranquilizer, hypnotic, anticonvulsant, the automonic thing, calcium is picked up drug resistance, the medicine of treatment chronic cardiac insufficiency, anti-arrhythmic, control angina pectoris medicine, peripheral vasodilators, hypotensor, blood lipid regulation medicine and antiatherosclerotic, medicine for respiratory system, antacid and treatment peptic ulcer disease medicine, the gastrointestinal antispasmodic medicine, digestant, Bendectin, emetic and the intestines and stomach promote medicine, the liver and gall diseases adjuvant drug, medicine for urological system, influence the medicine of blood and hemopoietic system, antihistaminic, anaphylaxis medium sustained-release agent, adrenocortical hormone and thyroliberin, gonadal hormone and short gonadal hormone, pancreas hormone and other influence the medicine of blood glucose, thyroid hormones medicine and antithyroid drug, penicillins, cephalosporins, beta-lactamase inhibitor, aminoglycoside, Tetracyclines, Macrolide, antituberculotic, antifungal agent, antiviral agents, antitumor drug, influence the medicine of body's immunity, vitamin and Amitin, appetrol and their mixture.

52. according to preparation method any in the claim 26 to 50, wherein said bioactive substance is selected from Chinese herbal medicine extract.

53. according to preparation method any in the claim 26 to 50, wherein said bioactive substance is selected from LECOZOTAN (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, the fumaric acid emedastine, gliquidone, gliclazide, potassium citrate, Tamoxifen Citrate, Tamoxifen Citrate, the succinic acid desmethylvenlafaxine, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, Tolterodine tartrate, Zolpidemtar Trate, clarithromycin, kurarinone, ranolazine, ribavirin, benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, rosiglitazone, Roxithromycin, lovastatin, Trimebutine Maleate, mesalazine, medetofazone, mizolastine, naftopidil, naproxen sodium, Ni Ketating, nimesulide, nitrendipine, nisoldipine, Paliperidone, Perprazole, darifenacin hydrobromide, galanthamine hydrobromide, huperzine A, bicyclol, stavudine, gastrodine, ketoprofen, cefaclor, cefixime, vitamin C (controlled-releasing vaginal sheet), vitamin E Nicotinate, urapidil, nicotinic acid, BUPROPIONE HCl, ambroxol hydrochloride, ditropan XL, Betahistine Hydrochloride, metformin hydrochloride, valaciclovir hydrochlordide, ciprofloxacin, labetalol hydrochloride, Licardipine Hydrochloride, paroxetine hydrochloride, minipress, propafenone hydrochloride, propranolol hydrochloride, dihydromorphinone hydrochloride, tramadol hydrochloride, Trimetazidine Hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, albuterol hydrochloride, levofloxacin hydrochloride, ofloxacin, etodolac, indapamide, guaifenesin, levodropropizine, bezafibrate, piribedil, theophylline, vincamine, dihydroergotoxine methanesulfonate, Carclura, spectinomycin hydrochloride, dihydrocodeine bitartrate, morphine sulfate, the sulphuric acid celebrating is mould greatly, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, diclofenac sodium, verapamil, dimension ferrum, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetacin, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, ibuprofen and codeine, Malotilate, naproxen, lithium carbonate, cefalexin, alfuzosin hydrochloride, Buflomedil Hydrochloride, the hydrochloric acid Ticlopidine, ibudilast, dextromethorphan, sinomenine, the single nitre Coronex of 5-, sodium valproate, Benserazide, chlorphenamine maleate, barnidipine, bunazosin, gallopamil, methylphenidate hydrochloride, oxycodone hydrochloride.

54. according to preparation method any in the claim 26 to 50, 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.

55. according to preparation method any in the claim 26 to 54, wherein said sublimable material and/or the material that can be biodegradable into innocuous gas under 1 normal atmosphere (101.325ka) fusing point and begin distillation (sublimation point) or the temperature of degraded exceeds (containing) 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.

56. according to preparation method any in the claim 26 to 55, wherein said sublimable material and/or the material that can be biodegradable into innocuous gas under 1 normal atmosphere (101.325ka) fusing point and begin distillation (sublimation point) or the temperature of degraded exceeds (containing) 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.

57. according to preparation method any in the claim 26 to 56, wherein said sublimable material and/or the material that can be biodegradable into innocuous gas are selected from benzoic acid, benzoate and benzoate compounds, vanillin, ethyl vanillin, natural or artificial camphor, gum camphor, left-handed Camphora, raceme Mentholum (alcohol), left-handed menthol, natural or synthetic borneol, dextro Borneolum Syntheticum, left-handed Borneolum Syntheticum, the dextrorotation isoborneol, left-handed isoborneol, the raceme isoborneol, dithiooxamide (dithio diamides), 6-methyl-2-deracil (methylthiouracil), azulene sulfonate, butylated hydroxyarisol, di-tert-butyl hydroxy-methylbenzene (2, the 6-d-tert-butyl-p-cresol), salicylic acid, aspirin, ethenzamide, the caffeine compounds, alanine, leucine, isoleucine, valine, phenylalanine, carbamide, urethane, ammonium halide, ammonium bicarbonate, ammonium carbonate, ammonium acetate or their mixture.

58. according to preparation method any in the claim 26 to 57, but wherein before distillation and/or decomposing the material of described sublimability and/or can be biodegradable into the material formation release micropore of innocuous gas, the core material of the described clothing film of coated polymer is placed under the temperature of the glass transition temperature that is higher than described polymer release-control clothing film healing to handle, has stable dissolution characteristic until this coating core material, healing handle terminal point by the coating core material that relatively just finishes healing and handle with 40 ± 2 ℃ temperature and be not less than 50% and the dissolution characteristic that is not higher than above-mentioned sublimable material grains and/or can be biodegradable into placement in the acceleration storage requirement under the relative humidity of (moisture absorption) critical relative humidity of material of innocuous gas the coating core material of 3 months and/or 6 months determine, in above-mentioned healing processing procedure and in the above-mentioned acceleration storage requirement in the 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.

59. according to the preparation method of claim 58, wherein said healing handle the condition when carrying out handled more than or equal to described healing as the equilibrium partial pressure of sublimable material as described under the temperature and/or the condition when carrying out handled more than or equal to described healing as the equilibrium partial pressure of all catabolites of the material that can be biodegradable into innocuous gas as described under the temperature under or be lower than described healing and handle under the temperature of condition when carrying out and carry out as the minimum degradation temperature of degradable material as described under the pressure.

60. according to preparation method any in the claim 26 to 59, 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 be lower than under the temperature of clothing film glass transition temperature below 5 ℃ and carry out.

61. according to preparation method any in the claim 26 to 60, the outer water solublity clothing film that further coats of described polymer release-control clothing film.

62. the controlled release preparation of a performance improvement is the controlled release preparation of zero level release particularly, this controlled release preparation comprises:

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

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 comprises pharmaceutically acceptable being insoluble to or the polymer and the pharmaceutically acceptable polymer reinforcing agent of water-soluble hardly and Digestive system, the contact angle of above-mentioned polymer and above-mentioned polymer reinforcing agent is lower than 90 °, and above-mentioned release micropore falls to be arranged in the pharmaceutically acceptable sublimable material of above-mentioned clothing film and/or decompose the pharmaceutically acceptable material that can be biodegradable into innocuous gas that is arranged in above-mentioned clothing film to obtain through distillation.

63. according to the controlled release preparation of claim 62, wherein said contact angle is less than or equal to 60 °.

64. according to the controlled release preparation of claim 62 or 63, wherein said contact angle is less than or equal to 30 °.

65. according to controlled release preparation any in the claim 62 to 64, wherein said contact angle is less than or equal to 10 °.