WO2012006963A1

WO2012006963A1 - Polymer reinforcing agent in controlled release preparation

Info

Publication number: WO2012006963A1
Application number: PCT/CN2011/077190
Authority: WO
Inventors: 钟术光
Original assignee: Zhong Shuguang
Priority date: 2010-07-16
Filing date: 2011-07-15
Publication date: 2012-01-19

Abstract

Disclosed is a use of a polymer reinforcing agent in production or storage of a controlled-release preparation and especially a controlled-release preparation of zero-order release. A performance-improved, controlled-release preparation and especially controlled-release preparation of zero-order release are further disclosed. The controlled-release preparation comprises a core containing a biologically active substance, and a controlled-release polymer coat externally applied to the core containing both numerous air-filled agent-releasing micro-pores and a polymer reinforcing agent, wherein the contact angle between the polymer and the polymer reinforcing agent is less than 90°, and the agent-releasing micro-pores are obtained by sublimating a sublimable substance and/or degrading a substance that is capable of being degraded into a harmless gas. The controlled-release coat of the controlled-release preparation has good mechanical performance, and has high storage stability with respect to drug releasing.

Description

Description Polymer enhancer in controlled release formulations

The present invention relates to the use of a polymeric enhancer in the manufacture or storage of a controlled release formulation, particularly a zero release sustained release formulation. It also relates to a controlled release formulation, in particular a zero release release controlled release formulation, and a process for its preparation. More particularly, it relates to a controlled release preparation having improved performance, particularly a zero-order release controlled release preparation comprising a core material containing a biologically active substance and a plurality of air-filled materials overlying the core material a microporous drug release controlled release film comprising a polymer enhancer, wherein the contact angle of the polymer with the polymer enhancer is less than 90°, and the above-mentioned release micropores are sublimated and sublimable Obtained by substances and/or degradation of substances that can be degraded into harmless gases. Background technique

Some water insoluble polymers control drug release by coating in controlled release formulations, particularly zero release sustained release formulations. Due to the water insolubility of the polymer, micropores of the coating film are often required to improve the permeability of the controlled release coating to facilitate moisture penetration and drug release, especially the low solubility of the drug and the total surface area of the formulation. When it is small.

For example, the prior art proposes a method for preparing a controlled release preparation for controlling release of a drug by forming a micropore by volatilizing a volatile component in the film or a component which degrades into a harmless gas in the film. . E.g:

EP 0425023 (or US Pat. No. 4,256, 1989, US Pat. No. 5,126, 146) discloses a device for the release of a drug by osmotic pressure controlled release containing a microporous fibrous film coating having an average pore diameter of 10 angstroms to 100 micrometers, which is 5 to the volume of the film coating. 95%. In this patented technical embodiment, the inventors have mentioned a method of forming micropores in a film by generating a gas in a film during a film curing process. The method of producing gas is to volatilize a volatile component in a film or to produce a gas by a chemical reaction.

5-30. The average pore size of the pores is 0. 1-30. The osmotic pump is filled with a gas. Micron, accounting for 5-15% of the film coat volume. In this patented embodiment, the inventors have referred to a method of forming micropores in a film coat using particles of sublimable or degradable constituents such as menthol, naphthalene, camphor, phenol, ammonium acetate, ammonium carbonate, and the like.

The above-mentioned two patented techniques do not have a method for forming micropores by using a volatile (or sublimating) component (substance) volatilized in a film or a component (substance) which degrades into a harmless gas which is degraded in a film. For further explanation, there are no such other related technologies. The present inventors conducted intensive studies on this method, and as a result, found that the prepared controlled release preparation has some serious problems, particularly when the glass transition temperature (T _g ) of the polymer after plasticization is low.

For example, the stability of the preparation has a big problem: after the controlled release preparation prepared by the technology is stored for a period of time, the release property or the rate of drug release often decreases greatly, and the drug content in the preparation does not substantially change or The magnitude of the change is relatively small. The products after storage for a certain period of time were observed with a microscope, and it was found that the size of the micropores in the film was smaller or even completely closed than the initial stage. The degree of micropore shrinkage is related to the storage time. The time is long and the aperture is reduced. The degree of micropore shrinkage is also related to the original pore size. The original pore size is large, the pore size is reduced by Yu Xiao, the original pore size is small, and the pore size is reduced. Yu Da.

For example, poor production reproducibility: Sometimes some batches of drugs are released relatively quickly, but most are very slow or even not released; that is, the same batch (consistent particle size) of sublimable material particles is used to prepare controlled release preparations. The resulting drug release rate of the controlled release formulation is very different between batches and is very difficult to control in actual production. Microscopic observation of the above different batches of products revealed that the size of the micropores in the film was significantly smaller or even completely closed than the original volatile component particles; the average pore size difference between different batches was very large, despite the original Volatile constituent particles have the same average size.

For example, the release property or release rate of the controlled release preparation prepared by the technique is often significantly lower than that of a membrane-controlled release preparation using a water-soluble material of the same size as the porogen, and theoretically adopted. Membrane controlled release preparations with controlled diameters of hollow pores (without porogens) of the same size should be faster or at least not lower than membrane controlled release preparations containing porogens of the same size. The porogen needs to be dissolved into micropores to control the release of the drug, and the porogen needs to dissolve for a certain period of time. Instruction manual

There is a certain time lag when the drug is released.

In addition, the mechanical strength of the preparation prepared by the above method is often unsatisfactory. In particular, when the glass transition temperature (Tg) of the polymer coating film is high, the controlled release coating film may be broken by an external force due to insufficient mechanical strength. Thus, dose-dumping of the controlled release formulation may be caused, which may affect the safety of administration.

However, in most cases, the coating process is carried out at a lower polymer glass transition temperature (Tg), such as the commonly used ethyl cellulose (EC) (Aquacoat® and Surelease®) and acrylic resins. (Eudragit) and so on. Therefore, in the reality, there is still a need for further technical improvements in the preparation of controlled release formulations of the above controlled release formulations, particularly zero-order release. Purpose of the invention

One of the primary objects of the present invention is to provide a use of a polymeric enhancer in a controlled release formulation as described above, particularly a zero release release controlled release formulation.

One of the main objects of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a preparation method thereof, which have relatively high storage stability in terms of release.

SUMMARY OF THE INVENTION A primary object of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a process for the preparation thereof, which formulation has a relatively high production reproducibility in terms of release.

SUMMARY OF THE INVENTION A primary object of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a process for the preparation thereof, which have a relatively large improvement in the performance in terms of release.

Another main object of the present invention is to provide a controlled release preparation, especially a zero-order release controlled release preparation, and a preparation method thereof, wherein the controlled release film of the preparation has relatively good mechanical properties and has a low dose release The possibility and higher medication safety.

For other purposes, please refer to the following instructions. Summary of the invention

The present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly The drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film. The polymer enhancer is used to delay the reduction of the pore diameter of the air-filled drug-releasing micropores during the production process and/or storage process, wherein the above polymer enhancer is as described above. The contact angle of the polymer in the polymer controlled release coating film is less than 90°.

The present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly The drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film. The polymer enhancer is used to improve the stability of the release rate of the above controlled release preparation during storage, and the polymerization of the above polymer enhancer and the above polymer controlled release coating film The contact angle of the object is below 90°.

The present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly The drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film. The polymer enhancer is used to improve the reproducibility of the release rate of the above controlled release preparation in the production process, and the above polymer enhancer is in the above-mentioned polymer controlled release coating film. The contact angle of the polymer is below 90°.

The present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly The drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film. The polymer enhancer is used to improve the above controlled release. The release property of the book preparation, such as increasing the release rate, is such that the contact angle of the above polymer reinforcing agent with the polymer in the above polymer controlled release coating film is less than 90°.

The present invention provides a controlled release preparation having improved performance, in particular a zero-order release controlled release preparation comprising: 1) a core material containing at least one biologically active substance; 2) overlying the core a controlled release coating comprising a plurality of air-filled drug delivery microwells, wherein the controlled release film comprises a pharmaceutically acceptable polymer which is insoluble or hardly soluble in water and a digestive juice and is pharmaceutically acceptable The polymer reinforcing agent having a contact angle of less than 90° with the above polymer reinforcing agent, wherein the release micropores are sublimed and pharmaceutically acceptable sublimable in the polymer controlled release coating film. Substance and/or degradation of a pharmaceutically acceptable material which is degradable into a harmless gas in the above polymer controlled release coating film.

The invention provides a method for preparing a controlled release preparation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, in particular a zero-order release controlled release preparation, the preparation method The following basic steps are included: 1) preparing a core material containing at least one biologically active substance; 2) using particles of a substance containing pharmaceutically acceptable sublimable material particles and/or degradable into a harmless gas and a solution or aqueous dispersion of a pharmaceutically acceptable polymer-enhancing agent in a polymer-insoluble or hardly soluble in water and a digestive solution, said core coated polymer controlled release coating film, wherein a sublimable substance and/or a substance degradable into a harmless gas and a solution or aqueous dispersion in which the above polymer reinforcing agent is insoluble or hardly soluble in the above polymer, and the contact angle of the above polymer with the above polymer reinforcing agent is low At 90°; 3) sublimating the pharmaceutically acceptable sublimable material in the above polymer controlled release coating film and/or degrading the pharmaceutically acceptable substance in the above polymer controlled release coating film Accepted substances that degrade into harmless gases. The term "controlled release coating film" as used herein means a material containing a sufficient amount of hydrophobic (polymeric) material coated on the outer surface of the core of the controlled release preparation and having sufficient mechanical strength to maintain the controlled release preparation. The non-ruptured coating film in the aqueous solution release process, the coating film can delay the release of the drug or the therapeutic active agent contained in the controlled release preparation when it is placed in an aqueous solution.

The term "polymeric enhancer" as used in the present invention means a polymer phase (continuous phase) which is distributed in a polymer film in a separate form (dispersion phase) and which can improve or enhance the polymer film including mechanical (mechanical). A pharmaceutically acceptable additive for mechanical properties including strength and stiffness.

As used herein, the term "contact angle" means that the polymer in a fluid state is at the liquid (polymer)-solid (polymer enhancer)-gas (air) tristate junction when it is on the solid surface of the polymer enhancer. The angle formed; especially when the polymer in the above fluid state is further solidified and cooled to room temperature at 25 ° C, at the equilibrium of the solid (polymer)-solid (polymer enhancer) - gas (air) tristate junction The angle formed.

The term "many" as used in the present invention means that the number of drug-releasing micropores which are coated on the polymer (controlled release) film of the preparation is not only one, but also plural, generally not less than 20, usually not low. In 50, especially not less than 100, more particularly not less than 1000, especially not less than 5,000.

The terms "active ingredient", "biologically active ingredient", "pharmaceutically active ingredient", "active substance", "active agent" and "biologically active substance", "drug" and the like as used herein mean any substance as it Detectable biological effects when administered to a living body include any physiological, diagnostic, prophylactic or pharmacological effects. This term is intended to include, but is not limited to, any pharmaceutically, therapeutic, prophylactic, nutritional material.

The terms "comprising" and "containing", as used in the present invention, are meant to include, but not limited to, or in addition to the meaning of other components and the like.

The term "a" as used in the present invention means at least one, and may be one type or two or more types. The term "pharmaceutically acceptable" as used in the present invention means that it can be mixed with each other in the preparation without adverse effects on each other without lowering the stability and/or efficacy of the preparation and is suitable for topical or systemic administration. detailed description

The main components in the polymer coating film (controlled release coating film) of the above controlled release preparation are described in detail below.

The present invention employs a pharmaceutically acceptable sublimable substance and/or a substance which can be degraded into a harmless gas as a porogenic substance in a polymer film (controlled release film) (hereinafter pharmaceutically acceptable sublimation) Substance and / or degradable into harmless gas Description

a substance called a porogen), which is formed by sublimation of a component having an ascending property in a polymer film (controlled release film) or a component degradable in a film which degrades into a harmless gas. Micropores to release controlled release of the drug.

The important factors affecting the properties of the above-mentioned porogens in polymer coatings (controlled release coatings) and controlled release preparations are their melting point and their sublimable or degradable temperature, solubility in the coating solution and their average granules. path. The melting point of the above porogen at 1 standard atmosphere (101. 325 ka) and its sublimation (sublimation point) or degradation at 1 standard atmosphere (101. 325 ka) is usually higher than 40 ° C, preferably not Below 60 ° C, more preferably not lower than 80 ° C, optimally not lower than 100 ° C; and the melting point of the above-mentioned porogen at 1 standard atmospheric pressure (101. 325 ka) and its sublimation (sublimation point) Or the temperature of degradation should be higher than the minimum film forming temperature of the mixed coating liquid of the above polymer or the glass transition temperature of the above polymer film, usually higher (including) 10 ° C, preferably higher (including ) 20 ° C, better than (including) 30 ° C, optimally higher (including) 40 ° C. The solubility of the above-mentioned porogen in the coating liquid (temperature 25 ° C, preferably the temperature at which the coating process is carried out) should be not higher than 30 mg/ml, preferably not higher than 10 mg/ml, more preferably Lmg/毫升。 Not more than lmg / ml, preferably not higher than 0. lmg / ml. The above pore-forming substance should have an average particle diameter of 30 to 1200 μηη, preferably 50 to 900 μm, more preferably 100 to 600 μm, and most preferably 150 to 400 μm. Since the average particle size of the porogen is the main factor affecting or determining the size of the released pores in the polymer coating (control release coating), the average size of the released micropores in the coating should be approximately 30 to 1200 μm. Preferably, it is located at 50 to 900 μm, more preferably between 100 and 600 μm, and most preferably between 150 and 400 μm.

Too low a melting point, too low sublimable or degradable temperature is detrimental to the formation of coating and release micropores, and also allows sublimable substances and/or substances that can be degraded into harmless gases during the coating process. It may be a large amount of sublimation and degradation, which is lost prematurely from the film, thereby affecting the release performance and reproducibility of the preparation. Too small release micropores may cause problems such as production reproducibility and poor storage stability. More importantly, too small release micropores will produce larger micropore additional pressure (Δ Ρ). (Because AP=2./r, where Δ Ρ denotes micropore additional pressure, polymer-air surface tension, r denotes micropore radius), and larger micropore additional pressure (Δ Ρ) will make micropores The production or storage process is gradually reduced by itself, so that the drug release of the membrane controlled release preparation becomes less stable and the production reproducibility is poor. It has been confirmed by repeated experiments that the stability is related to the pore size of the controlled release membrane, the pore size is large, the stability is good, the pore size is small, the stability is poor, and the stability is increased (or decreased). The magnitude is greater than the increase (or decrease) in the pore size of the micropore. Therefore, the present invention employs relatively large drug delivery micropores to control release of the drug to improve the stability of drug release of the formulation. However, excessive drug release micropores are also prone to problems such as poor production reproducibility.

The amount of porogenic material in the coating fluid is determined by the skilled artisan skilled in the art in light of the nature of the drug and the desired rate of drug delivery. The amount of the porogen is usually determined by the particle size, the type and amount of the polymer, the nature of the drug, the desired rate of release, etc., and is usually 5% to 95% by weight or volume ratio, preferably It is from 25% to 90%, more preferably from 40% to 80%, based on the total dry weight of the polymer film (controlled release film) component or the volume of the polymer film (controlled release film).

The amount of porogen is the main factor affecting or determining the porosity of the polymer film (controlled release film). Therefore, the porosity of the polymer film (controlled release film) should be basically 5%~95%. It is preferably between 25% and 90%, more preferably between 40% and 80%. The term "porosity" as used herein refers to the proportion of the space left by the porogen in the polymer coating film (controlled release film) to the volume of the original polymer film (controlled release film). .

Preferred examples of the sublimable component as the porogen or the component which can be degraded into a harmless gas, which is suitable for the present invention, include, but not limited to, benzoic acid (mpl 21. 5 to 123. 5 ° C, 100 ° C begins to sublimate (latm )), benzoate and benzoate compounds

(eg benzoic acid ethyl ester, phenyl benzoate, benzoic acid propyl ester, benzyl benzoate, methyl benzoate, benzoate such as sodium salt), vanillin (mp 81 ~ 83 ° C), ethyl vanillin (mp76~81 °C, pure mp77~78°C), natural or synthetic camphor (natural camphor mpl76~18rC, synthetic camphor 1^174~179°0, right-handed camphor (mp about 179. 8°C, 204 °C begins to sublimate

(latm)), left-handed brain (mp about 178.6 ° C, 204 ° C began to sublimate (latm)), racemic menthol (alcohol) (mp42 ~ 44 ° C), L-menthol (mp41 ~ 45 ° C), natural or synthetic borneol (mp205-210 ° C), right-handed borneol (mp about 208 ° C), left-handed borneol (mp about 204 ° C), right-handed borneol (mp about 214 ° C) , L-isobornanol (mp about 214 ° C), racemic isoborne brain (mp about 212 ° C), dithiooxamide (dithiodiamide) (mp about 4 ΓΟ, 6-methyl one 2 - thiouracil (methylthiouracil) (ie about 330 ° 0, 326 ~ 331 ° C decomposition), sulfonium sulfonate such as sodium salt, tert-butyl p-hydroxyanisole (mp57~ Instruction manual

65 °C), di-tert-butylhydroxytoluene (2,6 di-tert-butyl-p-cresol) (πιρ69~7ΓΟ, salicylic acid (mpl58°C, 76°C begins to sublimate), aspirin, salicylamine, Caffeine compounds (eg caffeine 1 hydrate (ie 238°, 178° sublimation), caffeine anhydrate, caffeine citrate, caffeine benzoate such as sodium salt), alanine, leucine , isoleucine, valine, phenylalanine, urea, urethane, ammonium halides such as ammonium chloride, ammonium hydrogencarbonate, ammonium carbonate, ammonium acetate, and mixtures thereof.

The coating polymer suitable for the present invention may be a pharmaceutically acceptable block polymer or copolymer which is insoluble or hardly soluble in water and digestive juices. Suitable polymers may be selected from, but not limited to, cellulose esters, acrylic polymers, polyvinyl acetates, polyvinyl chlorides, and combinations thereof that are insoluble or nearly insoluble in water and digestive juices. Examples of suitable polymers of preferred examples include, but are not limited to, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate (cel lulose acetate propionate^ nitrocellulose, triamyl) Acid cellulose, cellulose dodecanoate, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, polyvinyl acetate, methacrylate polymer, vinyl chloride-vinyl alcohol Terpolymer of vinyl acetate, polycarbonate, polymethyl methacrylate, ethyl acrylate, a methyl acrylate polymer, vinyl chloride-ethylene acetate copolymer, polyvinyl chloride, polyethylene, polyisobutylene , poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride).

It can be coated with commercially available latexes, pseudo-latexes and emulsions of the above polymers, such as ethyl cellulose (EC): Aquacoat® and Surelease®, acrylics are: Eudragit® RS30D, Eudragit® RE30D and Eudragit ® RL30D, Cellulose Acetate (CA): CA398-10.

An example of a water dispersion of a ternary copolymer containing 80 to 95% of polyvinyl chloride, 0.5 to 19% of polyvinyl acetate, and 0.5 to 10% of polyvinyl alcohol, which is provided by US Pat. Body coating solution.

Another useful example is an aqueous dispersion coating containing 50 to 100% polyvinyl chloride and 0 to 50% polyvinyl acetate copolymer.

The proportion of the coating polymer in the dry coat is determined by the type of polymer selected, the type and amount of the porogen, the nature of the drug, the selected dosage form and the desired mode of release, etc., usually 40. % to 95% by weight, preferably 50% to 90% by weight, more preferably 55% to 85°/. The weight ratio, which is based on the total dry weight of the polymer film (controlled release film) component.

In order to improve the quality of the film, plasticizers are often added to the coating formulation to lower the glass transition temperature (Tg) of the polymer to a suitable range, and to improve the film forming ability of the coating material and enhance the flexibility of the film. Sex and strength, improve the adhesion of the film to the substrate. Generally, the glass transition temperature (Tg) of the polymer is used at a lower value, such as 25-80 ° C, during the general coating process. In the present invention, the glass transition temperature (T _g ) of the plasticized plastic is usually required to be not higher than 90 ° C, not lower than 15 ° C, preferably 25 to 80 ° C, more preferably 35 to 70 °. C, more preferably 45 to 65 ° C; the glass transition temperature (7;) of the polymer film should also be lower than the sublimable substance and/or the substance degradable into a harmless gas at 1 standard atmosphere (101 The temperature at which 325 ka) begins to sublimate or degrade is usually 10 ° C lower, preferably 20 ° C lower, more preferably 20 ° C lower, and most preferably 40 ° C lower. In the present invention, a lower glass transition temperature (Tg) is adopted, so that a lower temperature can be used in the coating process, which is advantageous for the smooth progress of the coating process, and particularly for reducing the porosity of the pore-forming material during processing. Sublimation or degradation, which is beneficial to improve the release performance, process stability and production reproducibility of the preparation. The glass transition temperature of the polymer film should not be too high, which will increase the process difficulty and cost.

The plasticizer is usually a liquid substance having a high boiling point, a low volatility and being miscible with a polymer (Mr is about 150 to 800, preferably 300 to 500), or a solid substance having a low melting point. Examples of useful plasticizers are physiologically compatible from C ₆ to C ₄ . (preferably C _{6 to} C ₃ ., particularly preferably (^.~(: ₁₆ ) aliphatic or aromatic mono- to tricarboxylic acid and ~( ₈ (preferably C _{2 to} C ₆ , particularly preferably C _{2 to} C ₅ ) fat a lipophilic ester formed by a steroid. Examples of such plasticizers are dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, citric acid. Triethyl ester, acetyl triethyl citrate, triacetin, tributyl succinate, sorbitan ester, sucrose ester. Examples of other useful plasticizers such as glycerin, propylene glycol, polyethylene glycol Castor oil.

The amount of the plasticizer depends on the properties of the desired film, such as the glass transition temperature, mechanical properties, etc., the type of plasticizer, the type and amount of the film-forming agent (ie, the water-insoluble film-forming polymer), and usually The amount is 5 to 50% by weight, preferably 10 to 40% by weight, particularly preferably 10 to 30% by weight, based on the dry weight of the polymer film (controlled release film) component. total weight. It should be noted in the specification that the lower glass transition temperature (T _g ) of the polymer film generally reduces the storage stability of the prepared drug release, the reproducibility of drug release production, and the glass of the polymer film. The conversion temperature is lower, the ability or tendency of the polymer molecules to freely "flow" or "slip" is relatively strong, and the release micropores are easier to produce and/or store (in the present invention the term "storage process" generally refers to the preparation of the preparation from production. From the end to the time when the user (patient) is used, the process is reduced or even completely closed; in addition, there is still room for improvement in the functional properties of the above polymer film such as tensile properties. In order to improve these properties of the prepared formulations, the present invention requires the addition of a specific polymer reinforcing agent to the coating liquid. Specifically, a contact angle with the above polymer is added to the coating liquid or coating ((a polymer enhancer lower than 90°, preferably the above contact angle (Θ is lower than or equal to 60°, more Preferably, the content is lower than or equal to 30°, and most preferably lower than or equal to 10°. The term “polymer enhancer” as used herein refers to a distribution in a separate form (dispersed phase) to a polymer film (controlled release coating). a polymer phase (continuous phase) in the film) and a pharmaceutically acceptable additive that improves the mechanical properties of the polymer film including mechanical (mechanical) strength and stiffness. "Polymer contact angle" means the angle formed when the polymer in a fluid state is at the liquid (polymer)-solid (polymer enhancer)-gas (air) tristate junction when it is located on the solid surface of the polymer enhancer. More preferably, after the above fluid state polymer is further cured, in particular, after solidification and cooling to room temperature of 25 ° C, in a solid (polymer)-solid (polymer enhancer) - gas (air) tristate The angle formed when the junction is balanced. In the present invention, usually Refers to the static (state) contact angle (θ, a static (state) contact angle that can be used in the present invention (the θ, the measurement method is as follows: heating makes the temperature greater than the rheological temperature of the polymer to make the polymer in a fluid state, Add the polymer solution and let it rest on the surface of the polymer enhancer (usually clean and smooth horizontal plane). After the shape is stabilized (more preferably further solidified and cooled to room temperature 25 ° C), the contact measured by the appropriate method The angle, for example, is measured directly by a microscope or directly measured from a television image or photograph.

I hope that it is not completely limited by this principle, the contact angle (usually considered as the quantitative indicator that the solid is wet by the liquid, the contact angle ( ) Yu Xiao, the degree to which the solid is wet by the liquid is large, the compatibility between the two is good, two Affinity between the two. When the contact angle of the polymer with the polymer enhancer is lower than 90 °, more than 60 °, especially lower than or equal to 30 °, especially less than or equal to 10 At ° °, the polymer has good compatibility with the polymer reinforcing agent, and there is a strong affinity between the two, which can cause "surface wetting" or even "spreading". At this time, it is enhanced by polymer and polymer. The agents have a strong interaction with each other, and the polymer reinforcing agent is dispersed in the polymer in the form of particles (molecular aggregates) or in the form of "islands", and the ability of the polymer molecules to "flow" or "slip" freely Attenuated by polymer enhancers, the range of free "flow" or "slip" of polymer molecules is limited by the polymer enhancer to a relatively small range, and the polymer macroscopically exhibits "viscosity" rise, "flowability" Decline. Thus, The polymer reinforcing agent can attenuate or delay the production and/or storage process (such as sublimation and/or degradation of the above-mentioned sublimable substance located in the above polymer film and/or a substance degradable into a harmless gas, etc.) The tendency of the formed micropores to shrink or close by themselves has a stable release pore size. Therefore, the above polymer enhancer can improve (or improve) the storage stability and production reproducibility of the preparation, Release performance, etc., but also can increase the mechanical strength of the film, reduce the possibility of dose dumping of the preparation, and improve the safety of medication.

The above contact angles indirectly reflect the compatibility or affinity between the polymer and the polymer reinforcing agent. The compatibility or affinity between the polymer and the polymer enhancer can also be evaluated or predicted using the "similar compatibility" principle, such as polar or non-polar similarity.

When the polymer enhancer is a polymer, the solubility parameter between the polymer and the polymer enhancer can be evaluated using a solubility parameter that characterizes the cohesive force between the molecules of the polymer. 5之间,二。 The difference between the solubility parameter of the polymer and the organic solvent is less than 1.5. The person can be mixed in any proportion, and the two have good compatibility. For blends containing crystalline polymers or polymer molecules with strong polarity and ability to form hydrogen bonds, two- or three-dimensional solubility parameters can be used to determine system compatibility (see: Shaw MT, J Appl Polym) Sci, 1974, 18: 449).

The present invention recommends the following simple methods to prove or predict the compatibility between the polymer and the polymer: 1), the common solvent method, the two polymers are separately dissolved in the same solvent, and then mixed, according to The solution is mixed to judge the compatibility of the polymer. 2), microscopic method, phase contrast microscopy, especially electron microscopy, can directly observe the degree of compatibility. 3), solution viscosity method, the viscosity of the solution can reveal the compatibility degree of the polymer blend solution, in different polymers At the concentration of the specification, the viscosity is plotted against the percent composition of the polymer. If the relationship is linear, it indicates that the polymer is fully compatible at the molecular level; if the relationship is nonlinear, it is partially compatible; For the volume blending system, the relationship is s-shaped. 4), and dynamic mechanical thermal analysis method (measured glass transition temperature Tg), the present invention is especially recommend this method, a polymer alloy system, three kinds of change of Tg occurs, assuming the binary alloy system of two T _g of the polymer T _gl and Tg _{2 respectively} (T _gl < Tg ₂ (1), fully compatible system: only one Tg appears, T _gl <Tg<Tg ₂ ; (2), completely incompatible system: two Tg appear, Tg Tg ₂ ; (3), partially compatible system: two Tg/, Tg, T _gl <T _gl '<Tg ₂ '<Tg ₂ appear.

More or more detailed methods for evaluating or predicting the compatibility between polymers and coating polymers can be found in related literature, eg, prediction and characterization of polymer alloy compatibility, Ye Jiajia et al., Engineering Plastics Applications, 2007 Year, Vol. 35, No. 12, pp. 81-83; Research Progress in Improving the Interfacial Compatibility of Polymer Blends, Dong Meng et al., Coatings and Plating, October 2006, Volume 4, Section 5 Period, pp. 24-29; Prediction and Characterization of Polymer Interlinkage Compatibility of Polymer Alloy Membranes, Gu Xiaotong, et al., Polymer Materials Science and Engineering, January 2004, Vol. 20, No. 1, pp. 5-8 Polymer blending: II. Compatibility of polymers, Ginger Jiaodong, Polymer Bulletin, September 1993, No. 3, pp. 178-184; Compatibility of polymer blends and their theoretical calculations, Lu Feijie et al., Tropical Agricultural Sciences, 1985, 02, pp. 15-19.

Polymeric enhancers useful in the present invention include, but are not limited to, pharmaceutically acceptable filler reinforcing agents, microfiber reinforcing agents, and mixtures thereof.

The filler reinforcing agent useful in the present invention may be pharmaceutically acceptable rigid inorganic particles and rigid organic particles. Rigid inorganic particles useful in the present invention include, but are not limited to, carbonates, sulfates, metal oxides, metal powders, carbon compounds, silicon-containing compounds (such as silicon oxides, silicates), and mixtures thereof, or Ultrafine particles. Preferable examples of the rigid inorganic particles usable in the present invention include, but are not limited to, attapulgite, soap clay, calcium carbonate, calcium sulfate, barium sulfate, carbon black, silica, alumina, zinc oxide, titanium dioxide, white clay, Mica, talc, calcium phosphate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium trisilicate. The rigid inorganic particles used in the present invention preferably have used a surface active material (such as a higher fatty acid, a higher fatty acid salt, a higher fatty acid ester) or a polymeric dispersant (such as a polyolefin, a polyester, a polyacrylate or a polyether). Adsorption coating treatment or treatment with a coupling agent such as a silicone germanium coupling agent, a titanate coupling agent, a zirconium aluminate coupling agent, an aluminate coupling agent, or grafting or block polymerization on the surface of the particles. Alternatively, the surface modification can be carried out by encapsulation polymerization or by other suitable means. Preferred examples of rigid organic particles useful in the present invention include, but are not limited to, polymethyl methacrylate (PMMA), polystyrene (PS), methyl methacrylate/styrene copolymer (MMA/ST), and styrene. / Acrylonitrile copolymer (SAN).

The above-mentioned rigid particles have an average particle diameter (diameter) of usually not more than 1 m, preferably not more than 400 nm, more preferably not more than 100, more preferably not more than 20 nm, and most preferably not more than 5 nm. Nano-sized particles (not more than 100 can increase strength, toughness, impact resistance, and release pore size stability to a greater extent, and are therefore preferred.

Microfiber reinforcing agents useful in the present invention include inorganic microfibers, organic microfibers, and metal microfibers. Inorganic microfibers Chemical microfibers made of mineral materials, such as glass microfibers, quartz glass microfibers, boron microfibers, ceramic microfibers, and metal microfibers. Examples of useful organic microfibers such as synthetic microfibers such as aramid microfibers, aramid microfibers, polyester microfibers, nylon microfibers, vinylon microfibers, polypropylene microfibers, polyimide microfibers, etc.; Fibers such as cotton microfibers, sisal microfibers, wood microfibers, and the like. Examples of the metal microfibers are metal microfibers such as silver, copper, and nickel.

The term "microfiber" as used herein, refers to a particulate material that can be generally described as fibers due to their aspect ratio, and preferred microfibers for use herein have an aspect ratio of from about 10:1 to about 500:1. More preferably, it is about 25: 1-300: 1. The above fibers generally have an average diameter of not more than 1 μm, preferably not more than 400, more preferably not more than 100 nm, still more preferably not more than 20 nm, most preferably not more than 5 nm. The average length of the above fibers is usually not more than ΙΟΟ μ πι, preferably not more than ΙΟ μ πι, more preferably not more than 1 μ m, and most preferably not more than 100 nm.

The polymer-reinforced rigid particles used in the present invention, particularly rigid polymers, may also be coated with a polymeric toughening agent (herein referred to as "polymeric toughening agent" means having reduced film brittleness and improved film resistance. A pharmaceutically acceptable component of impact properties, the same as below, thereby forming a "hard shell-soft core structure". In the above "nuclear-shell structure", "shell" may completely or partially coat "nuclear";"shell" may contain one or more "nuclear";"shell" may also contain smaller "nuclear" The "core" in the shell may also contain a "shell" component or a smaller "core-shell structure"; it may also be a more complex hard/soft/hard layer; soft/ Instruction manual

Hard/soft/hard four-layer modal particles. The above-mentioned "core-shell structure" particles have a better reinforcing and toughening effect at the same time, and are superior to a simple polymer reinforcing agent or a polymer toughening agent, which is preferable. In the above "core-shell structure", the "shell" usually accounts for 0.5 to 50%, preferably 1 30%, more preferably 2 to 10%, of the entire structure volume.

It is believed that the above "nuclear-shell structure" particles also have the "fluidity" and "ductility" of increasing the film polymer at temperatures above its glass transition temperature (7;), reducing the "melt" internal tension. At the same time, it can maintain high "melt" strength, accelerate "melting", promote "plasticization", and improve "processability", which is beneficial to the coating and healing of polymer film (controlled release film). The time required for their processing is shortened, and the volatilization or degradation of the above porogen in the above process is reduced, thereby having a stronger effect of stabilizing the release pore size. Therefore, the above "core-shell structure" particles are most preferred in the present invention.

Polymeric toughening agents suitable as "nuclear" in the "core-shell structure" include natural and synthetic elastomeric polymers such as natural rubber, synthetic rubber and thermoplastic elastomers. They are usually derived from various monomers such as olefins (such as ethylene, propylene, 1 butene, 4 methyl-1-pentene in C2-C8 olefins), alkenyl aromatic monomers (such as C2-C8 olefins). Styrene and α-methylstyrene in aromatic monomers, conjugated dienes (such as butadiene, isoprene and chloroprene in C4-C8 conjugated dienes) and vinyl Carboxylic acids and derivatives thereof (such as vinyl acetate, acrylic acid, methacrylic acid, ethyl acrylate, methyl methacrylate, acrylonitrile). They may be homopolymers or copolymers.

More specifically, it includes, without limitation, all polymer rubber-based materials such as those derived from acrylic acid, methyl methacrylate-butadiene-styrene (MBS) type impact resistance improvers; silicon-containing rubber polymers And copolymers such as silicones, silicones, etc.; synthetic rubbers such as butadiene rubber, styrene-butadiene rubber (SBR), and isoprene, etc.; containing flexible chains to reduce vitrification Temperature-changing polymers, such as polyesters; polyolefins; vinyl aromatic hydrocarbon-diene block copolymers; polyurethanes; rubbery polyethers, polymers such as ethylene glycol and propylene glycol type, and the like; Blends, grafts, and copolymers.

The component of the "core" which is suitable for the "core-shell structure" of the present invention, that is, the polymer toughening agent may comprise a polyolefin polymer which is a general structure of C _n H _2n , including polyethylene, polypropylene and polyisobutylene, preferably The homopolymers are polyethylene, ULDPE (ultra low density polyethylene), LLDPE (linear low density polyethylene), HDPE (high density polyethylene) and MDPE (medium density polyethylene) and isotactic polypropylene. The general structure of polyolefin resins and methods for their preparation are well known in the art and are described, for example, in U.S. Patent Nos. 2,933,480, 3,309,621, 3,211,709, 3,646,168, 3,790,519, 3,884,993, 3,894,999, 4,059,654, 4,166,055, and 484,334.

The polymer toughening agent which is suitable for the "core" in the "core-shell structure" of the present invention may also include copolymers of various polyolefins such as ethylene and α-olefins of propylene and 4-methyl-1- a copolymer of pentene. A suitable example is a copolymer of ethylene and a C3-C10 monoolefin and a non-conjugated diene (referred to herein as an EPDM copolymer).

The "core" component of the "core-shell structure", i.e., the polymeric toughening agent, may also include conjugated diene homopolymers and random copolymers. Examples thereof include polybutadiene, butadiene-styrene copolymer, butadiene-acrylate copolymer, isoprene-isobutylene copolymer, chloroprene polymer, butadiene acrylonitrile polymer, Polyisoprene.

An example of a "core-shell structure" particle suitable as a mechanical property improver (polymeric enhancer) includes bismuth (double-block), (AB) mR (double-block), and ABA' (tri-block). Block copolymer. Blocks A and A' are typically alkenyl aromatic units, and block B is typically a conjugated diene unit. For the block copolymer of formula (AB) m-R, the integer m is at least 2, and R is a polyfunctional coupling agent for the block of structure AB. Particularly suitable examples are polystyrene-polybutadiene (SBR), polystyrene-poly(ethylene-propylene), polystyrene-polyisoprene, poly(α-methylstyrene)-polybutylene Diene, polystyrene-polybutadiene-polystyrene, polystyrene-poly(ethylene-propylene)-polystyrene, polystyrene-polyisoprene-polystyrene and poly(α-甲Styrene) - polybutadiene-poly(α-methylstyrene) and its selective hydrogenation products and the like. Mixtures of the foregoing block copolymers can also be used. Such copolymers are commercially available from a variety of sources, such as the product named S OLPRENE from Phi llips Petroleum, the product named KRAT0N from Shell Chemical Co., the product under the name VECTOR from Dexco, and the product named SEPT0N from Kuraray. .

Another example of a "core-shell structure" particle suitable as a mechanical property improving agent (polymer reinforcing agent) is a star block copolymer comprising a vinyl aromatic monomer and a conjugated diene monomer. Copolymers of this type generally comprise from about 60% to about 95% by weight of the polymeric vinyl aromatic monomer and from about 40% to about 5% by weight of the polymeric conjugated diene monomer. The copolymer has at least Description

Three polymer chains forming a star configuration. The ends of each chain are substantially inelastic segments to which are attached elastic polymer segments. These block copolymers are sometimes referred to as "branched" polymers (as described in U.S. Patent No. 4,097,550) and are used in amounts similar to other conjugated dienyl groups as mechanical property improvers.

Examples of "core-shell structure" particles suitable as mechanical property improvers (polymeric enhancers) include but are limited to polyethylene-vinyl acetate (EVA), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymers. (E-VA-C0), ethylene_C1~C8 (preferably C1~C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-CI~C8 (preferably CI~C4) methacrylic acid copolymerization And polyacrylonitrile-butadiene-styrene (ABS).

The above-mentioned "core-shell structure" particles used in the present invention are present in a polymer film (control release film) as a mechanical property improving agent (polymer reinforcing agent) in a certain shape and size. Regarding its shape, the particles constituting the "core-shell structure" are typically spherical. However, they may have any suitable shape, and particles of various shapes may be prepared by methods known in the art of polymer particle technology. Examples of other suitable particle shapes include, but are not limited to, ellipsoidal particles having a major aspect ratio greater than 1:1, raspberry shaped particles, multi-lobed particles, dumbbell shaped particles, agglomerated particles, double-lobed particles, and hollow spherical particles, and the like. . Regarding its size, usually its average particle diameter (diameter) is not more than l w m. Preferably, the average particle diameter is not more than 400 nm, more preferably not more than 100 nm, still more preferably not more than 20 minutes, and most preferably not more than 5 nm. Generally, smaller particles contribute to improved impact strength.

The melting point (or crystal melting temperature, Crystall ine Melt Temperature) or/and Vicat Softening Point of a "core-shell structure" particle suitable for the mechanical property improving agent (polymer reinforcing agent) of the present invention is generally not low. The glass transition temperature (Tg) of the polymer in the controlled release film is preferably 5 ° C (inclusive), more preferably 10 ° C (inclusive), and most preferably 20 °C (inclusive); and its (center) glass transition temperature (Glass Transition Temperature) is usually required to be lower than the glass transition temperature (Tg) of the polymer in the controlled release coating film, usually not higher than the temperature of 15 ° C, Preferably, the temperature is not higher than 0 ° C; in addition, the above "core-shell structure" particles should also have good mechanical properties, such as high tensile strength, high elongation at break or tensile strength at break. .

Other parameters of the "core-shell structure" particles suitable as mechanical property improvers (polymeric enhancers) are preferably as follows: Melting point (or crystal melting temperature, Crystall ine Melt Temperature) (DSC, via ASTM D3418 ISO 3146) or / and dimension Vicat Softening Point (via ASTM D1525 ISO 306) is preferably 60 to 2000 ° C, more preferably 80 to 1000 ° C, particularly preferably 100 to 500 ° C; Vicat Softening Point, via ASTM D1525 ISO 306) is preferably 45 to 150 ° C, more preferably 45 to 100 ° C, particularly preferably 50 to 80 ° C; elongation at break

(Tensi le Elongation @ Break) is preferably 200 to 5000% (via ASTM D638 / ISO 527-2); Tensile Strength (Tensi le Strength § Break) is preferably 1 to 50 MPa (via ASTM D638/IS0 527-2) ;

(Center) Glass Transition Temperature is preferably -10 to -200 ° C (via ASTM D5418 loss modulus peak at 1 hz ); Melt Flow Rate (190 ° C / 2.16 kg) It is preferably 0.5 to 150 g/10 min (via ASTM D1238 ISO 1133), more preferably 1 to 100 g/10 min, and particularly preferably 2 to 50 g/10 min.

The polymer reinforcing agent is usually used in an amount of from 0.5 to 50% by weight, preferably 1 ° /. ~30% (by weight), more preferably 2%~20%

(by weight), which is based on the total dry weight of the polymer film (controlled release film) component.

An example of a film-coated polymer in combination with a polymer reinforcing agent is that the film-forming polymer is selected from a polymer containing a polar group that is insoluble or hardly soluble in water and a digestive solution, such as a cellulose ester polymer, An acrylic polymer, polyvinyl acetate, and the polymer enhancer is selected from fine or ultrafine particles of polar rigid inorganic particles (particle diameter is preferably not more than 100 nm)

(diameter)), such as carbonates, sulfates, metal oxides, silicon oxides, silicates, and mixtures thereof, more preferably coated with a polar polymeric dispersant (such as polyacrylate) The surface is subjected to surface-modified fine or ultrafine particles (the particle diameter is preferably not more than 100 nm (diameter)). Examples of the above polar group-containing cellulose ester polymer are cellulose acetate, cellulose propionate, cellulose acetate butyrate, cel lulose acetate propionate. nitrocellulose, trivaleric acid Cellulose, cellulose succinate. Applicable examples of the above-mentioned polar group-containing acrylic polymer, polyvinyl acetate include, but are not limited to, polyvinyl acetate, methacrylic acid polymer, vinyl chloride-vinyl alcohol- Terpolymer of vinyl acetate, polymethyl methacrylate, ethyl acrylate, a methyl acrylate polymer, polyvinyl acetate, ethyl acrylate-ethyl acrylate-trimethylaminoethyl chloride Methyl acrylate polymer (poly Instruction manual

(ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride)).

An example of a preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from a cellulose ester polymer containing a non-polar group that is insoluble or hardly soluble in water and a digestive juice (such as B). Cellulose, cellulose dodecanoate, cellulose tripalmitate, cellulose dipalmitate), and polymer enhancer is selected from surfactants (such as higher fatty acids, higher fatty acid salts, higher fatty acid esters) Adsorption-encapsulation treatment of surface-modified polar rigid inorganic particles, such as carbonates, sulfates, metal oxides, silicon oxides, silicates, and mixtures thereof, fine or ultrafine particles (particle size is preferably not greater than 100 nm (diameter)), particularly preferably nano-sized calcium carbonate particles having a surface coated with stearic acid (particle diameter is preferably not more than 100 nm (diameter)).

An example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of cellulose ester polymers which are insoluble or hardly soluble in water and digestive juice, and the polymer reinforcing agent particles are selected from the group consisting of Methyl methacrylate-styrene copolymer (MMA-ST), styrene-acrylonitrile copolymer (SAN), styrene-butadiene-acrylonitrile terpolymer containing both polar and non-polar groups (ABS), methyl methacrylate-butadiene-styrene terpolymer (MBS), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1~ C8 (preferably C1 to C4) methacrylic acid-carbonyl (carbon monooxide) trimer, ethylene-(C1 to C8) (preferably C1 to C4) methacrylic acid copolymer or a mixture thereof (particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm (diameter), wherein methyl methacrylate-styrene copolymer (MMA-ST), methyl methacrylate-butadiene-styrene terpolymer (MBS) More preferred. Useful examples of the above cellulose ester-based polymer include, but are not limited to, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate

(cellulose acetate propionate ), nitrocellulose, cellulose trivalerate, cellulose succinate, and mixtures thereof.

An example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of acrylic acid polymers which are insoluble or hardly soluble in water and digestive juice, and polymer reinforcing agent particles are selected. Self-polymethyl methacrylate (PMMA), methyl methacrylate-styrene copolymer (MMA-ST), methyl methacrylate-butadiene-styrene terpolymer (MBS), ethylene-ethylene acetate -carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1~C8 (preferably C1~C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C8 (preferably C1 to C4) mercaptoacrylic acid copolymer, acrylic resin type impact modifier or a mixture thereof (particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm

(diameter)). Applicable examples of the above polymers include, but are not limited to, methacrylic acid polymers, polymethyl methacrylate, ethyl acrylate-m-methyl acrylate polymer, acrylic acid which are insoluble or hardly soluble in water and digestive juices. Ethyl ester-ethyl acrylate monomethyl trimethylaminoethyl methyl acrylate polymer (poly

(ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride)) and mixtures thereof.

An example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of polyvinyl acetate which is insoluble or hardly soluble in water and digestive juice, and the polymer reinforcing agent particles are selected from the group consisting of Methyl acrylate-styrene copolymer (MMA-ST), styrene-acrylonitrile copolymer (SAN), styrene-butadiene-acrylonitrile terpolymer (ABS), methyl methacrylate-butyl Alkene-styrene terpolymer (MBS), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1~C8 (preferably C1~C4) methacrylic acid-carbonyl (Carbon monooxide) terpolymer, ethylene-C1 to C8 (preferably C1 to C4) mercaptoacrylic acid copolymer and mixtures thereof (particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm (diameter)) . Useful examples of the above polymers include, but are not limited to, polyvinyl acetate, a terpolymer of vinyl chloride-vinyl alcohol-vinyl acetate, a vinyl chloride-vinyl acetate copolymer, and mixtures thereof.

An example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of polyvinyl chloride and the polymer reinforcing agent particles are selected from the group consisting of methyl methacrylate-styrene copolymer (MMA-ST). ), styrene-acrylonitrile copolymer (SAN), styrene-butadiene-acrylonitrile terpolymer (ABS), methyl methacrylate-butadiene-styrene terpolymer (MBS), ethylene- Ethylene acetate-carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1~C8 (preferably C1~C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-C1 ~C8 (preferably C1 to C4) methacrylic acid copolymer or a mixture thereof (particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm (diameter)).

The above ethylene-ethylene acetate-carbonyl (carbon monooxide) trimer (E-VA-C0), ethylene-C1 to C8 (preferably C1 to C4) Instruction manual

Alkylacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C8 (preferably C1~C4) mercaptoacrylic acid copolymers available on the market, such as DuPont's Elvaloy® series products (eg Elvaloy AC 1) , 2, 3 series, Elvaloy HP series). Acrylic anti-impact modifiers are available in listed products such as the PARALOID BP series of nanoscale products manufactured by Rohm and Haas.

A film-forming general additive material may be added to the coating liquid of the invention. The amount and application of the film-forming general additive material in the drug coating layer is well known to those skilled in the art. Common additives include, but are not limited to, anti-adherents (separators), stabilizers, pigments, defoamers, antioxidants, penetration enhancers, gloss agents, perfumes or flavoring agents. They are used as processing aids and should ensure safe and reproducible preparation methods as well as long-term storage stability or additional beneficial properties imparted to the pharmaceutical dosage form. They are added to the formulated polymer prior to processing and can affect the permeability of the coating, which can also be used as an additional conditioning parameter.

Some commonly used additives are described below.

•Anti-adhesive (separator)

The separating agent is typically a beneficial hydrophobic material and is typically added to the spray suspension. They prevent the accumulation of nuclei during film formation. Preference is given to using talc, magnesium stearate or calcium stearate, finely divided silicic acid, kaolin or a nonionic emulsifier having an HLB value of from 3 to 8. 5〜100% (重量百分比) The polymer is usually used in the coating layer of the present invention. In a particularly advantageous embodiment, the separating agent is added as a final coating in concentrated form. The coating is carried out by spraying in the form of a powder or a suspension having a solid content of 5 to 30%. 1〜2%。 The amount of the dosage of the pharmaceutical dosage form is 0. 1~2%.

•stabilizer

The stabilizer is preferably an emulsifier or a surfactant, and has an interfacial active substance to stabilize the aqueous dispersion. Examples of suitable stabilizers are diethanolamine, monoethanolamine, triethanolamine, fatty acids, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), nonoxynol, octoxynol, oil Acid, poloxamer, polyoxyethylene 50 stearate, polyoxyl fatty acid, polyoxyl hydrocarbon ether, polysorbate (Tween), dehydration Sorbic acid ester (Span), fatty acid salts, povidone, sodium lauryl sulfate, sodium decyl stearyl sulphate, sucrose stearate, polysorbate and mixtures thereof. The stabilizer is contained in an amount of from 1 to 15% by weight, preferably from 5 to 10% by weight, based on the wet weight of the component of the aqueous dispersion coating liquid.

• Pigments

Rarely added as a soluble pigment. Alumina or an iron oxide pigment is generally dispersedly added. Titanium dioxide is used as a white pigment. The pigment is added in the coating layer of the present invention in an amount of from 20 to 60% by weight based on the polymer mixture. However, due to the high pigment binding capacity, the addition amount can be as high as 100% by weight.

• Defoamer

The antifoaming agent is generally dimethicone.

In a particularly advantageous embodiment, the final coating is used directly in concentrated form. The coating is carried out in the form of a powder or by spraying with an aqueous suspension having a solid content of 5 to 30%. 1〜2%。 The amount of the dosage of the pharmaceutical dosage form is 0.1 to 2%.

All substances used in the film must in principle be pharmaceutically acceptable, non-toxic and not dangerous to the patient in the drug. The core material used in the present invention will be described below.

Coated cores (carriers) useful in the present invention include, but are not limited to, regular or irregular forms of tablets, granules, (micro) pellets, crystals, drug-loaded resins. The size of the granules, (micro) pellets or crystals is usually 0. 01~2. 5mm, the size of the sheet is usually 2. 5~ 30mm. They usually contain up to 95% (by weight, unless otherwise stated) bioactive substances (active substances) and up to 99.9% of other pharmaceutical additives.

The biologically active substance (active substance) used in the present invention has no other limitation except for those which are degraded, volatilized, and inactivated due to thermal effects during the preparation process, but there is no other limitation, if a certain method (such as a ring) is applied. Dextrin inclusion, microencapsulation technology) can prevent degradation, volatilization, and inactivation of biologically active substances during preparation, and these biologically active substances can also be used in the present invention.

As the active ingredient used in the present invention, it may be any of the above-mentioned pharmaceutically or nutritionally therapeutic effects. Description

Or a substance that prevents it. Examples of active ingredients useful in the present invention are listed below:

Central nervous system drugs:

Central stimulant: idebenone, benzotrizepine, piracetam, pyrithione, vinpocetine, dimethylformin, aniracetam, meclofenoxate, caffeine, modafinil, Pentylenetetrazol.

An analgesic: chlorpheniramine, buprenorphine, dihydroetorphine, florofinine, bicuculline, codeine, rotundine, morphine, ergotamine, meptazin, methadone, nai Fructus, pethidine, pirimidin, oxycodone, hydromorphol, tramadol, sumatriptan, tetrahydropalmatine, dextropropoxyphene, dextromethorphan, levonorol, left mala amine.

Antipyretic analgesics: aspirin, acetaminophen, phenacetin, hydroxybzon, thiramite, magnesium salicylate, imidazole salicylate, isopropylantipyrine.

Anti-inflammatory analgesics: aminclofen, acemetacin, azaprozin, ampoxicam, augusin, olsalazine, benolyl ester, pirfen, ibuprofen, bucillamine , aceclofenac, butyl hydroxy acid, diflunisal, fenbufen, flurbiprofen, flufenamic acid, citrictin, cyclohexanoic acid, mefenamic acid, meclofenamic acid , gold thioglucose, auranofine, leflunomide, chlorpheniric acid, loxoprofen, aristolochic acid, meloxicam, mesalazine, nabumetone, naproxen, niflut Acid, etodolac, zaltoprofen, guaiac blue hydrocarbon, etofenamate, escitoxicam, ketoprofen, tenoxicam.

An anti-gout drug: glucosamine, benzbromarone, allopurinol, colchicine, probenecid, etimabazole.

An anti-shock paralysis drug: trihexyphenidate, biperiden, dorepeptide, entacapone, adamantamine, carbidopa, quetiapine, rasagiline, memantine, selegiline, Tokapeng, bromocriptine, levodopa, mobilis, moxifensin, palitide, donepezil.

Antipsychotics: alipidide, anibirdolol, azaiperone, apixipide, amisulpride, oxaporone, oxaflurazine, oxybuterazine, chlorpromazine, fluoride Perphenazine, haloperidol, droperidol, flupentixol, flupriline, risperidone, linacazole, thiopril, thioridazine, clozapine, clopidogrel, chlorine Piperazine, cloprofen, loxapine, mazapamine, nemiride, piperazine, pimozide, pramipexole, rimopride, sulpiride, penfluridol, zooti Ping, epoprazol, olanzapine.

An anti-anxiety drug: alprazolam, estazolam, buspirone, flazodazole, lorazepam, clomiprazole, metaxalone, beta chlorophenidate, etidazolam, Fludisazine.

Antidepressant drugs: amitriptyline, amoxapine, bupropion, opipadol, desipramine, dexmedeline, fluvoxamine, fluoxetine, carbipipamine, chlorine Mipamamine, Maprotiline, Mianserin, Paroxetine, Methylphenidate, Protriptyline, Trimemamine, Sertraline, St. John's Wort Extract, Veloxacin, Venlafa Xin, Sibutramine, Citalopram, Icaroline.

An antiepileptic drug: oxcarbazepine, bequesamine, phenytoin, valproic acid and its sodium, magnesium salt, methyl ethyl ketone, carbamazepine, casinitide, lamotrigine, riluzole, primidone , Topiramate, esadiazepine, ethecoxibine, etoposide, ethosuxamine, zonisamide, tiagabin, mefentoin.

A sedative, hypnotic, anticonvulsant and others: oxazuron, barbital, phenobarbital, glutamine, quetiapine, niazophenone, gastrodin, bromoisoval, relying on Mimidate, acetyl gastrodin, zaleplon, zopiclone, zolpidem, betahistine, vincamine, flunarizine, flumethenone, fluentil, cyclomandelate, pentoxifylline , meglumine dihydroergotamine, rizatriptan, mesalamine, naratriptan, nicotinol, nigralin, kallikrein, niacin, iripusone, eletriptan , epoprostenol, isoprozol, papaverine, zolmitriptan, levetiracetam.

Autonomic nervous system drugs: arololol, aplolol, atenolol, esmolol, benzaltropium, bisoprolol, scopolamine, metoprolol tartrate, carteolol, carvedil Lo, Labetalol, Metoprolol, Mopelol, Moseselli, Nadolol, Anisodamine, Celilol, Cedarol, Thiololol, Tamsulosin, Sotalol, yohimbine, anisodine, carvedilol, tamsulosin, tropicamide, bromopropylamine.

A circulatory system drug:

One calcium antagonist: anipamil, benidipine, benidipine, bepridil, valparaprin, faripamil, cinnarizine, lacidipine, manidipine, thiophane, dimension Lapami, right Vera Paimi.

A drug for the treatment of chronic heart failure: Bradyxin, Digoxin, Dinomamine, Poisonin, Dobutamine, Instruction manual

Docarbaamine, paclitaxel, milrinone, enoxacin, levosimendan, alfifron.

An antiarrhythmic drug: aprilin, amiodarone, pyridoxine, propiamine, flecainide, quinidine, modicani, orexizine, procainamide, propa Ketone, ivabradine, itraconi, tocic bromide, mexiletine, stenicai.

A drug for preventing and treating angina pectoris: oxyxitox, isosorbide mononitrate, ligustrazine, diltiazem, tetrabutyl nitrite, hysopidine, cyclophosphamide, levopraz, musk ketone, dipyridamole, pentaerythritol Nitrate, nitroglycerin, imoramin, etanoterone, cyclic adenosine.

Peripheral vasodilator: apovinamine, vincamine, pinacidil, vinpocet, vinorelbine, dagapamil, buflomedil, fasudil, golopamil, hydralazine , kalazine, minoxidil, nicorandil, naproxil, tripidil, diterpenoid, urapidil, bromo-vincoamine, nicotinic acid inositol, enalappine, isopropanol, Isosaramine, poppy peony, valvadil, left emolim, zoelepine.

A blood pressure lowering drug: alfuzosin, alapril, analipide, amlodipine, betaxetidine, benazepril, octapeptide, bunazosin, diazepam, dilapid Lee, Delilorol, Butyzolamine, Doxazosin, Irbesartan, Felodipine, Fosinopril, Tetrandrine, Methyldopa, Daidzein, Tartrate Tartrate, Card Topily, candesartan, quinapril, clonidine, lisinopril, ramipril, limonidine, lishepine, spiropril, lofexidine, mecaramine, Nilvadipine, nicardipine, nimodipine, nitrendipine, nisoldipine, pagilin, perindopril, trandolapril, terazosin, temocapril, tolonedine, sira Puli, nifedipine, valsartan, isradipine, elishartan, enalapril, enalapril, enalapril, eprosartan, valeramine, zolofexine , Zofenopril, Zofenpril, Telmisartan.

Regulating blood lipids and anti-atherosclerosis drugs: atorvastatin, acixil, phenylpropanolamine, benzepressin, bezafibrate, pikacin, benzyl chloride, darvastatin, Elastase, dopamine, dopamine, fenofibrate, fluvastatin, ciprofibrate, gemfibrozil, colestipol, cholestyramine, kevastatin, clebate, lysibine , clofibrate, clofibrate, lovastatin, mevastatin, nicaratin, niketabate, pravastatin, probucol, cerivastatin, simvastatin, linoleic acid , Yiduoester, dextrothyroxine, hyodeoxycholic acid.

A respiratory system drug: aminophylline, ambroxol, oxycin, oxicillin, benproperine, bitoterol, benzonatate, pyrbuterol, sodium zoate, dimethoate Ester, putotropine, erdosteine, fenoterol, forcodine, hexolin, clenbuterol, chlorobutano, mabuterol, montelukast, picotazide Lin, terbutaline, guaifenesin, guaiacol sulfonate, zaloterol, levopropoxyphene, isomirier, acetylcysteine, ketotifen, terbutaline, Trolotrol, epradolone, terpineol.

A digestive system drug:

An antacid and a peptic ulcer drug: omeprazole, balsalazide, ornoprost, enprostin, famotidine, galac aluminum, bismuth potassium citrate, lansoprazole, Rabeprazole, sucralfate, aluminum-magnesium plus, barium aluminate, magnesium aluminum carbonate, rosaprost, roxatidine, misoprostol, nizatidine, pirenzepine, Pronoto, Pantoprazole, Traxapat, Sophorone, Tirenoxapine, Vitamin U, Isoladine, Ekabit.

Gastrointestinal antispasmodic: Adifenin.

A helper digestive drug: oxcarbin, trypsin amylase, citric acid, carnitine, pepsin, cisapride, trypsin, trypsin, pancreatic lipase.

An antiemetic, emetic, and gastrointestinal drug: ondansetron, domperidone, granisetron, metoclopramide, clopirol, tolztron, itopride, bergenin, sulpiride , quercetin, lystron, lintobili, mojistan, mosapride.

Auxiliary medication for hepatobiliary diseases: olamimet, chenodeoxycholic acid, non-bupropanol, anthranil, inositol, inosine, biphenyl diester, leucovorin, tiopronin, lipoic acid, marlow Terephthalate, glucurolactone, oleanolic acid, hydroxymethyl coumarin, hydroxymethanolamine, dehydrocholic acid, sodium dehydrocholate, deoxycholic acid, lactulose, silybin, silymarin, Sianiol, adenosylmethionine, ursodeoxycholic acid, sodium protoporphyrin.

A urinary system drug: amiloride, azosemide, triamterene, bethiazine, polibizine, bumetanide, Instruction manual

Pyrrhotanib, furosemide, cyclopentazine, clonsophan, spirronone, metyrapone, spironolactone, mefsit, lysine, indapamide, epitazine, yi Soxazole, etanic acid, sodium citrate, etazozoline, thiazide, acetazolamide, isopropyl iodide, isopamine, desmopressin, diclofenac, Purrexone, metyrapone.

A drug that affects the blood and hematopoietic system: sarpogrelate, bis-coumarin, ethyl acetophenone, warfarin, benzoquinone, acenocoumarol, ferrous sulfate, ferrous gluconate, ar Calcium folate, folic acid, iron dextran, mecobalamin, ferrous fumarate, iron glucoheptone, sodium ferulate, nucleotides, anethole, valerate, squalyl alcohol, chloramine, aca Dixin, anagrelide, aprostin, ozagrel, beraprost, picogreline, dalgregre, dazooxaphene, furoic acid, limatoprost, clopidogrel, rolagrel, imidazole , motodipine, narfagre, pamidrex, alprostadil, trox rutin, ticlopidine, tribexyrene, sartrimrel, sultagreride, cilostazol, cisprost, tobacco Greg ester, oxydresyl ester, iptagrel, calcium hydroxybenzene sulfonate.

Primary anti-allergic drugs:

Primary antihistamines: avastin, alimazine, astemizole, oxapramine, oxomamycin, diphenhydramine, benzoguanamine, propionylazine, bupizine, tea benzene Hamming, promethazine tea, azelastine, diflupromide, dolastatin, doxylamine, embramin, febrinamide, fexofenadine, dimethylformidine , loratadine, clemastine, cloperastine, chlorpheniramine maleate, mepyrazine, meclozine, mequitazine, niprazine, cyproheptadine, stastatin, Ebastine, estramustine, epilin, bromophenamine, zafirlukast, levocabastine.

An allergic reaction medium release agent and others: azastatin, amlexanox, lodosamide, tranilast, cromolyn, cetirizine, zapastast, pkromi, pu Hydrazine, his zastel.

An adrenocortical hormone and adrenocorticotropic hormone: difluxate, dexamethasone, methylprednisolone, prednisone, cortisone, triamcinolone.

Sex hormones and gonadotropins: bicalutamide, estrone, estriol, medroxyprogesterone acetate, danazol, prazzab, flutamide, diethylstilbestrol, hexaerythritol, diethylstilbestrol, nail Progesterone, medroxyprogesterone, raloxifene, nilutamide, gestrinone, toremifene, stanozolol, norgestrel.

Islet hormones and other drugs that affect blood sugar: acarbose, pioglitazone, metformin, voglibose, glibenclamide, glibenclamide, glipizide, glibenclamide, glibenclamide, lattice Derivazolone, glimepiride, gliclazide, tolbutamide, miglitol, troglitazone, repaglinide, tolazamide.

A thyroid hormone drug and an antithyroid drug: oltipreline, botinidrine, nitrexine, liothyronine, dibromotyrosine, thyropropionate, thyroidine, thyroglobulin, montetine Relin, miprazole, diiodotyrosine, telazocine, levothyroxine, levothyroxine sodium, aminothiazole, propylthiouracil, iodothiouracil, methylthiouracil, methimazole, Carbazole, thiazoline.

Antimicrobial / Antibiotics:

A penicillin: amoxicillin, ampicillin, bamcillin, oxacillin, flucloxacillin, hetacillin, cyclohexillin, sulfacillin, carbocillin, cloxacillin, lenazocillin, nafcillin , pirazicillin, pimecillin, penicillin ¥, sultamicillin, diclocillin, and acesulfame.

Cephalosporins: chlorocarbon cephalosporin, cephalexin, cefprozil, cefpodoxime, ceftibuten, cefaclor, cefaclor, cefradine, cefradine, ceftriaxone, cefadroxil, cefacitdine, cephalosporin Telun, cefdinir.

Beta-lactamase inhibitors: clavulanic acid, sulbactam, bromobactam.

Aminoglycosides: Paromomycin, kanamycin, gentamicin, neomycin.

One tetracyclines and others: dimecycline, doxycycline, indomethacin, metacycline, minocycline, oxytetracycline, tetracycline, chloramphenicol.

Macrolides: azithromycin, oleandomycin, dirithromycin, erythromycin, erythromycin ethylsuccinate, guitarmycin, josamycin, clarithromycin, roxithromycin, rosacea , spiramycin, melamycin, medimycin, erythromycin, erythromycin, acetylspiramycin.

Other antibacterial agents: levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, polymyxin £, clindamycin, lincomycin, fosfomycin, micammycin, mold , yellow saponin, berberine, gentian, houttuyfonate sodium. Instruction manual

Antituberculosis drugs: pyrazinamide, salicylic acid, sodium salicylate, propionamide, cycloserine, rifabutin, rifapentine, rifampicin, ethambutol, isoniazid .

An antifungal drug: flucytosine, fluconazole, griseofulvin, miconazole, itraconazole, ketoconazole, nystatin. An antiviral drug: acyclovir, famciclovir, valaciclovir, lamivudine, ribavirin, morpholinium, zidovudine, deoxyfluorouridine, didanosine, zhaxi coast.

Antineoplastic agents: busulfan, cyclophosphamide, lomustine, semustine, thioguanine, guanidine, idarubicin, aminoglutethimide, tamoxifen, anastrozole, procarbazine Quinoa, cantharidin, capecitabine, letrozole, melphalan.

Drugs that affect the body's immune function: acetalivir, propacetam, azathioprine, imidazolyl, tacrolimus. A protein: DNase, alginate, superoxide dismutase and lipase, peptide, oligopeptide.

One nucleotide.

Vitamins and nutrients: vitamins A, B, C, D, E, K, etc. and their derivatives, amino acids;

A diet pill: Amiris, amfepramone, amphetamine, amphetamine, oltipamine, fenfluramine, phenyltol, benzethetamine, propylhexidine, p-chloro Phentermine, non-Nyles, fenbufen, fluramine, fenmetrazine, fenpres, phentermine, furfurex.

One other drug: finasteride, alendronate, alosetron, orlistat, eric acid, epalrestat, tolterodine, torista, herbal extracts.

More preferred examples of the medicament for use in the present invention include, but are not limited to, LEC0Z0TAN (SRA-333), amoxicillin, amoxicillin-clavulanate potassium compound, asdamamo, aspirin-phosphoric acid ligustrazine compound, aspirin-dipyridamole Mo Fufang, piperazine ferulate, acyclovir, paracetamol-pseudoephedrine-d-butenoic acid dextrobromide compound, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, Aceclofenac, isosorbide mononitrate-aspirin compound, isosorbide mononitrate, diazepam, metformin-roglitazone combination, famciclovir, felodipine, fenofibrate, pseudoephedrine hydrochloride pseudoephedrine Compound, fluvastatin sodium, acyclovir and compound, felodipine-metoprolol tartrate compound, lovastatin-nicotinic acid compound, vitamin B6 compound, cetirizine-pseudoephedrine compound, fesofine hydrochloride That is a compound of pseudoephedrine hydrochloride, guaifenesin-pseudoephedrine-dextromethorphan, quetiapine fumarate, metoprolol fumarate, ezetimidate fumarate, grid Pyrazine-Metformin Hydrochloride, Glipizide, Glimepiride-Metformin Compound, Gliclazide, Potassium Citrate, Tamoxifen Citrate, Tamoxifen Citrate, Succinic Acid Venlafaxine, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, tolterodine tartrate, zolpidem tartrate, clarithromycin, oxymatrine, ranolazine, ribavirin , benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, loratadine-paracetamol-pseudoephedrine compound, loratadine-pseudoephedrine compound, rosiglitazone, roxithromycin, lo Rutastatin, trimebutine maleate, enalapril maleate-felodipine, mesalazine, metotropine, mizolastine, naftopidil, naproxen sodium, niketatin , nimesulide, nitrendipine, nisoldipine, paliperidone, paprazole, dafenazone hydrobromide, galantamine hydrobromide, huperzine A, bicyclol, statin Fuding, gastrodin, ketoprofen, cefaclor, cefac , vitamin C vaginal controlled release tablets, vitamin E nicotinate, pseudoephedrine, naproxen sodium compound, urapidil, niacin, niacin-simvastatin compound, bupropion hydrochloride, ambroxol hydrochloride, hydrochloric acid Xibutin, betahistine hydrochloride, metformin hydrochloride, valacyclovir hydrochloride, ciprofloxacin hydrochloride, labetalol hydrochloride, nicardipine hydrochloride, paroxetine hydrochloride, prazosin hydrochloride, propafenone hydrochloride, Propranolol hydrochloride, hydromorphone hydrochloride, tramadol hydrochloride, trimetazidine hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, l-salbutamol hydrochloride, levofloxacin hydrochloride, ofloxacin, etodolac, Indapamide, guaifenesin, guaifenesin-pseudoephedrine hydrochloride, levodropropizine, bezafibrate, pyridyl, theophylline, vincamine, dihydroergotamine mesylate, A Doxazosin sulfonate, metoprolol tartrate, dihydrocodeine tartrate, carbidopa-levodopa compound, morphine sulfate, gentamic sulfate, ferrous sulfate, potassium chloride, domoti, Furanamine, nimodipine, diclofenac sodium, verapamil, retinoic iron, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetacin , theophylline-salbutamol compound, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, loffeine, marlotidate, naproxen, carbonic acid Lithium, cephalexin, alfuzosin hydrochloride, buflomedil hydrochloride, ticlopidine hydrochloride, ibudilast, dextromethorphan, Zhengqingfengtongning, 5-mononitrate, sodium valproate , dopas, gentamicin sulfate, zirconia Description

Compound, chlorpheniramine maleate, bainidipine, bunazosin, golopamil, methylphenidate hydrochloride, oxycodone hydrochloride, herbal extracts.

Since the controlled release preparation, in particular the osmotic pump type controlled release preparation, can simultaneously push out various components of the herbal extract, and there is no problem that the release of the active ingredients is not synchronized due to the different nature of the ingredients, Therefore, the controlled release preparations, particularly the osmotic pump type controlled release preparations, to which the present invention relates are particularly suitable for use in controlled release Chinese herbal extracts.

The actives useful in the present invention include the pharmaceutically acceptable salt forms, free acid forms, free base forms, hydrates, various crystal forms, and optical isomers of the following active ingredients.

In addition to bioactive substances, the core material may also contain other pharmaceutical auxiliaries such as slow release materials, porogens, fillers, binders, disintegrants, disintegrators, lubricants (including glidants, anti-adhesion). An agent, an osmotic pressure active substance (ie, an osmotic pressure promoter), a permeation-promoting polymer (a penetration enhancer), and the like. In addition, it may also contain solubilizers, suspending agents, sweeteners, aromas, pigments, absorbents and surfactants (such as wetting, dispersing, solubilizing, emulsifying, etc.). Pharmaceutical auxiliaries and their use are selected by those skilled in the art based on actual conditions such as the nature of the drug, the desired rate of drug release, and the like. The basic steps in the preparation method of the controlled release preparation are described in detail below.

1) preparing a core material containing at least one biologically active substance

The preparation method of the core material used in the present invention is not particularly limited in the present invention. In general, the core preparation method may employ a direct extrusion method, a dry, wet or sintered particle extrusion method, extrusion and subsequent rounding, wet or dry granulation or direct pelleting (for example on a disk). Alternatively, a method of bonding a powder (powder layer) to a sphere (particle) of an inactive material or a particle containing an active material, or a method of forming a tablet in a certain manner such as pressing, or a mixture of the above methods may be employed.

2) Coating step: a solution or aqueous dispersion of a polymer which is insoluble or hardly soluble in water and a digestive liquid containing a substance which can be sublimed and/or which can be degraded into a harmless gas and a polymer reinforcing agent. For the above-mentioned core coating film, the sublimable substance and/or the substance which can be degraded into a harmless gas is insoluble or hardly soluble in the solution or aqueous dispersion of the polymer, and the polymer and the polymer reinforcing agent The contact angle is below 90°.

In the present invention, the step of coating the coating film of the core material containing at least one biologically active substance, in more detail, usually includes the following steps (process).

a) dispersing and suspending or dissolving a sublimable substance and/or a substance particle which can be degraded into a harmless gas and a polymer enhancer or a solution of a polymer which is insoluble or hardly soluble in water and a digestive solution or (water) In the dispersion suspension, if necessary, other polymer coating film (controlled release film) general additives such as polymer plasticizer may be added, and even bioactive substances may be added, and the mixed coating liquid may be uniformly mixed. It should be particularly noted that the above-mentioned sublimable substance and/or a substance which can be degraded into a harmless gas is insoluble or hardly soluble in a solution or an aqueous dispersion of the above polymer, and the contact angle of the above polymer with the polymer reinforcing agent is low. At 90°. The solvent or dispersing agent of the above polymer is a pharmaceutically acceptable organic solvent and water or a mixture thereof. When the above-mentioned sublimable substance and/or substance degradable into a harmless gas is insoluble or hardly soluble in a pharmaceutically acceptable organic solvent, and the organic solvent can dissolve the above polymer, the organic solvent can be used as the organic solvent a solvent for the above polymer; when the above sublimable substance and/or a substance degradable to a harmless gas is insoluble or hardly soluble in water, water is preferably used as a dispersing agent for the polymer, that is, a polymer is selected. Aqueous dispersion. Organic solvents which may be used in the present invention include, but are not limited to, ethanol, propylene glycol, tetrahydrofuran, n-butanol, 2-butanol, methyl ethyl ketone, propyl acetate, isopropyl acetate, ethyl formate, pentamidine, n-propanol, 2-propene Alcohol, dichloromethane, acetone, diethyl ether, methyl ethyl ether, ethyl acetate, methyl acetate, and mixtures thereof. The content of the above polymer in the organic solution is usually from 0.5 to 12%, preferably from 1 to 8%, more preferably from 2 to 5%. The content of the above polymer in the aqueous dispersion suspension is usually from 5 to 30%, preferably from 8 to 20%, more preferably from 10 to 15»/. .

b), preparing a coating layer of the above-prepared core material by a coating method such as melting, casting, painting or spraying by using the mixed coating liquid obtained above. It is preferably carried out by spraying. The film formation process is carried out by energy input independent of the coating method. This can be done by convection (heat), radiation (infrared or microwave) or conduction. Thereby, the organic solvent or water used as a solvent or a suspending agent for coating is evaporated, and if necessary, vacuum accelerated evaporation may be applied. This process requires high drying efficiency, so the present invention often employs high efficiency coating equipment (e.g., fluidized bed, high efficiency coating pan).

Before the core material is coated, it can also be separated according to the actual core package, which helps: 1 Avoid the drug with solvent or dispersant Description

(water) and migrate to the film; 2 improve the brittleness of the core material, avoid the breakage during the coating process; 3 improve the surface flatness of the core material, reduce the porosity, ensure the continuity of the film; 4 improve the core material The surface is hydrophobic to facilitate the spreading of the aqueous coating solution; 5 to avoid hydrolysis of the water sensitive drug during the coating process. Depending on the actual situation, a water-soluble polymer such as hydroxypropylmethylcellulose solution and hydroxypropylcellulose solution may be selected for the barrier coating. However, any of these coatings should be sufficiently thin to avoid the release properties of the formulation.

When coating, the surface temperature of the core should be higher than the minimum film forming temperature (MFT) of the polymer. (The minimum film forming temperature refers to the lowest temperature at which the polymer forms a continuous film. Below the minimum film forming temperature, the polymer particles cannot be deformed. Fusion film), usually higher than the minimum film forming temperature of 10~20 ° C, but the surface temperature of the core material should not be so high that some substances in the coating material are completely softened or melted to cause adhesion of the film, and should not Some of the components in the core material are completely softened or melted or degraded. The surface temperature of the core material should not be so high that the sublimable material of the coating material and/or the substance degradable into a harmless gas can be sublimated and degraded. Therefore, the surface temperature of the core material is preferably lower than the melting point of the sublimable substance and/or the substance degradable to a harmless gas or its sublimable or degradable temperature is at least 10 ° C, more preferably 20 ° C , optimally 30 ° C. The surface temperature of the core material can not be too low in the present invention, because the surface temperature of the core material is too low, the coating film is brittle and cracks may occur, which affects the release characteristics of the preparation; meanwhile, the surface temperature of the core material cannot be too high, because the surface temperature of the core material is too high. Excessive softening of the polymer leads to adhesion of the film, and also causes sublimation and degradation of the sublimable substance and Z or a substance degradable into a harmless gas, which is prematurely lost from the film.

When coating, the core material is usually preheated (the temperature is relatively low when the polymer organic solution is used, and the temperature is relatively high when the polymer aqueous dispersion is used) to 20 to 70 ° C, preferably 30 to 60 ° C. More preferably 30~50 ° C, first coating at a lower spray rate, after the surface of the core material has been coated with a thin film, and then increasing the spray rate to the end of the coating, this operation can avoid solvents especially It is the dispersant (water) that penetrates into the core material, causing changes in the properties of the core material during storage.

The most suitable or suitable process parameters are determined by those skilled in the art based on the coating material and core properties and experimental results. The fluidized bed coating is used for pouring, and the process conditions such as coating temperature, fluidizing air volume, atomization pressure and liquid spraying rate can be optimized according to actual conditions.

To protect the unstable active ingredient from degradation during the healing process, nitrogen can be used to replace the air in a confined environment such as a closed enclosure.

3), wave the porogen

In the present invention, the porogenic substance in the coating film needs to be volatilized to obtain a film having a porosity which is satisfactory in controlling the release rate.

The porogen is volatilized, usually at a temperature lower than the glass transition temperature of the film and under normal pressure, reduced pressure or vacuum, preferably at a temperature below 5 ° C below the glass transition temperature of the film, most Preferably, it is carried out at a temperature below 10 ° C below the glass transition temperature of the film. Too high a temperature may cause the formed micropores to shrink or even heal completely, and the most severe cause adhesion of the coating.

4), healing (curing) treatment

The present invention is intended to improve the stability of drug release of the formulation, preferably during the step 2) (coating) and/or after the step 2) (coating), and before the step 3) (without the porogen) The above-mentioned coating film is healed to eliminate a large number of tiny pores in the coating film during the coating process and form a dense coating film to ensure relatively stable drug release.

After the coating is finished, the solvent or dispersant of the polymer in the film is substantially volatilized, leaving many tiny pores in the film, and the polymer particles in the film are often not completely fused. It is believed that under the action of the micropore additional pressure (Δ Ρ) generated by the interfacial tension between the polymer and the air, these tiny micropores are automatically and gradually reduced, and fusion occurs during storage to make the membrane permeability. Constant changes occur, making the drug release behavior of the formulation unstable. According to the formula of microporous additional pressure (AP) ( Δ Ρ = 2 σ / _Γ , where Δ Ρ represents micropore additional pressure, σ polymer - air surface tension, r represents micropore radius) can be derived, fusion The time required is usually related to the pore size of the membrane, the interfacial tension between the polymer and the air, and the like. Polymer - When the surface tension of the air is constant, the smaller the micropore diameter of the membrane, the larger the additional pressure of the micropores, the shorter the time required for fusion, the larger the pore diameter of the membrane, the smaller the additional pressure of the micropores, and the longer the time required for fusion. Because of this, the present invention employs relatively large pores to control release of the drug and eliminates numerous tiny pores resulting from evaporation of the solvent or dispersant during the coating process.

The invention is characterized in that it has sublimation in a film having an ascending component or a degradation in a film which is degradable into a harmless gas. Description

The microporous controlled release drug release is formed, and these relatively large micropores still produce a certain micropore additional pressure (AP) during the healing process, so that the micropore is reduced to some extent (for example, when the micropore is less than 30 nm) , especially when it is less than lwm). In order to prevent or delay the relatively large micropores that have been produced for controlled release drug release, the healing process is reduced, the stability of the permeability of the film is improved (related to the release performance), and the production reproducibility is improved. The stability and production reproducibility of the mechanical properties of the film, in the present invention, the film healing process is optimally before the formation of relatively large pores for controlled release of the drug (ie, the wave-forming hole Material before) is completed.

The healing process is completed before the porogen is removed. Compared with the porogen and the healing process, the healing process has many incomparable advantages after the porogen is removed. The healing process is performed simultaneously with the wagging substance and the healing process is performed after the porogen is removed or the end of the healing process is not achieved, or although the healing reaches the end point, the drug release is very slow or even non-released. During the healing process, the micropores that have been formed, including controlled release of the drug, are constantly shrinking or even completely closed, and the permeability or release properties, mechanical properties, etc. of the film are difficult to stabilize and reproduce. . The healing process can be completed before the porogen is removed, so that the sublimable and/or degraded porogen can be kept in the film at all times, so as to avoid the release of micropores produced by the porogen. It shrinks during the healing process, and the film can be completely healed. It can completely eliminate many tiny micropores produced by solvent evaporation during the coating process and form a dense film to stabilize, reproduce and improve the clothes. Membrane permeability or release properties, mechanical properties, etc.

In the present invention, the curing treatment includes the following process: after the solvent or dispersant (water) in the above film is substantially evaporated, the core of the coated polymer film is placed in a closed environment. At a temperature of the glass transition temperature of the above film, which is long enough to reach the end point, the polymer particles in the coating film of the above formulation are completely or substantially completely fused, and the micropores formed during the coating process are eliminated or substantially eliminated. The fully dense or substantially intact dense film, the permeation performance or the release property of the above controlled release film reaches a stable state or a substantially constant state. More specifically, the above-mentioned coating preparation is healed at a temperature higher than the glass transition point of the above film until the preparation is at a temperature of, for example, about 40 ± 2 ° C and not less than 50% and not higher than the above. Sublimated material particles and/or substances that can be degraded into harmless gases (hygroscopic) are placed under accelerated storage conditions at a relative humidity of 3 months and/or 6 months or longer, such as 9 months or 12 The dissolution characteristics of the month are basically unaffected. Or in other words, the in vitro dissolution of the biologically active substance immediately after the healing treatment is at a temperature of about 40 ± 2 ° C and not less than 50% and not higher than the above-mentioned sublimable substance particles and / or degradable into harmless The in vitro dissolution of biologically active substances placed under accelerated storage conditions of gaseous (sublimation) critical relative humidity at relative humidity for 3 months and/or 6 months or longer, such as 9 months or 12 months. The healing treated coating formulation has stable dissolution characteristics. In addition, the term "stable" means that the dissolution in vitro is within acceptable limits compared to the dissolution characteristics of a cured coating formulation, which is acceptable to regulatory agencies such as the China Food and Drug Administration. The US Food and Drug Administration et al. Stable dissolution characteristics that are substantially unaffected by accelerated storage conditions. The above dissolution test preferably employs all of the components contained in the above-mentioned controlled release polymer coating film (but does not include the above-mentioned water-soluble porogen substances (i.e., the above-mentioned sublimable substance particles and/or substances which can be degraded into harmless gases). Particles), here is the release medium (dissolution medium) which is required to dissolve the pores and which is saturated with all of the above components. Using the saturated solution of all the components in the controlled release polymer coating film, the net dissolution amount of all the components in the controlled release polymer coating film is 0 in the above dissolution test (excluding the above water-soluble porogen Dissolution), thereby facilitating the judgment that the dissolved drug is eluted from the micropores of the original controlled release polymer coating film rather than being dissolved in the micropores produced by the dissolution of the components therein, since it is more advantageous to judge the above controlled release The polymeric film has healed completely or has reached the end state or has healed substantially completely or has been substantially to the end state.

In the present invention, the time required for the healing treatment is usually several tens of hours or longer. The temperature selected for the healing treatment should be higher than the glass transition temperature of the coating film, preferably higher than the glass transition temperature of the coating film by 10 ° C or higher, more preferably higher than the glass transition temperature of the coating film by 20 to 30 ° C, and healed. The selected temperature is treated and should be such that the ingredients in the coating material are not completely softened or melted or the film adhesion does not occur. It is preferable to use a certain humidity during the healing treatment, and the glass transition temperature of the controlled release coating film is significantly lowered by the action of moisture or moisture, thereby facilitating the accelerated healing treatment. The selected humidity is usually not lower than 50% relative humidity, preferably not lower than 60% relative humidity, and more preferably not lower than 70% relative humidity. The selected humidity is usually not too low, because the humidity is too low. The healing process takes a long time. However, the selected humidity is usually generally not higher than the above-mentioned sublimable substance particles and Z or the (hygroscopic) critical relative humidity of the substance degradable into a harmless gas, because it is higher than the above. Description

After the material particles and/or the (hygroscopic) critical relative humidity of the substance degradable into a harmless gas, the above-mentioned sublimable substance particles and/or substances degradable into harmless gases may significantly absorb moisture, particularly water solubility. Sublimable material particles and/or substances which can be degraded into harmless gases, and the above-mentioned sublimable substance particles and/or substances which can be degraded into harmless gases will exhibit partial or total dissolution-crystallization after significant moisture absorption, thereby It may precipitate from the film, and the phenomenon of "pan-cream" may appear, which may cause the release micropores to shrink during the healing process and affect the stability of drug release.

During the above-described healing process and during the above-described accelerated storage conditions, it is required that the above-mentioned sublimable substance and/or the refractory substance which can be degraded into a harmless gas in the above polymer film are not reduced in net solid content. . In order to prevent the sublimable or degradable porogens from being undone or lost before the film is completely fused, the micropores are prevented from being smaller than expected, or the above sublimable substances and/or degradable into harmless gases are caused. The net solid content of the pore material is not reduced, thereby further preventing the inter-batch variability of the microporous with the same batch of porogen, improving the production reproducibility, stability and release rate of the preparation, usually healing treatment The equilibrium partial pressure of the sublimable porogen which is greater than or equal to the conditions, such as temperature, and/or the equilibrium partial pressure of all degradation products of the refractory porogen at greater than or equal to the conditions such as temperature. Performing at or below a temperature below the lowest degradation temperature of the degradable porogen, such as under pressure, during which the above-described sublimable and/or degradable in the polymer film is The net solids of the porogenic material of the harmless gas will not decrease. The equilibrium partial pressure of a porogen (or its degradation product) means that the porogen in the gas phase (or all of its degradation products) and the porogen in the solid phase are in equilibrium at a certain temperature in a closed environment. The partial pressure at which the solid or net reduction of the pore material is zero. In order to obtain a balanced partial pressure greater than or equal to the sublimable or degradable porogen, it is common practice to blow (charge) a sublimable porogen in a closed environment (eg, a closed enclosure). A balanced partial pressure sublimable porogen gas and/or all degradation products of a equilibrium partial pressure greater than or equal to the degradation product of the degradable porogen, or placed in a closed environment (or tank) A sublimable or degradable porogen that is in excess (ie, usually has a portion of the balance of solids present), raised at a temperature for a period of time to allow degradation of the porogen or degradable porogen in the gas phase It is in equilibrium with the sublimable porogen or the degradable porogen in the solid phase.

The healing treatment can be carried out by heat treatment such as an oven and a fluidized bed. The fluidized bed heat treatment has the characteristics of high efficiency and time saving, and the coating and heat treatment operations can be completed in the same equipment, and the industrial applicability is high. After the coating is finished, the temperature of the system is raised, and the material is continuously fluidized and dried in the same fluidized bed apparatus, which promotes the healing of the membrane in a short time. However, compared with the oven mode, the fluidized bed method has higher requirements on the mechanical properties of the film, and the degree of film healing is relatively low after heat treatment. Therefore, the present invention preferably employs an oven heat treatment method.

The most suitable or suitable process parameters, such as healing temperature, humidity, time, are determined by those skilled in the art based on experimental results and the like.

The preparation prepared by any of the above methods may be coated with a thin layer of water-soluble coating material to improve the surface integrity of the preparation or prevent the preparation from sticking to each other during storage or to prevent or delay the release of micropores during storage. Variety. Suitable coating materials include, but are not limited to, disaccharides such as sucrose, polysaccharides such as maltodextrin and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose, however, any coating It should be sufficiently thin and water soluble so as not to interfere with the release properties of the formulation. After the thin layer is coated, the water-soluble coating material partially seals the release pores and leaves the release micropores (occupying the original part of the air), so that the formed release micropores are (size) stable. effect.

The pharmaceutical dosage form prepared by any of the above methods can be used substantially directly, such as directly orally. The granules, pellets or granules prepared as described above may also be filled into a gelatin capsule, a pouch (small sachet) or a suitable multi-meter container by means of a metering device. If possible, it is obtained by pressing after mixing with other auxiliaries. The preparation is decomposed after taking it, and most of the coated small units are released. It is also conceivable to embed the aggregates in polyethylene glycol or lipids to prepare a test or vaginal dosage form. The coated tablets are packaged in semi-spherical containers or multi-dose containers and taken directly before administration.

The present invention has been described in detail, and it is obvious to those skilled in the art that various modifications may be made without departing from the scope of the invention. Example

The following non-selective examples further describe preferred embodiments within the scope of the invention. Within the scope of the invention There are many variations to the description of the embodiment. Example 1 and Comparative Example 1

1. Preparation Example 1 Sample

1), prepare the core according to the following prescriptions and processes:

Component mg/tablet

Diltiazem hydrochloride 90

Lactose 255

Hydroxypropylcellulose (Klucel HXF) 250

Povidone (K29/32) 25

Magnesium stearate 10

Total 630

Diltiazem hydrochloride, lactose, hydroxypropylcellulose and povidone are uniformly mixed and granulated with ethanol; the wet granulated material is forced through an 18-mesh sieve and dried for 24 hours; after the granules, magnesium stearate is added. Uniformly, the sheet was pressed with a standard concave circular die of 12 mm, using a pressing force of 1200 to 2000 kg and a pressing time of 2 s. The hardness is 6~10kg.

2), the core of the film is coated according to the following prescriptions and techniques:

Coating liquid prescription:

Component content (g)

Aquacoat (ethyl cellulose dispersion) 96. 0

Dibutyl sebacate 4. 8

Salicylic acid (61~80 μ ιη) 37. 05

Calcium carbonate coated with stearic acid (WINN0FIL® 3. 45

FX) ^ (average diameter about 20nm)

Deionized water 321. 9

Total 463. 2

* The calcium carbonate (WIN IL® FX) coated with stearic acid on the surface, produced by Solvay, has a contact angle of 2 Γ with the coated polymer.

The cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 40~42 ° C; core temperature 40 ° C; core weight gain 16%.

A water-soluble film coat is applied before the above-mentioned controlled release film. The coating material for the water-soluble film coating was 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52 ° /. An aqueous solution of PEG 400 and 1.5% micronized talc. Coating conditions parameter inlet temperature, 55 ° C; outlet temperature, 30 ° C. The water-soluble film coat has a weight gain of about 1%.

3), healing controlled release film

The healing treatment is carried out in a closed oven. The tank is filled with a sufficient amount of salicylic acid (that is, there is always a surplus of solids). Before the healing treatment, hot air containing a saturated amount of salicylic acid gas at a temperature of 65 ° C was charged. The healing temperature was 50 ° C and the healing time was 56 hours.

4), whistling agent

The salicylic acid in the film was removed at a temperature of 20 ° C and an approximate vacuum.

2. Preparation of Comparative Example 1 Sample

The surface of the coating liquid was removed by the stearic acid-coated calcium carbonate, and the others were unchanged. The same procedure as in Example 1 was carried out. Example 2 and Comparative Example 2

1. Preparation Example 2 Sample

1), preparation of the core: Specification component mg/piece

Glipizide 20

Polyethylene oxide (PE0- 100K) 380

Sodium chloride 100

Magnesium stearate 2

Total 502

Mixing glipizide, polyethylene oxide and sodium chloride, mixing with magnesium stearate, molding into 502 _mg core, pressing a 12 standard concave circular die, using the pressed The force is 1200 1800kg, pressing time l 2s 6 8kg

2), preparation of coating liquid:

Adding 5% solution of acetic acid to ethyl acetate monoacetate (95:5) as an oil phase, using 3 mg/ml aqueous solution of sodium sulfonate as the aqueous phase; using a high-speed emulsion homogenizer, stirring The water phase is slowly added dropwise to the oil phase at a speed of not less than 3000 rpm to form a W/0 type emulsion, and the dropwise addition is continued until a 0/W type colostrum is formed. The colostrum was passed through a high pressure homogenizer for 6 times. The organic solvent was removed from the obtained emulsion using a rotary evaporator at 40 ° C under reduced pressure.

3), coating:

The controlled release film is coated with a moisture barrier protective coating. The coating for the moisture barrier protective coating is a suspension containing 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc. . Coating conditions Parameters: Spraying time is about 20 seconds, blasting time is about 30 40 seconds, blasting temperature is 50 55 °C, core temperature is 30 40 °C, moisture barrier coating weight gain is about 1%

Ethyl vanillin (60 80 mesh) and polyacrylate-coated nano-alumina dispersion slurry (average diameter 10 nm, contact angle Θ with coated polymer) were added to the cellulose acetate aqueous dispersion prepared above. 70 ° ) and as a plasticizer diacetin, wherein cellulose acetate: ethyl vanillin: nano alumina (by dry weight): diacetin is 1: 2 : 0. 06 : 1 (Weight ratio), a coating liquid was prepared by diluting with water to a suspension containing 3% cellulose acetate. The core-coated release film was coated with the prepared coating liquid. Controlled release film coating weight gain of 18%

Coating with a timed automatic film coater, the coating conditions are: spraying time of about 20 seconds, blasting time of about 30 40 seconds, blast temperature 50 70 ° C, core temperature 45 50 ° C

4), healing controlled release film

The healing treatment is carried out in a closed oven. The oven contains a sufficient amount (ie, there is always a residual solids) of ethyl vanillin. The healing air was filled with hot air at a temperature of 70 ° C containing a saturated amount of ethyl vanillin gas. The healing temperature was 65 °C and the healing time was 64 hours.

5), whistling agent

The ethyl vanillin in the coating film was removed at a temperature of 35 ° C and an approximate vacuum.

2. Preparation of Comparative Example 2 Sample

The nano-alumina in the coating liquid prescription was removed, and the others were unchanged. Comparative Example 2 was prepared according to the method of Example 2 Example 3 and Comparative Example 3

1. Preparation Example 3 Sample

1), prepare the core according to the following prescriptions and processes:

Component mg/tablet

Diltiazem hydrochloride 300

Sodium dihydrogen citrate 218

Povidone (K25) 42. 4

Magnesium stearate 12. 6

Total 573 In the instructions, diltiazem hydrochloride, sodium dihydrogen citrate and povidone are uniformly mixed and granulated with an anhydrous ethanol solution; the wet granulated material is forced through an 18-mesh sieve and dried for 24 hours; after the granules, stearin is added. The magnesium acetate was mixed and pressed with a standard concave circular die of 12 mm, using a pressing force of 1200 to 2000 kg and a pressing time of 2 s. The hardness is 6~10kg.

Coating liquid prescription (1000 tablets):

Component Content (g) Dry weight g

Kol l icoat SR 30 D (polyvinyl acetate 77. 8 21

Aqueous dispersion

Benzoic acid (38~58 μ πι) 49 49

Methyl methacrylate-styrene copolymer 2. 52 2. 52

(MMA/ST) (average material diameter 15nm)

Deionized water 323. 93

Total 453. 25 72. 52

*, Methyl methacrylate / styrene copolymer (MMA / ST), wherein the methyl methacrylate content is about 52%, the styrene is about 48%, and the contact angle with the coated polymer is 12 °.

The cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 35~37 ° C; core temperature 36~38 ° C; core weight gain 12. 6%.

3), healing controlled release film

The healing process is carried out in a closed supply tank. The oven has a sufficient amount of benzoic acid (ie, there is always a residual solids). Before the healing treatment, hot air containing a saturated amount of benzoic acid gas at a temperature of 50 ° C was charged. The healing temperature was 45 ° C and the healing time was 48 hours.

4), whistling agent

The benzoic acid in the film was removed at a temperature of 20 ° C and an approximate vacuum.

2. Preparation of Comparative Example 3 Sample

The methyl methacrylate/styrene copolymer (Li A/ST) in the coating liquid formulation was removed, and the others were unchanged. A sample of Comparative Example 3 was prepared according to the method of Example 3. Example 4 and Comparative Example 4

1. Preparation Example 4 Sample

1), preparing the core according to the prescription and process of Example 3.

Coating liquid prescription (1000 tablets):

Component content (g) dry weight

EUDRAGIT® RS 30 D 54. 6 16. 38

EUDRAGIT® RL 30 D 15. 4 4. 62

Tert-butyl-p-hydroxyanisole (96~150 μm) 49 49

PARALOID BPM- 500 2. 1 2. 1

Triethyl citrate 3. 15 3. 15

Deionized water 346. 05

Total 470. 3 75. 25

*, PARALOID BPM-500 is a nano-sized acrylic hard shell-soft core structured impact modifier produced by Rohm and Haas. The contact angle with the coated polymer 9 is determined as Γ.

The cores were coated on a Hicoater/Fruend coater. 6%。 The coating temperature parameters: inlet temperature, 50~60 ° C; outlet temperature, 30~35 ° C; core temperature 31~36 ° C; core weight gain 12.6%. Instruction manual

3), healing controlled release film

The healing treatment is carried out in a closed oven. The oven contains a sufficient amount (i.e., there is always a residual solids) of tert-butyl p-hydroxyanisole. Before the healing treatment, hot air containing a saturated amount of tert-butyl-p-hydroxyanisole gas at a temperature of 50 °C was charged. The healing temperature was 45 °C and the healing time was 60 hours.

4), whistling agent

The tert-butyl p-hydroxyanisole in the film was removed at a temperature of 10 ° C and an approximate vacuum.

2. Prepare a comparative sample 4.

The PARALOID BPM-500 in the coating liquid prescription was removed, and the others were unchanged. A comparative example was prepared according to the method of Example 4 Example 5 and Comparative Example 5

1. Preparation Example 5 Sample

1), preparing the core according to the prescription and process of Example 1.

Coating liquid prescription:

Component content (g)

Aquacoat (ethyl cellulose dispersion) 96

Dibutyl sebacate 4. 32

Di-tert-butylhydroxytoluene (96~ 150 μ m) 36

Methyl methacrylate-butadiene-styrene terpolymer 2. 88

(MBS) latex ※ (size: 200-300nm) (to dry

Recalculation)

Deionized water

Total 450

※, methyl methacrylate-butadiene-styrene terpolymer (MBS), wherein the polybutadiene content is about 70%, the styrene content is about 20%, the methyl methacrylate content is about 10%, and the coating The contact angle 聚合物 of the polymer was determined to be 47°.

A water-soluble film coat is applied before the above-mentioned controlled release film. The coating for water-soluble film coating was an aqueous solution containing 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc. Coating conditions parameter inlet temperature, 55 ° C; outlet temperature, 30 ° C. The water-soluble film coat has a weight gain of about 1%.

3), volatizing porogen

Dit-butylhydroxytoluene in the film was removed at a temperature of 15 ° C and an approximate vacuum.

2. Prepare a comparative sample 4.

The methyl methacrylate-butadiene-styrene (MBS) in the coating liquid formulation was removed, and the others were unchanged. A sample of Comparative Example 5 was prepared in the same manner as in Example 5. Example 6 and Comparative Example 6

1. Preparation Example 6 Sample

1), preparation of the core:

Component mg/tablet

Simvastatin 40

CARBOP (CARB0P0L) 974P 26. 7

Sodium citrate (dihydrate) 26. 7 Instruction manual

--lactose 26. 6

Polyvinylpyrrolidone (Κ29-32) 6. 0

Tert-butyl-p-methoxyphenol (ΒΗΑ) 0. 08

Magnesium stearate 0. 6

Total 126. 68

Mix simvastatin, carbopol, sodium citrate, lactose and polyvinylpyrrolidone ground through a 200 mesh sieve, and use a 10% (by weight) aqueous solution of ethanol (containing the desired hydrazine). Granulation is carried out. The wet material was sieved through a 18 mesh screen and dried overnight. The whole pellet was lubricated by adding magnesium stearate. The uniform mixture was pressed with a 1/4 inch standard concave circular tool. The pressing force was 1000 lbs. . The tablet after pressing has a thickness of 3.89 mm and a hardness of 8-10 kg.

2), the core pack water-soluble film coat

A water-soluble film coat was applied to the core piece by a timed automatic film coater. The coating material for the water-soluble film coating was an aqueous solution containing 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc. The water-soluble film coat has a weight gain of about 2%.

3), for the water-soluble film coated core of the package according to the following prescription and process control release:

Controlled release coating solution

Component content ω

Cellulose acetate butyrate CAB381-20 80

three ,

Ethyl citrate 3 ≤

Methyl methacrylate-butadiene-styrene (MBS) ^ 9. 6

Urea (96~150 μ πι) 120

Chloroform 4000ml

※, methyl methacrylate-butadiene-styrene (MBS), wherein the content of butadiene is about 70%, the content of styrene is about 15%, the content of methyl methacrylate is about 15%, and the contact with the coated polymer The angle of Θ was determined to be 16°.

A 120 mm thick coating was applied to the tablets using a Freand type HCT micro high performance coater (8 inch disc).

Note: ※, adjust the amount required for the glass transition temperature (7;) of the film (dry) to 50 °C as needed.

4), whistling agent

The urea in the film was removed at a temperature of 30 ° C and an approximate vacuum.

2. Preparation of Comparative Example 6 Sample

The sample of Comparative Example 6 was prepared by the method of Example 6 by removing the polymethyl methacrylate (PMMA) from the coating liquid formulation and leaving the others unchanged. Example 7

The polyacrylate-coated nano-alumina dispersion slurry of Example 2 was replaced with an equal-weight (dry weight) methyl methacrylate/styrene copolymer latex (average particle size of about 15 nm, wherein, methacrylic acid The ester content was about 60%, the styrene content was about 40%, and the contact angle with the coating polymer was determined to be 39°.) Example 7 was prepared in the same manner. Example 8

Replace only the polyacrylate-coated nano-alumina dispersion in Example 2 with an equal-weight (dry weight) Elvaloy® HP 662 latex (ethylene/butyl acrylate/carbonyl (carbon monooxide) terpolymer, average The particle size was about 60 nm, and the contact angle with the coated polymer was measured to be 30°.) Example 8 was prepared in the same manner. Example 9

Replace the methyl methacrylate/styrene copolymer of Example 3 with an equal weight (dry weight) of Elvaloy® AC 2618 Instruction manual

The latex (ethylene/ethyl acrylate copolymer) having an average particle diameter of about 200 nm and a contact angle with the coating polymer was measured to be 5 °). Example 10

The methyl methacrylate/styrene copolymer in Example 3 was replaced by an equal weight (dry weight) methyl methacrylate-butadiene-styrene terpolymer latex (average particle size about ΙΟΟηιη, wherein, The butadiene content was about 70%, the styrene content was about 15%, the methyl methacrylate content was about 15%, and the contact angle with the coating polymer was determined to be 12°.) Example 10 was prepared in the same manner. Example 11

The PARAL0ID BPM-500 in Example 4 was changed to an equal weight (dry weight) methyl methacrylate latex (average particle diameter of about 4 nm, and the contact angle with the coating polymer was measured to be 4°). Example 11. Example 12

The PARALOID BPM-500 in Example 4 was replaced with an equal weight (dry weight) methyl methacrylate/styrene copolymer latex (average particle size of about 55 nm, wherein methyl methacrylate content was about 70%, benzene The ethylene content was about 30%, and the contact angle with the coating polymer was measured to be 2 Γ.) Example 12 was prepared in the same manner. Example 13

Replace the methyl methacrylate-butadiene-styrene (MBS) in Example 6 with an equal weight (dry weight) of DuPontTM Elvaloy® HP4051 latex (average particle size of approximately 150 nm, contact with the coated polymer) The angle of enthalpy was determined to be 14 °). Example 13 was prepared in the same manner. Example 14

The methyl methacrylate-butadiene-styrene (MBS) in Example 6 was replaced with an equal weight (dry weight) DuPontTM Elvaloy® HP441 latex (average particle size of about 150 nm, contact with the coated polymer). The angle of enthalpy was determined to be 28°.) Example 14 was prepared in the same manner. Test Example 1 In vitro release performance (release) test

Sampling method: Take 12 preparations in each batch of samples, and take 9 batches of samples according to the average release rate of each batch (the production process is the same for each batch, and the raw materials used in all batches are all from the same Batch product), ie n=9.

Diltiazem Hydrochloride Release Test Method: Determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The rotation speed is 100r/min, the temperature is (37 ± 1) °C, and the transmitter is 1000 mL each of artificial gastric juice (pH 1.2 hydrochloric acid) and artificial intestinal juice (pH 7.5 phosphate buffer). The samples of the examples and the control samples were directly placed in a dissolution cup, and 5 mL was sampled at regular intervals, and the same volume of the eluted carrier was added. The amount of diltiazem hydrochloride into the dissolution medium was determined by HPLC, and the release of each tablet at different dissolution times was calculated.

Glipizide release test method: Take the sample at 37 ° C according to the release method (Chinese Pharmacopoeia 2005 edition Appendix XD first method), with Tris buffer (0. 004M Tris, pH 8.7) 1000ml Solvent, rotating at 100 rpm, operate according to law. Sampling 5 mL at regular intervals and replenishing the same volume of dissolved transmitter. The amount of glipizide into the dissolution medium was determined by HPLC. The release of each elution time of glipizide was calculated.

The simvastatin release test method is as follows: after each sampling at 37 ° C, with a USP 2 type device at 50 rpm, under laboratory conditions, the value of 7.4, containing sodium decyl sulfate 0. The drug release test was carried out in 1000% of a 4% citrate buffer solution. Sampling 5 mL at regular intervals and replenishing the same volume of dissolved transmitter. The amount of simvastatin entering the dissolution medium was determined by HPLC. The release rate of each dissolution time of simvastatin was calculated. The test results are shown in Table 1-6.

Table 1 Sample drug release rate test results of Example 1 and its Comparative Example 1 (X ± 5 _r (%) ( n = 9)

4 hours «) 8 hours (%) 16 hours (%) Specification Example 1 35.4±8.2 63.7±8.6 91.8±8.8 Comparative Example 1 19.6士32.6 37.5士33.9 72.8士34.4 Table 2 Example 2 and its Comparative Example 2 Sample drug release rate test results (± (%)) (n= 9)

Test article 2 hours (%) 4 hours (%) 6 hours (%) Example 2 33.7 ± 5.7 62.7 ± 5.9 85.5 ± 6.2 Example 7 38.7 ± 6.8 75.3 ± 7.7 91.3 ± 9.8 Comparative Example 2 20.4 ± 12.7 41.3 ± 13.2 60.2±13.5 Table 3 Sample drug release rate test results of Example 3 and its Comparative Example 3 ± _τ {%» (η=9)

Test article 4 hours (°/.) 8 hours (%) 12 hours (%) Example 3 32.2 ± 7.7 59.8 ± 7.6 85.4 ± 7.8 Example 10 33.6 ± 8.2 64.2 ± 7.9 89.5 ± 8.6 Comparative Example 3 18.8 ± 21.8 35.6 ±22.6 53.2±23.7 Table 4 Sample drug release rate test results of Example 4 and its Comparative Example 4 ( :±.S _; .(3⁄43⁄4)) (n=9)

Test article 2 hours (%) 4 hours (%) 8 hours (° /.) Example 4 33.7 ± 7.2 58.3 ± 7.5 92.5 ± 8.7 Example 11 35.3 ± 7.9 67.8 ± 8.6 95.4 ± 9.3 Comparative Example 4 17.2 ± 31.6 32.4 ±31·4 57· 2±32·8 Table 5 Sample drug release rate test results of Example 5 and its Comparative Example 5 (S.± (3⁄4)) (n=9)

Test article 3 hours (%) 6 hours (%) 9 hours (%) Example 5 38.7 ± 5.3 72.3 ± 5.8 94.5 ± 6.2 Comparative Example 5 23.7 ± 30.7 42.7 ± 30.9 70.6 ± 32.3 Table 6 Example 6 and its comparative example 6 sample drug release rate test results (l ± S _r (%}) (n = 9)

Test article 2 hours (%) 4 hours (%) 6 hours ( ) Example 6 30.6 ± 5.0 57.3 ± 5.1 84.5 ± 6 · 4 Example 13 32.8 ± 5.0 61.7 ± 6.7 90.2 ± 8 · 3 Comparative Example 6 18.5 ± 15.6 32.7±16.6 52.9±17·4 The test results of Examples 1-6 and Comparative Examples 1-6 show that the release performance and production reproducibility of the pharmaceutical preparations of the examples are better than the control examples (relative release rate is relatively large, relative deviation) 5 relatively few) Test Example 2 Preparation drug release stability test Description

Measurement samples: Samples of Examples 1-6 and Comparative Examples 1-6 Batch 1.

Detection method: The sample was placed in the same environment at a temperature of 25 ° C and a relative humidity of 60% (wherein Examples 2, 6 and Comparative Example 2, 6 were placed at an accelerating temperature of 42 ° C and a relative humidity of 80%), Sampling and measuring the drug content and drug release rate of the preparation without drug release test (12 tablets, on average), wherein drug release rate (%) = amount of drug dissolved in the dissolution medium / preparation The amount of drug X is 100%. Test method for the amount of drug eluted into the dissolution medium: See Test Example 1; Test Method for Drug Amount in Preparation: The drug was completely extracted into the preparation and then determined by HPLC. The test results are shown in Table 7-12.

Table 7 Test results of the drug release amount of Example 1 and its Comparative Example 1 for 8 hours Test article 0 (%) December (%) ^ 24 (%) ^ 36 (%) ^ Example 1 65. 3/ 100 97. 5 95. 1 91. 3 Comparative Example 1 40. 5/100 76. 5 52. 6 28. 2 Table 8 Example 2 and its control 2 sample 4 hours of drug release: test results test article 0 month (%) acceleration of 3 months (%) ^ June acceleration (° /.) Example ^¾ 2 57. 6/100 92. 7 87. 9 61. 7/100 Example 7 95.3 91.7 Example 8 64. 5/100 96. 7 93. 2 Comparative Example 2 42. 3/100 85. 3 64. 5 Table 9 Example 3 and its control 3 sample 8 hours of drug release test results Test article 0 (%) December (%) ^ 24 months (%) ^ 36 months (%) ^ Example 3 58. 6/100 96. 2 90. 4 82. 1 Example 9 58. 6/100 97. 3 93. 6 88 6 Example 5 59. 2/100 96. 9 90. 1 83. 4 Comparative Example 3 33. 7/100 86. 6 50. 1 30. 6 Table 10 Example 4 and its Comparative Example 4 sample 4 hours of drug Release amount: test result test article 0 month (%) December (%) 24 months (%) ⁵⁸ 36 months (%) ⁵⁵ Example 4 56. 6/100 95. 9 92. 0 88. 9 Example 11 58 . 7/100 97. 5 94 3 91. 6 Example 12 52. 2/100 92. 3 89. 2 82. 5 Comparative Example 4 30. 8/100 76. 0 51. 6 21. 8 Table 11 Example 5 and its Comparative Example 5 Sample 6 Hours of drug release: test results test product 0 months (%) December (%) * 24 months (%) 36 months (%) ^ Example 5 72. 6/100 97. 1 93. 4 89. 0 Control Example 5 45. 7/100 84. 2 61. 7 39. 6 Table 12 Example 6 and its Comparative Example 6 Samples of drug release for 4 hours: Test results Test article 0 (%) Accelerated 3 months (%) Acceleration 6 Month (%) <<- Example 6 60. 7/100 96. 92. 2 Specification Example 13 59. 6/100 97. 7 93. 8 Example 14 57. 4/100 93. 7 84. 8 Comparative Example 6 35. 8/100 65^ 37^ Note, ※, indicates original with 0 month The percentage of the amount compared to the example ").

The test results of the examples and their comparative examples show that the release stability of the pharmaceutical preparations of the examples is superior to that of the comparative examples. Test Example 3 Preparation of controlled release film mechanical properties test

Test Example 1 in vitro release (release degree) test test 1-6 and its comparative examples 1-6 test half of the wet residue (ie, the controlled release film directly taken out from the eluate) and another Half of the dry residue obtained by vacuum drying at a temperature below 0 ° C, the maximum tensile force at which the tensile force is broken at a temperature of 25 ° C and the percentage of the elongation length at the time of being pulled off and the original length are determined ( That is, elongation at break). The test results are shown in Table 13.

Examples 1-6 and Comparative Examples 1-6 Preparation Controlled Release Film Mechanical Properties Test Results Port Breakage Maximum Tensile Elongation at Break (%) Wet Dry and Wet Dry Example 1 9 4 250 180 Comparative Example 1 2 1 120 80 Example 2 25 18 340 240 Example 7 31 23 450 320 Example 8 37 28 870 450 Comparative Example 2 12 7 210 130 Example 3 11 5 330 170 Example 9 15 8 520 330 Example 10 13 6 410 220 Example 3 4 1 220 60 Example 4 13 7 440 370 Example 11 15 9 470 380 Example 12 10 5 380 220 Comparative Example 4 3 1 120 90 Example 5 15 7 390 290 Comparative Example 5 2 1 110 70 Example 6 24 17 350 250 Example 13 26 19 390 280 Example 14 21 14 310 230 Comparative Example 6 9 5 180 120 Example The test results of the comparative examples show that the mechanical properties of the controlled release film of the example formulation are superior to those of the comparative example. This shows that the formulation of the embodiment has better anti-drug release properties and higher drug safety. Test Example 4 Polymer film release micropore average pore size test

Method: Take the 0 month sample (just prepared sample) in the first batch of the preparation sample and place the sample for 24 and 36 months under the same environment at a temperature of 25 ° C and a relative humidity of 60%, and separate the stripping polymerization. For the coating film, the micropore (arithmetic) average (orientation) pore diameter of the coating film was measured according to the microscopic image using an IM4000 type Image Concept Analyzer (IM4000). The results are shown in Table 14.

Table 14 Mesoporous average pore diameter test results of polymer coating film release ( μ m) Instruction manual

October 24 months 36 months

Example 1 74. 6 72. 2 70. 3

Comparative Example 1 57. 1 40. 9 31. 0

Example 2 223. 6 217. 8 212. 4

Example 8 233. 5 231. 5 228. 6

Comparative Example 2 180. 4 150. 4 130. 5

Example 3 52. 7 50. 1 48. 2

Example 9 55. 6 54. 7 52. 8

Comparative Example 3 36. 8 24. 6 18. 9

Example 4 116. 8 112. 2 109. 4

Example 12 114. 6 108. 7 103. 7

Comparative Example 4 78. 3 55. 6 36. 8

Example 5 103. 7 100. 8 96. 8

Comparative Example 5 80. 5 64. 2 47. 2

Example 6 125. 8 123. 8 120. 9

Example 14 122. 6 119. 6 115. 7

Comparative Example 6 94. 6 74. 2 55. 8

The results show that the addition of an effective polymer enhancer to the polymer film is advantageous in delaying the shrinkage of the drug release micropores during the production process and during storage.

Claims

Claim

A polymeric enhancer for use in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled release micropores, particularly in a zero-order release controlled release formulation, for delaying said release The reduced pore size of the micropores during production and/or storage, wherein the polymer enhancer has a contact angle with the polymer of less than 90.

2. A polymer enhancer for use in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly in a zero-order release controlled release formulation for enhancing said controlled release The use of the release rate of the formulation for stability during storage wherein the polymer enhancer has a contact angle with the polymer of less than 90.

3. A polymeric enhancer for use in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled release micropores, particularly in a zero-order release controlled release formulation for enhancing said controlled release The use of a release rate of a formulation for reproducibility in a production process wherein the contact angle of the polymer enhancer with the polymer is less than 90.

4. A polymeric enhancer for use in a controlled release formulation coated with a polymer controlled release coating comprising a plurality of air-filled release micropores, particularly in a zero-order release controlled release formulation for improving said controlled release The release properties of the formulation, such as the use for increasing the rate of drug release, wherein the contact angle of the polymer enhancer to the polymer is less than 90.

The use according to any of the preceding claims, wherein the contact angle is lower than or equal to 60°.

6. Use according to any of the preceding claims, wherein the contact angle is lower than or equal to 30°.

The use according to any of the preceding claims, wherein the contact angle is lower than or equal to 10°.

The use according to any one of the preceding claims, wherein the release micropores are sublimed and pharmaceutically acceptable sublimable substances located in the polymer controlled release coating film and/or degraded Obtained from a pharmaceutically acceptable substance that degrades into a harmless gas in the polymer controlled release coating film.

The use according to any of the preceding claims, wherein the polymer reinforcing agent has a "hard shell-soft core" structure.

10. The use according to claim 9, wherein the polymer enhancer has a melting point (or crystal melting temperature) or/and a Vicat Softening Point of not less than the polymer in the controlled release film. Glass transition temperature

(Tg), and its central glass transition temperature is not higher than 0 °C.

11. The use according to claim 9, wherein said polymer enhancer has a melting point (or crystal melting temperature) or/and a Vicat Softening Point higher than 10 ° C (inclusive) of said controlled release The glass transition temperature (/3⁄4) of the polymer in the film and its central glass transition temperature is -10 to -200 °C.

12. The use according to claim 9, wherein the polymer reinforcing agent has an elongation at break of 200 to 5000%.

The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose tridodate, cellulose tripalmitate, cellulose dipalmitate or a mixture thereof The polymer reinforcing agent is selected from the group consisting of polar rigid inorganic particles surface-modified by a surface active material adsorption coating treatment.

The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose tridodate, cellulose tripalmitate, cellulose dipalmitate or a mixture thereof The polymer enhancer is selected from calcium carbonate particles whose surface is coated with stearic acid.

The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate (cel) Lulose acetate propionate) nitrocellulose, cellulose trivalerate, cellulose succinate or a mixture thereof, the polymer reinforcing agent being selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymerization , styrene-butadiene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1 ~C4 Alkylacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1 to C4 alkyl acrylate copolymer or a mixture thereof.

The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate (cel) Lulose acetate propionate), nitrocellulose, cellulose trivalerate, cellulose succinate or a mixture thereof, the polymer reinforcing agent being selected from the group consisting of methyl methacrylate-styrene copolymer, methyl methacrylate a butadiene-styrene trimer or a mixture thereof.

The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of insoluble or almost insoluble Claim

a methacrylic acid polymer of water and digestive juice, polymethyl methacrylate, ethyl acrylate methylmeracrylate trimethylamonioethylmetacrylate chloride, or a mixture thereof, said polymer reinforced The agent is selected from the group consisting of polymethyl methacrylate, methyl methacrylate-styrene copolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) III Polymer, ethylene-C1 C4 mercaptoacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1 C4 mercaptoacrylic acid copolymer, acrylic resin impact modifier or a mixture thereof.

The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of polyvinyl acetate, vinyl chloride-vinyl alcohol-vinyl acetate, which is insoluble or hardly soluble in water and digestive juice. a terpolymer, a vinyl chloride-ethylene acetate copolymer or a mixture thereof, the polymer enhancer being selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymer, styrene- Butadiene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1 C4 methacrylic acid- a carbonyl (carbon monooxide) terpolymer, an ethylene-C1 C4 alkyl acrylate copolymer or a mixture thereof.

The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of polyvinyl chloride, and the polymer reinforcing agent is selected from the group consisting of methyl methacrylate-styrene copolymer, styrene- Acrylonitrile copolymer, styrene-butadiene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, Ethylene-C1 C4 mercapto acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-C1 C4 alkyl acrylate copolymer, and mixtures thereof.

The use according to any one of the preceding claims, wherein the polymer reinforcing agent has an average particle diameter (diameter) of not more than 400 nm

The use according to any one of the preceding claims, wherein the polymer reinforcing agent has an average particle diameter (diameter) of not more than 100 nm

The use according to any one of the preceding claims, wherein the polymer reinforcing agent has an average particle diameter (diameter) of not more than 20 nm

The use according to any one of the preceding claims, wherein the polymer reinforcing agent has an average particle diameter (diameter) of not more than 5

The use according to any one of the preceding claims wherein the polymer controlled release film has a glass transition temperature (3⁄4) of 25 80 ° C

The use according to any of the preceding claims, wherein the polymer reinforcing agent is used in an amount of 1% 30°/(by weight) based on the total dry weight of the polymer controlled release coating component. .

26. A method for preparing a controlled release formulation having improved properties, in particular a controlled release formulation of zero order release, the method comprising:

1) preparing a core material containing at least one biologically active substance;

2) pharmaceutically acceptable insoluble or nearly insoluble in water with particles of pharmaceutically acceptable sublimable material and/or particles which are degradable into a harmless gas and a pharmaceutically acceptable polymer enhancer And a polymer solution or aqueous dispersion of the digestive juice coated with the polymer controlled release coating film, wherein the sublimable substance and/or the substance degradable into a harmless gas and the polymer enhancer are insoluble a solution or an aqueous dispersion of the above polymer which is or is insoluble in the above polymer, the contact angle of the above polymer with the above polymer reinforcing agent is less than 90°

3) sublimating the pharmaceutically acceptable sublimable material in the above polymer controlled release coating film and/or degrading the pharmaceutically acceptable degradable gas into the controlled release film of the above polymer Substance.

27. The preparation method according to claim 26, wherein said contact angle is lower than or equal to 60

28. The preparation method according to claim 26, wherein said contact angle is lower than or equal to 30

29. The preparation method according to claim 26, wherein said contact angle is lower than or equal to 10

The production method according to any one of claims 26 to 29, wherein said polymer reinforcing agent has a "hard shell soft core" structure.

The preparation method according to claim 30, wherein said polymer reinforcing agent has a melting point (or crystal melting temperature) or/and a Vicat Softening Point of not lower than that in said controlled release coating film. Vitrification temperature Claim

Degree (3⁄4), and its central glass transition temperature is not higher than o °c.

32. The production method according to claim 30, wherein said polymer enhancer has a melting point (or crystal melting temperature) or/and a Vicat Softening Point higher than 10 ° C (inclusive) of said control The glass transition temperature (3⁄4) of the polymer in the release film, and its central glass transition temperature is -10 to -200 °C.

The preparation method according to claim 30, wherein the polymer reinforcing agent has an elongation at break of 200 to 5000%.

The production method according to claim 26, wherein said polymer is selected from the group consisting of ethyl cellulose, cellulose tridodate, cellulose tripalmitate, cellulose dipalmitate or a mixture thereof, said polymerization The material enhancer is selected from the group consisting of polar rigid inorganic particles surface-modified by a surface active material adsorption coating treatment.

The production method according to claim 26, wherein said polymer is selected from the group consisting of ethyl cellulose, cellulose tridodate, cellulose tripalmitate, cellulose dipalmitate or a mixture thereof, said polymerization The enhancer is selected from calcium carbonate particles whose surface is coated with stearic acid.

The preparation method according to claim 26, wherein said polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate, and nitrocellulose. a cellulose, cellulose triacetate, cellulose succinate or a mixture thereof, the polymer reinforcing agent being selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymer, styrene-butyl Diene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C4 alkyl acrylate- a carbonyl (carbon monooxide) terpolymer, an ethylene-C1 to C4 methacrylic acid copolymer or a mixture thereof.

37. The production method according to claim 26, wherein said polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate, nitric acid. Cellulose, cellulose trivalerate, cellulose disuccinate or a mixture thereof, the polymer reinforcing agent being selected from the group consisting of methyl methacrylate-styrene copolymer, methyl methacrylate-butadiene-benzene Ethylene terpolymer or a mixture thereof.

The production method according to claim 26, wherein said polymer is selected from the group consisting of methacrylic acid polymers, polymethyl methacrylate and ethyl acrylate which are insoluble or hardly soluble in water and digestive juice. Methyl acrylate polymer, poly

(ethylacrylate , methylmetacrylate , trimethylamonioethylmetacrylatchloride ) or a mixture thereof, the polymer enhancer selected from the group consisting of polymethyl methacrylate, methyl methacrylate-styrene copolymer, methyl methacrylate-butadiene-benzene Ethylene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene

-C1 to C4 mercaptoacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1 to C4 mercaptoacrylic acid copolymer, acrylic resin impact modifier or a mixture thereof.

The production method according to claim 26, wherein said polymer is selected from the group consisting of polyvinyl acetate, vinyl chloride-vinyl alcohol-vinyl acetate terpolymer which is insoluble or hardly soluble in water and digestive juice, a vinyl chloride-ethylene acetate copolymer or a mixture thereof, the polymer enhancer being selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymer, styrene-butadiene-propylene Nitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C4 methacrylic acid-carbonyl (carbon single Oxide) terpolymer, ethylene-C1 to C4 alkyl acrylate copolymer or a mixture thereof.

40. The production method according to claim 26, wherein said polymer is selected from the group consisting of polyvinyl chloride, said polymer reinforcing agent is selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymer, Styrene-butadiene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C4 Alkylacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1 to C4 mercaptoacrylic acid copolymer, and mixtures thereof.

The production method according to any one of claims 26 to 40, wherein said polymer enhancer has an average particle diameter (diameter) of not more than 400 nm.

The production method according to any one of claims 26 to 40, wherein said polymer reinforcing agent has an average particle diameter (diameter) of not more than 100 nm.

43. The production method according to any one of claims 26 to 40, wherein the average particle of the polymer enhancer Claim

The diameter (diameter) is not more than 20 nm.

The production method according to any one of claims 26 to 40, wherein said polymer reinforcing agent has an average particle diameter (diameter) of not more than 5 nm.

The preparation method according to any one of claims 26 to 44, wherein said release micropores have an average size of 50 to 900 μm.

The preparation method according to any one of claims 26 to 44, wherein said release micropores have an average size of from 100 to 600 μm.

The production method according to any one of claims 26 to 46, wherein the polymer controlled release film has a glass transition temperature (Tg) of 25 to 80 °C.

The production method according to any one of claims 26 to 47, wherein said polymer controlled release film has a porosity of from 5% to 95%.

The production method according to any one of claims 26 to 48, wherein the polymer reinforcing agent is used in an amount of from 1% to 30% by weight based on the dry weight of the polymer controlled release coating film component. The total weight.

The production method according to any one of claims 26 to 49, wherein the core material is a sheet, a pellet, a pellet, a crystal or a drug-loading resin in a regular or irregular form.

The preparation method according to any one of claims 26 to 50, wherein the biologically active substance is selected from the group consisting of a central stimulant, an analgesic, an antipyretic analgesic, an anti-inflammatory analgesic, an anti-gout, and an antibiotic Tremor palsy, antipsychotics, anxiolytics, antidepressants, antiepileptics, sedatives, hypnotics, anticonvulsants, autonomic nervous drugs, calcium antagonists, drugs for chronic heart failure, anti-heart rhythm Disorders, prevention and treatment of angina pectoris, peripheral vasodilators, blood pressure lowering drugs, blood lipid regulating and anti-atherosclerotic drugs, respiratory medicines, antacids and peptic ulcer drugs, gastrointestinal antispasmodics, digestion Medicine, antiemetics, emetics and gastrointestinal drugs, hepatobiliary diseases, urinary system drugs, drugs that affect blood and hematopoietic system, antihistamines, allergic mediators, adrenocortical hormones and adrenocorticotropic hormones , sex hormones and gonadotropins, islet hormones and other drugs that affect blood sugar, thyroid hormones and antithyroid drugs, Penicillins, cephalosporins, β-lactamase inhibitors, aminoglycosides, tetracyclines, macrolides, antituberculosis drugs, antifungals, antivirals, antitumor drugs, affecting immune function Drugs, vitamins and nutrients, diet pills and mixtures thereof.

The preparation method according to any one of claims 26 to 50, wherein the biologically active substance is selected from the group consisting of herbal extracts.

The preparation method according to any one of claims 26 to 50, wherein the biologically active substance is selected from the group consisting of LECOZOTAN (SRA-333), amoxicillin, asdamamo, piperazine ferulate, acyclovir. Wei, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, aceclofenac, isosorbide mononitrate, diazepam, famciclovir, felodipine, fenofibrate, fluvastatin sodium , acipimox, vitamin B6, quetiapine fumarate, metoprolol fumarate, ezetimidate fumarate, gliclazone, gliclazide, potassium citrate, citrate Tamoxifen, tamoxifen, venlafaxine succinate, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, tolterodine tartrate, zolazole tartrate Tantan, clarithromycin, oxymatrine, ranolazine, ribavirin, benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, rosiglitazone, roxithromycin, lovra Statins, trimebutine maleate, mesalazine, metoprolazine, mizolastine, naftopide , naproxen sodium, niketatin, nimesulide, nitrendipine, nisoldipine, paliperidone, paprazole, dafenazone hydrobromide, galantamine hydrobromide, stone Alkaloids, bicyclol, stavudine, gastrodin, ketoprofen, cefaclor, cefixime, vitamin C (vaginal controlled release tablets), vitamin E nicotinate, urapidil, niacin, hydrochloric acid Bupropion, ambroxol hydrochloride, oxybutynin hydrochloride, betahistine hydrochloride, metformin hydrochloride, valacyclovir hydrochloride, ciprofloxacin hydrochloride, labetalol hydrochloride, nicardipine hydrochloride, hydrochloric acid Roxioxine, prazosin hydrochloride, propafenone hydrochloride, propranolol hydrochloride, hydromorphone hydrochloride, tramadol hydrochloride, trimetazidine hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, L-salbutamol hydrochloride, hydrochloric acid Levofloxacin, ofloxacin, etodolac, indapamide, guaifenesin, levodropropizine, bezafibrate, piracetil, theophylline, vincamine, dihydroergotamine mesylate , doxazosin mesylate, metoprolol tartrate Dihydrocodeine tartrate, morphine sulfate, Qing Trappe sulfate, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, Claim

Diclofenac sodium, verapamil, ferrotitanium, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetame, dexamethasone, p-acetyl Aminophenol, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, pirfenine, malotilate, naproxen, lithium carbonate, cephalexin, alfuzosin hydrochloride, butyl chloride Lodil, ticlopidine hydrochloride, ibudilast, dextromethorphan, sinomenine, 5-mononitrate, sodium valproate, dopasine, chlorpheniramine maleate, Banidipine, bunazosin, golopamil, methylphenidate hydrochloride, oxycodone hydrochloride.

The preparation method according to any one of claims 26 to 50, wherein the biologically active substance is selected from the group consisting of amoxicillin-clavulanate potassium compound, aspirin monophosphate complex, ligustrazine compound, aspirin-dipyridamole compound, paracetamol Pseudoephedrine hydrochloride, dextrobromide compound of maleic acid, isosorbide mononitrate-aspirin compound, metformin-roglitazone combination, fesopidine hydrochloride-pseudoephedrine hydrochloride, felodipine-tartaric acid Torolol compound, lovastatin-nicotinic acid compound, cetirizine-pseudoephedrine compound, fexofenadine hydrochloride pseudoephedrine hydrochloride compound, guaifenesin-pseudoephedrine-dextromethorphan compound, glipizide Metformin hydrochloride compound, glimepiride-metformin compound, loratadine-paracetamol-pseudoephedrine compound, loratadine-pseudoephedrine compound, enalapril maleate-felodipine compound, pseudoephedrine-naproxen sodium compound , niacin-simvastatin combination, guaifenesin-pseudoephedrine hydrochloride, Kabi Dopa-levofopa compound, theophylline-salbutamol compound, gentamicin sulfate-zirconia compound.

The production method according to any one of claims 26 to 54, wherein the sublimable substance and/or the substance degradable to a harmless gas has a melting point at 1 standard atmospheric pressure (101. 325 ka) and the start thereof The sublimation (sublimation point) or degradation temperature is higher than (including) the minimum film formation temperature of the mixed coating solution of the polymer at 10 ° C or the glass transition temperature of the polymer controlled release coating film.

The production method according to any one of claims 26 to 55, wherein the sublimable substance and/or the substance degradable to a harmless gas has a melting point at 1 standard atmospheric pressure (101. 325 ka) and the start thereof The sublimation (sublimation point) or degradation temperature is higher than (including) the minimum film formation temperature of the mixed coating liquid of the polymer at 20 ° C or the glass transition temperature of the polymer controlled release film.

The production method according to any one of claims 26 to 56, wherein the sublimable substance and/or the substance degradable to a harmless gas is selected from the group consisting of benzoic acid, benzoate and benzoate compounds. , vanillin, ethyl vanillin, natural or synthetic camphor, right-handed camphor, left-handed camphor, racemic menthol (alcohol), levo-menthol, natural or synthetic borneol, right-handed borneol, left-handed borneol, right-handed Iso-borne brain, L-isobornolone, racemic isoborneol, dithiooxamide (dithiodiamide), 6-methyl-2-thiouracil (methylthiouracil), sulfonic acid Salt, tert-butyl-p-hydroxyanisole, di-tert-butylhydroxytoluene (2,6-di-tert-butyl-p-cresol), salicylic acid, aspirin, salicylamine, caffeine, alanine, Leucine, isoleucine, valine, phenylalanine, urea, urethane, ammonium halide, ammonium hydrogencarbonate, ammonium carbonate, ammonium acetate or a mixture thereof.

The production method according to any one of claims 26 to 57, wherein before the release micropores are formed by sublimation and/or degradation of the sublimable substance and/or a substance degradable into a harmless gas, The core material of the coated polymer controlled release coating film is subjected to a healing treatment at a temperature higher than a glass transition temperature of the polymer controlled release coating film until the coating core material has stable dissolution characteristics. The end point of the healing treatment is obtained by comparing the coating core material which has just finished the healing treatment with the temperature at 40 ± 2 ° C and not less than 50% and not higher than the above-mentioned sublimable substance particles and/or degradable into a harmless gas. Determination of the dissolution characteristics of the coated core material in an accelerated storage condition at a relative humidity of the relative relative humidity at a relative humidity of 3 months and/or 6 months, during the above healing process and in the above accelerated storage conditions. During the placement process, the above-mentioned sublimable substance located in the above polymer film and the net solidity of the substance degradable into a harmless gas are not reduced.

59. The production method according to claim 58, wherein said healing treatment has a equilibrium partial pressure of said sublimable substance at a temperature greater than or equal to said healing treatment, such as temperature, and/or at greater than or equal to Said healing treatment is carried out under conditions such as equilibrium at a partial pressure of all degradation products of said substance degradable to a harmless gas at a temperature or at a lower than said healing treatment, conditions such as pressure The lowest degradation temperature of the substance is carried out at a temperature.

The production method according to any one of claims 26 to 59, wherein sublimating said sublimable substance and/or degrading said substance degradable into a harmless gas is under reduced pressure or under vacuum Below the film glass transition temperature Claim

It is carried out at a temperature below 5 °C.

The preparation method according to any one of claims 26 to 60, wherein said polymer controlled release coating film is coated with a water-soluble coating film.

62. A controlled release formulation having improved properties, in particular a zero release release controlled release formulation, the controlled release formulation comprising:

1) a core material containing at least one biologically active substance;

2) a controlled release coating film comprising a plurality of air-filled drug delivery micropores covering the core material, wherein the controlled release coating film comprises pharmaceutically acceptable insoluble or hardly soluble in water and digestive juice. a polymer and a pharmaceutically acceptable polymer enhancer, wherein the contact angle of the polymer with the polymer enhancer is less than 90°, and the release micropores are pharmaceutically acceptable by sublimation in the controlled release coating film The acceptable sublimable material and/or the degradation of the pharmaceutically acceptable material which is degradable into a harmless gas in the above controlled release coating film.

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

64. A controlled release formulation according to claim 62 or 63 wherein said contact angle is less than or equal to 30°.

A controlled release preparation according to any one of claims 62 to 64, wherein said contact angle is lower than or equal to 10°.