WO2012006959A1

WO2012006959A1 - Controlled release preparation

Info

Publication number: WO2012006959A1
Application number: PCT/CN2011/077167
Authority: WO
Inventors: 钟术光
Original assignee: Zhong Shuguang
Priority date: 2010-07-16
Filing date: 2011-07-14
Publication date: 2012-01-19
Also published as: CN101987081B; CN101987081A

Abstract

Disclosed are a controlled release preparation with improved performance and a method for preparing the controlled release preparation. The controlled release preparation comprises: a core containing drugs and a controlled release coating coated on the core. The controlled release coating contains a plasticizer, a polymer that is insoluble in water and gastrointestinal digestive juice, and particles of a porogen which are embedded in the polymer and coated by a polymer coating soluble in gastric juice and/or intestinal juice but insoluble in water. The reproducibility of drug release of the controlled release preparation is improved, the release time lag is reduced, and the bioavailability is improved. Therefore, targeted and controlled release of drugs in gastrointestinal track is achieved.

Description

Controlled release preparation

Technical field

The present invention relates to a controlled release formulation. More particularly, the present invention relates to a controlled release formulation having improved properties, particularly a zero release release controlled release formulation. The invention also relates to a process for the preparation of the controlled release formulation. 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, it is often necessary to form micropores in the coating film to improve the permeability of the controlled release coating to facilitate the penetration of water and the release of the drug, especially the solubility of the drug. When the total surface area of the preparation is small.

To date, there are three typical representatives of the relevant coated film controlled release preparation technology:

One is represented by US4629619: This technology disperses and suspends a water-soluble porogen in an organic solvent containing a water-insoluble polymer, and the water-soluble substance is present in the coating of the water-insoluble polymer by coating. In the film, the water-soluble porogen in the film is dissolved in the digestive tract by the digestive juice to form larger micropores. One of the drawbacks of this technique is that the organic solvent is used in the final molding of the formulation.

The second is represented by US5472712 and US5639476: This type of technology dissolves water-soluble porogen in an aqueous dispersion containing water-insoluble polymer (Aqueous polymeric dispersion), and makes water-soluble substances through coating. It is present in the coating film of the water-insoluble polymer, and the water-soluble substance in the film is dissolved in the digestive tract by the digestive juice to form small pores. The advantage of this technique is that the use of organic solvents is avoided. However, there are also many defects: The water-soluble porogen is present in the film in a single molecule state, and the pore size of the pores is controlled by the molecular size of the water-soluble porogen, and the pore diameter is much smaller than that prepared by the suspension state (for example, US4629619). It is not conducive to the penetration of drugs with large molecular radius; therefore, when the permeability of the coating film can meet the requirements of practical applications, especially when the solubility of the drug is low and the total surface area of the preparation is small, the mechanical strength is very weak; The actually available holes are not well controlled and the production reproducibility is poor.

The third is represented by US6974591: This type of technology generally disperses and suspends a porogen which is insoluble in water but soluble in an acidic or alkaline digestive solution in an aqueous dispersion containing water-insoluble polymer (Aqueous). In the polymeric dispersion, the porogen is present in the coating film of the water-insoluble polymer by coating, and the porogen in the coating film is dissolved in the digestive tract by the digestive juice to form larger micropores. This technology combines the advantages of the first two types of technology to a certain extent, and also overcomes the shortcomings of the first two types of technology to a certain extent. However, there are many defects in this technology: For example, the formation of micropores or the dissolution of porogens are greatly affected by the in vivo factors such as the acidity or alkalinity of the digestive juice or the pH value and the amount of digestive juice; The formation of micropores or the dissolution of porogens (especially non-polymeric porogens such as potassium hydrogen tartrate) require relatively long periods of time, and the release of the drug exhibits high time lag (especially non-polymeric). A pore agent such as potassium hydrogen tartrate). These factors will make the release behavior of the drug unstable, and the in vivo factors may result in poor drug release stability or reproducibility.

In particular, the technology represented by US4629619 and US6974591, in which the dilute liquid soluble small molecular substance is used as a general porogen, and the digestive liquid insoluble non-polar polymer is a general coating material, When the two are blended, there will be a problem that the interfacial energy between the two phases is very high, and the compatibility and adhesion are poor. As a result, the dispersion is uneven, and the granular porogen will also become the stress concentration point in the film. It becomes a weak link in the film, which greatly reduces the mechanical strength of the film, which may lead to the release of the controlled release preparation (d _0Se -dumpin _g ). These drawbacks not only limit the amount of porogen added in the film, but also seriously affect the performance of the product, especially the completeness of the drug. (See: Polymer Chemistry and Physics, edited by Wang Yijie, China Light Industry Press, 1st edition, April 1992, p. 345; "The Surface and Interface of Polymers", edited by Wu Renjie, Science Press (Beijing) ), pp. 104~110; Modification of Inorganic Fillers, Jiangxi Chemical Industry, 2001, No. 4, pp. 17~18).

In addition, due to poor compatibility, especially under the action of moisture, these water-soluble substances are easily precipitated from the polymer film, and a so-called "pan-cream" phenomenon occurs; the water-soluble substance is easily precipitated from the polymer film and remains. Under the micropores, the micropores shrink or even heal under the action of surface tension and other factors such as water vapor, so that the release behavior of the drug becomes unstable, and the body appears. External factors drug release stability or reproducibility worse.

In addition, the technique represented by US6974591 also uses some digestible-soluble but water-insoluble polymers as porogens. These polymeric porogens and digestive-insoluble polymeric coating materials generally exhibit partial compatibility and complete compatibility. When the two polymers are in contact with each other, they first wet each other at the interface, and then the two-phase macromolecular segments are mutually diffused by thermal motion, and as a result of the diffusion, the two polymers produce a significant concentration gradient on both sides of the interface. This region with a significant concentration gradient constitutes the interfacial layer between the two phases. The thickness of the interfacial layer is primarily determined by the compatibility of the two polymers. As the compatibility increases, the degree of diffusion increases, the phase interface becomes more and more blurred, and the thickness of the interface layer becomes larger and larger, so that the final phase interface disappears completely and becomes a homogeneous blend, achieving complete compatibility (see: Polymer) Compatibility and Compatibilization of Alloys, Journal of Qingdao University, May 1995, Vol. 10, No. 1, p. 91). It is precisely because of this interdiffusion penetration between the polymers that the interface between the macroporous porogen and the controlled release coating becomes more and more blurred with time, and the micropores that can be formed also change with time. It becomes more and more blurred, and the pore size also becomes non-constant, so that the release behavior of the drug becomes unstable, and the drug release stability or reproducibility of the in vitro factors is deteriorated.

Therefore, there is a need in the art for a controlled release formulation, particularly a zero-order release controlled release formulation preparation technique which not only inherits or further advances the advantages of the prior art described above, but also overcomes many of the deficiencies of the prior art described above. Purpose of the invention

SUMMARY OF THE INVENTION One object of the present invention is to provide a controlled release preparation having improved performance as described above, particularly a zero-order release controlled release preparation, and a preparation technique thereof, wherein the release stability or reproducibility of the preparation prepared by the technique is improved.

Specifically, it is to provide a controlled release preparation having improved performance as described above, particularly a zero-order release controlled release preparation, and a preparation technique thereof, wherein the release pore size of the controlled release preparation is more stable during storage and/or production The effect of external factors is smaller. For example, in the storage and/or production process, the water-soluble porogen in the controlled release film of the controlled release preparation is not easily precipitated from the polymer film, and the macromolecule in the controlled release preparation is large. The interdiffusion of the interface between the porogen and the controlled release coating film becomes blurred and the release instability is limited to a certain acceptable range.

One of the objects of the present invention is to provide a controlled release preparation having improved performance as described above, particularly a zero-order release controlled release preparation, and a preparation technique thereof, wherein the controlled release preparation has less influence on the formation of receptor micropores. It has better drug release behavior in vivo.

One of the objects of the present invention is to provide a controlled release preparation having improved performance as described above, particularly a zero-order release controlled release preparation, and a preparation technique thereof, wherein the time required for the release of the release micropores of the controlled release preparation is shortened, and the dissolution performance of the drug is provided. The time lag is smaller.

One of the objects of the present invention is to provide a controlled release preparation having improved performance as described above, in particular, a zero-order release controlled release preparation, and a preparation technique thereof, wherein the controlled release coating has improved mechanical strength and is not susceptible to sudden release (dose) -dumping), medication completeness is improved.

One of the objects of the present invention is to provide a controlled release preparation having improved performance as described above, in particular, a zero-order release controlled release preparation and a preparation technique thereof, which can realize the controlled release release of a drug in the gastrointestinal tract, such as stomach and intestine. Controlled release of colon, especially controlled release of intestinal and colon;

One of the objects of the present invention is to provide a controlled release preparation having improved performance as described above, particularly a zero-order release controlled release preparation, and a preparation technique thereof, which can realize delayed release of a drug in the gastrointestinal tract, gap type or Pulsed controlled release release; for other purposes of the invention, reference is made to the following description. Summary of the invention

The present invention relates to a controlled release preparation having improved properties, in particular a zero-order release controlled release preparation comprising: a) a core containing a drug;

b) a controlled release coating film overlying the core, wherein the controlled release film comprises a pharmaceutically acceptable plasticizer, pharmaceutically acceptable insoluble or almost insoluble in water, and gastric and intestinal digestive juices And a pharmaceutically acceptable soluble or non-plasticizer-containing pharmaceutically acceptable plasticizer or a plasticizer which is embedded in the stomach and/or intestinal digestive solution but is insoluble as a porogen Or a water-insoluble polymer coated film coated with a water-soluble pharmaceutical additive, the above soluble in water The medicinal additive and the above-mentioned polymer soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water can not undergo chemical reaction or chemical reaction in the body digestive juice but does not generate water insoluble. And a pharmaceutically unacceptable product which is a solid or liquid product at normal temperature (25 ° C), and the above polymer film which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water The amount used does not exceed 700% of the amount of the above water-soluble pharmaceutical additive (weight

/weight).

The present invention also relates to a method for preparing a controlled release film-coated controlled release preparation having improved performance, in particular a zero-order release controlled release preparation, which comprises the following basic steps: 1) Preparation of a drug The core material; 2), the granules of the water-soluble medicinal additive are pharmaceutically acceptable soluble in the stomach and/or intestine containing pharmaceutically acceptable plasticizer or no plasticizer a coating or dispersion of a polymer which is insoluble or hardly soluble in water, the above water-soluble pharmaceutical additive and the above-mentioned soluble in the stomach and/or intestinal digestive juice but insoluble or almost The water-insoluble polymer cannot undergo a chemical reaction or chemical reaction in the in vivo digestive juice, but does not produce a product including a water-insoluble non-gaseous state (ie, solid or liquid at normal temperature (25 ° C)). a pharmaceutically unacceptable product, and the above-mentioned polymer film which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water is used in an amount not exceeding the amount of the above-mentioned water-soluble pharmaceutical additive. 700% (weight / 3), for the above core material containing a drug, a solution containing a pharmaceutically acceptable plasticizer insoluble or almost insoluble in water and a solution of a stomach and intestinal digestive juice or The dispersion is coated with a controlled release coating film, wherein the solution or dispersion of the polymer is dispersed as a porogen and is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water. a particulate matter of the above water-soluble pharmaceutical additive coated with a coating film, the solution or dispersion of the polymer is insoluble or non-degradable or hardly dissolved or hardly degraded, said soluble in the stomach and/or A polymer that is insoluble or hardly soluble in water in the intestinal digestive juice; 4), if necessary, healed (aging) the above-mentioned coating film. 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 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 during the release of the aqueous solution, the coating film can delay the release of the drug or therapeutic active agent contained in the controlled release preparation when it is placed in an aqueous solution.

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 deteriorating the stability and/or efficacy of the preparation and is suitable for topical or systemic administration.

The term "about" as used in the present invention means that the amount of change is ± 30% (for example, if the amount is p, then the value of p is in the range of 0. 7p~1. 3p), preferably ± 20%, The best is ± 10%.

The term "porogen" as used in the present invention means a substance which contributes to the formation of pores in the controlled release coating film of the present invention or improves the permeability or water permeability of the controlled release coating film. The porogen is used in an application environment. The pores may be formed by dissolving, extracting, leaching, and/or chemically reacting (forming water-soluble products and/or gases) from the controlled release coating. detailed description

It is an object of the present invention to provide a controlled release preparation, in particular a zero-order release controlled release preparation, which has been pharmaceutically acceptable as a porogen dispersed or embedded in an outer coating. Acceptable plasticizer or pharmaceutically acceptable water-soluble drug coated with a plastic film which is soluble in the stomach and/or intestinal digestive solution but which is insoluble or hardly soluble in water. Controlled drug release is controlled by a controlled release coating of particulates of the additive. The porogen forms a release in the digestive juice Drug hole.

It is not intended to be completely limited by this principle or theory, as a part of the space of the macromolecular polymer particles which are soluble in the stomach and/or intestinal digestive solution but which are insoluble or hardly soluble in water as a porogen are soluble in water. By the substitution of medicinal additives, the interdiffusion penetration between the polymers (ie, between the porogen coating film and the controlled release coating film) is limited to a certain range (because of the porogen polymer and the water-soluble pharmaceutical additive phase) Poor capacitive, hardly interdiffused, and at least a certain amount of unaltered space between the porogen polymer particles to form relatively stable micropores, so that the release behavior of the drug becomes relatively stable within a certain range; The dissolution of the water-soluble medicinal additive in water is relatively fast, and the influence of the internal factors of the receptor is usually relatively small. After replacing the internal part of the porogen polymer particle, the porogen polymer to be dissolved is dissolved. The amount of drug decreased, the time lag of drug dissolution will be relatively small, and the effect of drug release receptors will be relatively small. In addition, the porogen polymer coated with a water-soluble pharmaceutical additive prevents the water-soluble pharmaceutical additive from being precipitated from the controlled release polymer film in a humid environment ("pan-frost"). The stability or reproducibility of drug release is improved.

Water-soluble pharmaceutical additives usually have very high polarity, while polymers of controlled release coatings are generally hydrophobic, so compatibility between them is poor; water-soluble pharmaceutical additives are certain Poor mechanical properties, such as greater brittleness, and porogen polymers that are soluble in the stomach and/or intestinal digestive juice but insoluble or nearly insoluble in water are usually (polymerized relative to hydrophobic controlled release coating material) a certain amount of acidic and/or basic polar groups, so they have relatively good compatibility; in addition, soluble in the stomach and / or intestinal digestive juice, but insoluble or almost insoluble in water The affinity of the porogen polymer to the hydrophobic controlled release coating material polymer is generally greater than the affinity of the water soluble pharmaceutical additive to the hydrophobic controlled release coating material polymer, due to solubility Porous polymers which are insoluble or hardly soluble in water in the stomach and/or intestine digestive juice often contain more hydrophobic genes. Therefore, the water-soluble pharmaceutical additive can be coated with a polymer which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water to improve the mechanical properties of the controlled release film.

It is particularly noted that after a part of the space of the macromolecular polymer particles as a porogen is replaced by a water-soluble pharmaceutical additive, the macromolecular polymer particles as a porogen need to be dissolved or degraded by the span ( Its meaning is greatly reduced by the following "Ar"). The gastrointestinal fluid only dissolves a small portion of the film polymer in the thin layer to quickly dissolve the water-soluble pharmaceutical additives in the film. After the rapid dissolution of the medicinal additive of water, the surface of a larger amount of the polymer coating film is exposed to the gastrointestinal fluid, so that the dissolution rate of the polymer coating film is greatly accelerated, and the time lag of the drug dissolution is also greatly reduced. The dissolution rate of the drug is greatly accelerated, and the influence of factors in the dissolution of the polymer film is also greatly reduced, and the reproducibility or stability of the drug release is greatly improved. The following is a mathematical model, assuming that the density of the water-soluble pharmaceutical additive and the film polymer which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water is ^, P "The particle size (radius) of the two is ^, r ₂ , respectively, and the weights of the two are respectively, then the relationship between the weight and the particle size is as follows:

W _s , _ P r, ^{: The} water-soluble pharmaceutically acceptable additive coating weight gain/Wi and the particle size increase ΔΙΤ/Γ: of the above formula are:

ΔΓ ― r _: .

1

Γ-

■

Density ratio of the above-mentioned water-soluble pharmaceutical additive to a film polymer which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water

^ When approximating 1, the above formula can be used to obtain different water-soluble medicinal additive coating weight gain W^Wi particle size increase ΔΓ / Γ _: value, as shown in the following table:

7 100. 0%

6 91. 3%

5 81. 7%

4 71. 0%

3 58. 7%

2 44. 2%

1 26. 0%

0. 8 21. 6%

0. 5 14. 5%

0. 4 11. 9%

0. 3 9. 14%

0. 2 6. 27%

0. 1 3. 23%

0. 05 1. 64%

0. 03 0. 990%

0. 02 0. 662%

0. 01 0. 332%

As can be seen from the data in the table, the water-soluble pharmaceutical additive is coated with a polymer film which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water, and the particle size is increased. The increase is very small, usually less than one-third of the weight gain of the polymer coating.

In addition, it is particularly pointed out that the drug release time is advanced and the time lag of the drug dissolution is reduced, which is particularly advantageous for the controlled release preparation of the controlled release drug. Controlled-release preparations of controlled release drugs have limited time to stay in specific sites, such as small intestine-controlled release-release drugs, especially gastric-controlled release-release drugs, especially colon-controlled release-release drugs are particularly short, and control The release time of the release preparation is longer than that of the conventional preparation. Therefore, the advancement of the drug release time is equivalent to the prolongation of the effective release time, thereby facilitating the exertion of the drug efficacy and facilitating the high bioavailability of the drug.

According to the data listed in the above table, the above-mentioned polymer film soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water for use in the present invention is usually used in the porogen in an amount not exceeding the above-mentioned The amount of the medicinal additive dissolved in water before coating

700% (w/w), preferably not more than 300% by weight (weight/weight) of the water-soluble medicinal additive before coating, more preferably the above water-soluble medicinal additive package Preferably, the amount before use is from about 2 to about 200% (weight/weight), more preferably from about 2 to about 100% (weight/weight), more preferably from about 3 to about 50% (weight/weight), optimally 5p〜1. 3p) 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。 Preferably, it is ± 20%, and most preferably ± 10%, which is not specifically indicated in the other places. Generally, less weight gain of the coating is not conducive to the formation of a complete film, and more weight gain will reduce the expected effect.

The term "water-soluble pharmaceutical additive" as used in the present invention means that the solubility in water (temperature 25 ° C) is not less than 33 mg/ml, preferably not less than 50 mg/ml, more preferably not less than 100 mg/ml. More preferably, it is not less than 500 mg/ml, and most preferably not less than 1000 mg/ml, and the average particle diameter is usually from 1 to 500 μm, preferably from 5 to 250 μm, more preferably from 10 to 150 μm. , preferably from 25 to 100 μm and insoluble in or soluble in the stomach and/or intestinal digestive solution (and other components in the coating film containing the polymer) in vivo An inorganic or organic substance in a digestive juice that does not undergo a chemical reaction or that can undergo a chemical reaction but does not form a pharmaceutically unacceptable product including a water-insoluble non-gaseous product, and is not specifically indicated as other The meaning is the same. Too little solubility is not conducive to the formation of pores. Particle sizes that are too large or too small may cause unpredictable problems such as production reproducibility, reproducibility of material release, or poor stability.

Examples of water-soluble pharmaceutical additives useful in the present invention include, but are not limited to, water-soluble amino acids, oligopeptides (2-10 peptides), water-soluble monosaccharides, and pharmaceutically acceptable derivatives thereof. , an oligosaccharide (2-6 saccharide) and a pharmaceutically acceptable derivative thereof, an inorganic salt soluble in water of sodium, potassium or ammonium ions, an organic acid soluble in water having not more than 6 carbon atoms and Its a sodium, potassium or ammonium ion salt soluble in water, an organic base having a water atom number of not more than 6 and a water-soluble salt thereof, a water-soluble nonionic surfactant, soluble A pharmaceutically acceptable nonionic polymer in water (preferably water soluble, low viscosity (herein the term "low viscosity" means that the viscosity of a 2% aqueous solution is not higher than 300 centipoise ( mPa * s), not specifically labeled with the same meaning), and mixtures thereof.

Examples of water-soluble amino acids or oligopeptides which can be used in the present invention are, for example but not limited to: alanine, glycine, serine, proline, asparagine, lysine, glutamine, methotrexate Acid, arginine, hydroxyproline, proline, force peptide (L-alanyl-L-glutamine), glutathione.

Useful water-soluble monosaccharides and pharmaceutically acceptable derivatives thereof include, but are not limited to, levorotatory and/or dextrorotatory monosaccharides and sugar alcohols thereof, for example, but are not limited thereto: triose (eg, D - glyceraldehyde and dihydroxyacetone), butyrate (such as D-erythrose, D-erythrulose, erythritol), pentose (such as D-ribose, D-2-deoxyribose, D-xylose, L arabinose), ketopentose (eg D-ribulose, D-xylulose, xylitol), hexose (eg glucose, galactose, mannitol, mannose), ketohexose (if sugar, Sorbose)), heptose (such as D mannoheptulose, D-sedoheptulose).

Examples of useful water-soluble oligosaccharides and pharmaceutically acceptable derivatives thereof are, but are not limited to, disaccharides (such as maltose, lactose, sucrose, cellobiose, gentiobiose, melibiose) , seaweed disaccharide, isomalt, maltitol, lactitol, trehalose, chitosan, trisaccharide (such as raffinose, chitosan), tetrasaccharide (such as stachyose, chitosan) Four sugars), five sugars (such as mullein, malto-pentose), and six sugars (such as maltohexaose).

Examples of useful inorganic salts of water-soluble sodium, potassium or ammonium ions are as follows, but are not limited to: water-soluble sodium, potassium or ammonium ions of halogen counterions such as bromine, fluorine, iodine and chloride Water-soluble sodium of salt, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, bisulfite, pyrosulfite, nitrate, carbonate, bicarbonate and percarbonate , a salt of potassium or ammonium ions.

Examples of useful organic acids which have a water-soluble carbon number of not more than 6 and water-soluble sodium, potassium or ammonium ion salts are as follows, but are not limited thereto: adipic acid, trans/maleic acid , malic acid, citric acid, tartaric acid, phytic acid, succinic acid, glycolic acid and its sodium, potassium, ammonium salts.

Examples of useful organic bases having a water-soluble carbon number of not more than 6, such as, but not limited to, water-soluble basic amino acids, meglumine, and water-soluble salts thereof.

Examples of useful water-soluble nonionic surfactants are, but are not limited to: water-soluble polyoxyethylene decyl ether surfactants (e.g., Brij 35, Brij 98, Cremophor A6, Cremophor A25) , Ethylan 2560, Ritox 35, Ritox 721, Texofor A1P, Texofor A10, Texofor A14, Texofor A30, Texofor A45, Texofor A60, Volpo S10, Volpo S20, Volpo S20, Volpo CS10, Volpo CS20, Volpo L4, Volpo L23 ) Water-soluble polyoxyethylene castor oil surfactant (eg Jeechem CA-200, Jeechem CAH-60, Jeechem CAH-100, Jeechem CAH-200, Lipocol HCO-βθ Polysorbate 61, Polysorbate 65, soluble in water Polyoxyethylene stearate surfactant (such as Polyoxyl 150 di stearate, Polyoxyl 32 distearate, Polyoxyl 100 stearate, Polyoxyl 50 stearate).

Examples of useful pharmaceutically acceptable water-soluble, nonionic polymers such as, but are not limited to: water-soluble cyclodextrin and cyclodextrin derivatives (e.g., alpha-cyclodextrin, hydrazine) - cyclodextrin, 2,6-dimethyl-β-cyclodextrin, hydroxypropyl/ethyl-β-cyclodextrin, branched-β-cyclodextrin, glycosyl-cyclodextrin, sulfobutyl ether a β-cyclodextrin, a water-soluble low molecular weight cyclodextrin polymer (eg, molecular weight 3000 6000), a glucan binding agent (Dextrates), a water-soluble pharmaceutically acceptable oligosaccharide ( Degree of polymerization 7-20) (eg oligofructose (degree of polymerization 7-20), oligo-isomaltose (degree of polymerization 7-20)), water-soluble dextran (such as 1200-2000 molecular weight) Sugar), hydroxyethyl cellulose (such as low viscosity products with the following trade names: WP 02, WP and QP 09, WP and QP 3 WP and QP 40 WP and QP 300), hydroxyethyl methyl cellulose, hydroxy Propyl cellulose (such as low viscosity products with the following trade names: Klucel JF, Klucel LF, Klucel EF), hydroxypropyl methyl cellulose (such as low viscosity products with the following trade names) Methocel K100 Premium LVEP Methocel F50 Premium^ Methocel E3 Premium LV Methocel E5 Premium LV Methocel E6 Premium LV Methocel E15 Premium LV Methocel E50 Premium LV Low Viscosity Metolose 60SH, Low Viscosity Metolose 65SH, Low Viscosity Metasolose 90SH), Low Viscosity A Cellulose (such as the trade name such as The following products: A15-LV), polyvinyl alcohol, povidone (such as the low viscosity products with the following trade names: Kl l/14, Κ_16/18, Κ- 24/27, Κ- 28/32, Κ- 85/95), PEG (polyethylene glycol) having a molecular weight of 2000 to 20000.

The water-soluble pharmaceutical additive useful in the present invention is preferably selected from the group consisting of dissolving enzymes and microorganisms which are substantially unaffected by acids and bases in the digestive juice, and more preferably substantially free of enzymes and microorganisms in the digestive juice. A water-soluble pharmaceutical additive that affects and slows down, thereby greatly reducing the effects of in vivo factors such as acids, bases, enzymes, and microorganisms in the drug release receptor. Suitable examples of water-soluble pharmaceutical additives which dissolve substantially slowly by the acid or alkali in the digestive juice include, but are not limited to: water-soluble monosaccharides, disaccharides, sugar alcohols and by them a water-soluble oligosaccharide (2-6 saccharide) or an oligosaccharide (degree of polymerization 7-20), a water-soluble neutral inorganic salt, a water-soluble nonionic surfactant, A pharmaceutically acceptable water-soluble, non-ionizing polymer (preferably water-soluble, low-viscosity (herein the term "low viscosity" means that the viscosity of a 2% aqueous solution is not higher than 300 centipoise (mPa · s), which is not otherwise indicated as otherwise), pharmaceutically acceptable polymers), and mixtures thereof.

The above-mentioned usable water-soluble monosaccharides, disaccharides, sugar alcohols and water-soluble oligosaccharides composed of them which are substantially slow to be affected by acids, alkalis, enzymes and microorganisms in the digestive juice ( Examples of 3-6 sugars include, but are not limited to: triose (such as D-glyceraldehyde and dihydroxyacetone), butyrate (such as D-erythrose, D-erythrulose, erythritol), Pentose (such as D-ribose, D-2 deoxyribose, D-xylose, L-arabinose, ketopentose (such as D-ribulose, D-xylulose, xylitol), hexose ( Glucose, galactose, mannitol, mannose, ketohexose (if sugar, sorbose), heptose (such as D-mannoheptulose, D-sedoheptulose), disaccharide (such as maltose, lactose) , sucrose, cellobiose, gentiobiose, melibiose, trehalose, isomalt, maltitol, lactitol, trehalose), trisaccharide (such as raffinose), tetrasaccharide (such as stachyose) ), pentasaccharides (such as mullein, malt pentasaccharide), and hexoses (such as maltohexaose).

Examples of water-soluble neutral inorganic salts which are soluble in the above-mentioned available solutions which are substantially unaffected by acids, bases, enzymes and microorganisms in the digestive juice are as follows, but are not limited thereto: Neutral water-soluble halogen balance Ionic salts such as sodium and potassium chlorides; neutral water-soluble anionic materials such as sodium and potassium nitrates.

Examples of the water-soluble nonionic surfactants which are soluble in the above-mentioned useful solutions which are substantially unaffected by acids, bases, enzymes and microorganisms in the digestive juice are as follows, but are not limited thereto: water-soluble poly Oxyethylene vinyl ether (e.g., Bri j 35, Brij 98, Cremophor A6, Cremophor A25, Ethylan 2560, Ritox 35, Ritox 721, Texofor A1P, Texofor A10, Texofor A14, Texofor A30, Texofor A45, Texofor A60, Volpo SlO, Volpo S20, Volpo S20, Volpo CS10, Volpo CS20, Volpo L4, Volpo L23 ), water-soluble polyoxyethylene castor oil surfactants (eg Jeechem CA-200, Jeechem CAH-60, Jeechem CAH-100, Jeechem CAH-200, Lipocol HC0-60 Polysorbate 61 , Polysorbate 65, water soluble polyoxyethylene stearate (eg Polyoxyl 150 distearate, Polyoxyl 32 distearate, Polyoxyl 100 stearate, Polyoxyl 50 stearate).

Examples of pharmaceutically acceptable water-soluble nonionic polymers in which the above-mentioned usable dissolution is substantially unaffected by acids, bases, enzymes and microorganisms in the digestive juice are as follows, but are not limited thereto: soluble Cyclodextrin and nonionic cyclodextrin derivatives in water (eg α-cyclodextrin, γ-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, hydroxypropyl/ethyl-β-) Cyclodextrin, branched-chain β-cyclodextrin, glycosyl-cyclodextrin, water-soluble nonionic low molecular weight cyclodextrin polymer (eg molecular weight 3000-6000), glucan binding agent ( Dextrates), water-soluble pharmaceutically acceptable oligosaccharides (degree of polymerization 7-20) (eg oligofructose (degree of polymerization 7-20), oligoisomaltose (degree of polymerization 7-20)), Water-soluble glucan (such as dextran with a molecular weight of 1200-2000), hydroxyethyl cellulose (such as low viscosity products with the following trade names: WP 02, WP and QP 09, WP and QP 3, WP And QP 40, WP and QP 300), hydroxypropyl cellulose (such as low viscosity products with the following trade names: Klucel JF, Klucel LF, Klucel EF), hydroxyethyl methyl Cellulose, hydroxypropylmethylcellulose (such as low viscosity products with the following trade names: Methocel K100 Premium LVEP, Methocel F50 Premium^ Methocel E3 Premium LV Methocel E5 Premium LV Methocel E6 Premium LV Methocel E15 Premium LV, Methocel E50 Premium LV , low viscosity grade Metolose 60SH, low viscosity grade Metolose 65SH, low viscosity grade Metolose 90SH), low viscosity methyl cellulose (such as the following products: A15-LV), polyvinyl alcohol, povidone (such as the trade name The following low viscosity products: Kl l/14, Κ-16/18, Κ-24/27, Κ_28/32, Κ-85/95), PEG (polyethylene glycol) having a molecular weight of 2000-200. Preferably, the water-soluble pharmaceutical additive contains or is added with a disintegrant to facilitate dispersion and dissolution of the water-soluble pharmaceutical additive, and to fully exert its effects. Disintegrants useful in the present invention are well known to those skilled in the art and are more specifically described in the Journal of Pharmaceutical Sciences (Vol. 85, No. 11, November 1996). Preferred disintegrants for use in the present invention include, but are not limited to, low substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, crospovidone, croscarmellose sodium or calcium, cellulose fibers. , cross-linked polyacrylic acid, cross-linked succinite resin, alginate, carboxymethyl starch or microcrystalline starch, microcrystalline cellulose and mixtures thereof. Microcrystalline cellulose is preferred. An example of a water-soluble pharmaceutical additive that can be used is a spherical particle product containing crystalline cellulose and lactose, for example, manufactured by Freund Industrial Co., Ltd. (Japan) under the trade name Nonparei l series, 100 to 200 μm. And a spherical granule product Nonparei l 105 (70-140), 100-200 μm containing crystalline cellulose (3 parts) and lactose (7 parts) and containing crystalline cellulose (4.5 parts) and lactose (5.5) Part of the spherical particle product Nonparei l 105 T (70-140); 150~250 μm and spherical cellulose product containing crystalline cellulose (3 parts) and lactose (7 parts) Nonparei l NP-7: 3, 150~ 250 μm and containing spherical cellulose (5 parts) and lactose (5 parts) spherical particle product Nonparei l NP_5: 5, and so on.

The disintegrant is used in an amount of 5 to 50% by weight, preferably 10 to 40%, based on the amount of the water-soluble pharmaceutical additive. The amount of disintegrant used in water-soluble pharmaceutical additives is not excessively high, especially high-performance super disintegrants. Excessive expansion may damage the controlled release film.

The term "polymer soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water" as used in the present invention means that the solubility in water (temperature 25 ° C) is not more than 30 mg/ml, Preferably, it is not more than 10 mg/ml, more preferably not more than 1 mg/ml, and most preferably not more than 0.1 mg/ml of acid, alkali, enzyme and/or microorganism in the digestive juice of the stomach and/or intestine. The pharmaceutically acceptable polymer, which is dissolved or degraded, is not otherwise specifically indicated. Membrane materials which are soluble in the stomach and/or intestinal digestive solution but which are insoluble or hardly soluble in water according to the invention include, but are not limited to, gastric soluble polymers, enteric polymers, both enteric and gastric soluble. Polymers, enzymes and/or microbial degradable polymers, biodegradable polymers and mixtures thereof.

The gastric soluble and/or enteric polymers are typically polymers containing acidic and/or basic groups.

A gastric-soluble polymer suitable for use in the present invention, usually a polymer material which is soluble in water having a pH of 6 or lower and which has a film forming property, including but not limited to (a) cellulose having a mono- or disubstituted amino group. a derivative, (b) a polyethylene derivative having a mono- or disubstituted amino group, (c) an acrylic polymer having a monosubstituted amino group, (d) other types of chitosan and a mixture thereof. Specific examples of (a) include, but are not limited to, benzylaminomethylcellulose, diethylaminomethylcellulose, piperidinylethylhydroxyethylcellulose, cellulose acetate diethylaminoacetate, and Specific examples of (b) include, but are not limited to, vinyl diethylamine-vinyl acetate copolymer, ethylene benzylamine-vinyl acetate copolymer, polyacetal diethylaminovinyl acetate, ethylene Piperidinyl-acetylacetal ethylene copolymer, polydiethylaminomethylstyrene and mixtures thereof; specific examples of (c) include, but are not limited to, Eudragit E (trade name of Rohm-Pharma, ie methacrylic acid) Methyl ester-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, polydimethylaminoethyl methacrylate and mixtures thereof; (d) Other examples include, but are not limited to, polyamino Sugar (Chitosan). Among them, a more preferred gastric soluble polymer is polyacetal diethylaminovinyl acetate or Eudragit E.

Enteric polymers suitable for use in the present invention, generally having a film forming property and soluble in water at pH 5 or higher, including but not limited to (1) carboxymethyl cellulose, (2) having a binary a cellulose derivative of an acid monoester bond, (3) a polyvinyl derivative having a dibasic acid monoester bond, (4) a maleic acid monovinyl polymer, (5) an acrylic polymer, (6) Other classes and mixtures thereof. Specific examples of (1) include, but are not limited to, carboxymethylcellulose, carboxymethylethylcellulose (CMEC), and mixtures thereof, and specific examples of (2) include, but are not limited to, phthalate cellulose , cellulose acetate succinate, methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl succinate Base cellulose esters and the like and mixtures thereof; (3) specific examples include, but are not limited to, dibasic acid monoesters of vinyl polymers, such as polyvinyl phthalate, polyvinyl phthalate Esters, acetyl acetal phthalic acid polyvinyl esters and the like and mixtures thereof; (4) Specific examples include, but are not limited to, vinyl acetate-maleic anhydride copolymer, butyl vinyl ether-maleic anhydride Copolymer, styrene-maleic acid monoester copolymer and mixtures thereof; (5) Specific examples include, but are not limited to, methyl acrylate-methacrylic acid copolymer, styrene-acrylic acid copolymer, methyl acrylate-methacrylic acid-octyl acrylate copolymer, Eudragit L and S, Eudragit FS (for colon positioning). And mixtures thereof; (6) Other examples of special types include, but are not limited to, shellac. Among the more preferred enteric polymers are carboxymethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, Eudragit. L, Eudragit S, Eudragit FS or shellac.

An enteric and gastric-soluble polymer suitable for use in the present invention, usually a polymer which is film-forming and soluble in water at pH 4.5 or lower and water at pH 6 or higher, including but It is not limited to a vinylpyridine-acrylic copolymer, a carboxymethylpolysaccharide or a polyethylene amino acid derivative having a mono- or disubstituted amino group, and a mixture thereof. Specific examples of vinyl pyridine-acrylic acid copolymers include, but are not limited to, 2-methyl-5-vinylpyridine/methyl methacrylate/methacrylic acid copolymer, 2 methyl-5-vinylpyridine/methyl acrylate/ Methacrylic acid copolymer, 2-vinyl-5-vinylpyridine/methacrylic acid/styrene copolymer, 2-vinyl-5-vinylpyridine/methacrylic acid/methacrylic acid formic acid copolymer, 2— Vinylpyridine/methacrylic acid/methacrylic acid copolymer, 2-vinylpyridine/methacrylic acid/acrylonitrile copolymer and mixtures thereof. Specific examples of the carboxymethyl polysaccharide having a mono- or di-substituted amino group include, but are not limited to, carboxymethyl piperidinyl starch, carboxymethylbenzylaminocellulose, and mixtures thereof. Specific examples of the polyvinyl amino acid derivative include, but are not limited to, poly-2-(vinylphenyl)glycine, N-vinylglycine-styrene copolymer, and mixtures thereof.

Examples of suitable biodegradable polymers include, but are not limited to, natural biodegradable polymers (such as fibrin and collagen), aliphatic polyesters (such as polylactide, polyglycolide, polylactide-polyethyl) Lactide, polycaprolactone, polylactide monocaprolactone), polyamine and its copolymer, polyamino acid, polyorthoester, polycyanoacrylate, polyacrylic acid, poly(3_hydroxybutyrate) and copolymers thereof, Polyanhydries poly (methyl vinyl ether-maleic acid), a polyurethane, bioerodible hydrogel (such as N-vinylpyrrolidone or acrylamide and N, N' - methylene to acrylamide copolymerization Hydrogel polymer, which is obtained by condensing an unsaturated diacid with a low molecular weight diol to obtain a vinyl-containing unsaturated prepolymer, and then crosslinking it with vinylpyrrolidone (VP) to obtain a dissolution type of main chain hydrolysis. Hydrogels) and mixtures thereof.

Examples of suitable enzymes and/or microbial degradable polymers include, but are not limited to, polymers containing azo bonds or disulfide bonds (such as polymers composed of acrylic resins and azo aromatic crosslinking groups, by different packages) The coating material (or vinyl monomer) is substituted or unsubstituted with a polymerizable monomer containing an azo aromatic group such as an azo aromatic crosslinking group degraded by an acrylic resin and capable of being deactivated by azo. a polymer obtained by crosslinking or copolymerization of vinyl azo aryl styrene), a special polysaccharide enzyme (such as a glycosidase) which can be produced by intestinal bacteria but which is insoluble or incapable of being digested by small intestinal digestive enzymes and insoluble water Polysaccharides (if gum, dextran, galactomannan, 9 d-glucuronide, etc.) and mixtures thereof.

The (type) selection of the film material which is soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water, in addition to the compatibility with the controlled release coating film polymer, usually according to the nature of the drug and the drug Release requirements, clinical applications, etc. Such as for absorption in the stomach or near the stomach end (such as in the alkali-labile, acid-soluble, gastric or gastric proximal end such as the duodenum has an absorption window or local treatment of the stomach or proximal stomach The drug is suitable for the selection of gastric-soluble polymers; for those that are suitable for absorption in the intestine (such as acid-labile, alkali-soluble, and more toxic side effects to the stomach, such as strong stimulation of the stomach, The intestine is directly used as a therapeutic agent, and the intestine is generally well absorbed, and the intestine is the basic absorption site or needs to be released in a delayed manner. The drug is suitable for enteric polymer; for the absorption in the colon (such as for digestion) Enzyme-sensitive (such as peptides, proteins), for (local, direct) treatment of colonic diseases, have strong toxic side effects on the upper part of the digestive tract (such as the stomach, small intestine), or have a strong stimulation effect The delayed release of the drug is selected from Eudragit S, Eudragit FS, enzymes in the colon and/or microbial degradable polymers. For example, if the drug needs to be absorbed after a certain period of time to be absorbed (ie, the drug release requires time lag, that is, delayed release), the preparation may be a polymer that dissolves or degrades slowly, such as a biodegradable polymer (eg, Aliphatic polyester polymers), digestive enzymes and/or polymers with slow degradation of the digestive tract microorganisms (eg polysaccharides, pectin, peach gum). Among them, for the absorption in the intestine (such as acid-labile, alkali-soluble, more toxic side effects on the stomach, such as a strong stimulation of the stomach, directly in the intestinal part of the treatment, in A drug which is substantially well absorbed in the intestinal segment, which is a basic absorption site of the intestinal segment or which needs to be released for a prolonged period of time. It is most preferred in the present invention to select an enteric polymer. In general, the above-mentioned polymer which is soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water and the above-mentioned water-soluble pharmaceutical additive cannot undergo chemical reaction or chemical reaction in the body digestive juice. Does not produce pharmaceutically unacceptable products including water-insoluble, non-gaseous (ie, solid or liquid at room temperature (25 ° C)), because if it is insoluble in water and at room temperature (25 ° C) Under the production of solid or liquid products, they will adhere or deposit in the formed drug release pores, so that the release of the drug is blocked and the speed is slow.

In addition, different thicknesses (such as an increase in the thickness of the film) which are soluble in the gastric and/or intestinal digestive solution but insoluble or hardly soluble in water, and the type of the film material, the type of drug release rate adjusting substance And different amounts (increment or decrease in the amount of drug release rate adjusting substance, see below), etc., etc., or tablets or tablets which can release the drug at different intervals, which are combined together (for example, capsuled or bonded together) Pulsed or gapped drug delivery system.

A preferred porogen of the present invention is an example of a particulate material of a water-soluble pharmaceutical additive coated with a polymer film which is soluble in the stomach and/or intestinal digestive solution but which is insoluble or hardly soluble in water. a polymer soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water is selected from the group consisting of acidic and/or basic groups of water-insoluble polymer materials soluble in the digestive juice, ie enteric And/or a gastric-soluble polymer, the water-soluble pharmaceutical additive coated therewith is selected from the opposite of the acidity and alkalinity of the polymer and is neutralized in the digestive juice in the body but is not formed including A pharmaceutically acceptable product which is insoluble in water and which is a product of a non-gaseous (ie solid or liquid at room temperature (25 ° C)), which is soluble in water at room temperature (25 ° C) A basic substance or an acidic substance, the above-mentioned usable basic substance is selected from, but not limited to: an inorganic basic salt of a water-soluble sodium, potassium or ammonium ion, and a water-soluble carbon atom of not more than 6 a solid organic base at room temperature (25 ° C) (such as diamine, Methylamine) and its basic salt, a water-soluble organic polybasic acid having not more than 6 carbon atoms, a salt of a basic sodium, potassium or ammonium ion, and a mixture thereof, the above-mentioned available acidity The substance is selected from, but not limited to: a solid organic acid (such as adipic acid, trans/maleic acid, malic acid, hydrazine) which is soluble in water and has a carbon number of not more than 6 at room temperature (25 ° C). Acid, tartaric acid, phytic acid, succinic acid) and acidic sodium, potassium or ammonium acid salts thereof. The acidic or alkaline water-soluble medicinal additive has the strong binding force in the coating film, and the polymer has a strong binding force in the film, which is beneficial to improve the mechanical properties of the film and dissolve the polymer. Or the degradation has a good promoting effect, the drug release time is advanced earlier, and the drug dissolution exhibits a greater reduction in time lag.

A more preferred porogen of the present invention is an example of a particulate material of a water-soluble pharmaceutical additive coated with a polymer film which is soluble in the stomach and/or intestinal digestive solution but which is insoluble or hardly soluble in water. The polymer which is soluble in the stomach and/or intestinal digestive juice but which is insoluble or hardly soluble in water is selected from the group consisting of an acid-insoluble polymer material which is soluble in the digestive juice, that is, an enteric polymer. The water-soluble pharmaceutical additive coated by the same is capable of reacting with the gas in the body to produce gas (including but not limited to C0 ₂ , S0 ₂ , 0 ₂ , Cl ₂ ) but does not form water-insoluble and normal temperature. (25 ° C) is a solid or liquid product and a pharmaceutically unacceptable product of water-soluble pharmaceutical additives, such water-soluble pharmaceutical additives can be selected as examples of sodium bicarbonate, Potassium or ammonium salt, sodium, potassium or ammonium salt of carbonate, glycine carbonate, carbonate of L-lysine, carbonate of arginine, sodium, potassium or ammonium carbonate of amino acid, Sodium, potassium or ammonium glycosyl carbonate, sodium, potassium or ammonium sulfite, sulfurous acid Root sodium, potassium or ammonium salts, sodium pyrosulfite root, potassium or ammonium, sodium, potassium or ammonium percarbonates, and mixtures thereof. They not only have a strong binding force with the acidic polymer in the film, but also help to improve the mechanical properties of the film, and have a stronger promoting effect on the dissolution or degradation of the polymer because of the interaction between the two. The main products are water-soluble polymer salts and particularly useful gases such as carbon dioxide, sulfur dioxide, etc., while other products are water or water-soluble small molecular salts, so it is particularly beneficial for soluble in stomach and / or intestinal digestive juices. However, the dissolution of the polymer which is insoluble or hardly soluble in water is particularly advantageous for the rapid formation of the micropores of the drug release, the drug release time is more advanced, the dissolution time lag is further reduced, the drug is rapidly dissolved, and the drug is improved. bioavailability.

In the above polymer film (dry) which is soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water, soluble in the stomach and/or intestinal digestive juice but insoluble or almost insoluble in water The polymer is preferably used in an amount of from 35% to 100% by weight, more preferably from 50% to 100% by weight, most preferably from 65% to 100% by weight, based on the above-mentioned soluble in the stomach and/or The total dry weight of the polymer film of the intestinal digestive juice but insoluble or hardly soluble in water. If necessary, plasticizers and other general-purpose additives may be added to the film, as described below.

Soluble by the above polymer film which is soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water The amount of particulate medicinal additive of water (ie, porogen, stomach and/or enteric coating + water soluble core) in the dispersion (body) suspension coating liquid is thus skilled in the art. It is determined by the nature of the drug and the desired rate of drug release. The amount of the porogen is usually determined by the particle size, the type and amount of the controlled release film polymer, the nature of the drug, the desired release rate, etc., usually 5% to 95% (weight ratio or volume ratio). Preferably, it is from 25% to 90%, more preferably from 40% to 85%, based on the total dry weight or volume of the controlled release coating component. Generally a relatively high level of porogen is beneficial to improve the mechanical properties of the controlled release coating film.

Since the amount of the porogen is the main factor affecting or determining the porosity of the controlled release coating film, the porosity of the controlled release coating film is usually from 5% to 95%, preferably from 25% to 90%, more preferably The ground is located at 40%~85%. The term "porosity" as used herein refers to the proportion of the space left by the porogen dissolved or degraded in the release film to the volume of the original intact controlled release film, which is not specifically indicated elsewhere. For ease of calculation, and because the dissolution or degradation of the porogen does not affect the intrinsic or external size of the original release coating film, the "porosity" can also be used as the porogen in the controlled release coating. The proportion of the weight of the controlled release film is approximately expressed. Therefore, "porosity" can be calculated in the present invention by the following two calculation formulas:

Formula 1 : Volume of porogenic material _ Weight of porogenic material / Density of porogen

Porosity =

Volume of ί empty release film = volume of technical release film

―The weight of the porogen/the density of the porogen

= surface of the preparation 厚度 controlled release thickness of the pancreas Equation 2:

The weight of the porogen

Porosity =

The weight of each component of the controlled release film

In order to delay the dissolution or degradation of the above-mentioned dilute-soluble but water-insoluble coating film, and to adjust the drug release rate, a drug release rate adjusting substance such as an acid or an alkaline pharmaceutical additive may be added to the film, such as an embodiment. The membrane is added with an acid or a base such as an alkali or acid which is soluble in the digestive solution but insoluble in water to delay the rate of drug release. Further, as an embodiment, an organic acid such as citric acid is added to the gastric-soluble polymer coating film to promote dissolution of the coating film, or an organic base such as a basic amino acid or meglumine is added to delay dissolution of the coating film. As still another embodiment, an organic acid such as decanoic acid is added to the enteric polymer film to delay dissolution of the film. As another embodiment, in a biodegradable polymer film, such as an aliphatic polyester (such as polylactide, polyglycolide, polylactide-polyglycolide, polycaprolactone, polypropylene) Ester monocaprolactone), polyamino acid, polyorthoester, polycyanoacrylate, organic base such as basic amino acid, meglumine or the like or an organic acid such as citric acid to promote dissolution of the coating film. The acid or base which can be used herein is a solid or alkaline substance which is not soluble at room temperature (25 ° C) which does not react with a film polymer which is soluble in the digestive solution but insoluble in water to form a water-insoluble product, and is suitably used. The basic substance in the present invention is selected from, but not limited to, an inorganic basic salt of water-soluble sodium, potassium or ammonium ions, and a water-soluble carbon atom having a carbon number of not more than 6.

(25 ° C) solid organic base and its basic salt, water-soluble organic polybasic acid having not more than 6 carbon atoms, basic sodium, potassium or ammonium ion salts and mixtures thereof The above-mentioned usable basic substance is selected from, but not limited to: the acidic substance is selected from the group consisting of organic acids having a water-soluble carbon number of not more than 6 at room temperature (25 ° C) and acidic sodium or potassium. An acid salt of ammonium ion. The amount and type of these materials in the film which is soluble in the stomach and/or intestinal digestive juice but which is insoluble or hardly soluble in water is thus determined by the skilled person in the art based on the nature of the film material and the desired The rate of drug release, etc., is usually from 1% to 50% by weight, preferably from 3% to 30%, more preferably from 5% to 20%, based on the dry weight of the controlled release film component. . In order to prevent the above from being dissolved by water during the preparation, a thin layer of a coating which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water may be applied, or a non-aqueous coating technique may be employed. The thickness of the coating layer is usually from 1% to 100%, preferably from 2% to 50%, more preferably from 3% to 30%, of the thickness of the inner layer.

In order to obtain a higher functional performance of the controlled release coating, it is preferably soluble in the stomach and/or intestinal digestive juice but insoluble or almost The water-insoluble coating film polymer is selected to be completely compatible or partially compatible with the controlled release coating film polymer, i.e., a polymer that is not completely incompatible, particularly a fully compatible polymer. More preferably, in order to further obtain better drug release stability of the controlled release film, the film polymer and the controlled release film polymer which are soluble in the stomach and/or intestinal digestive solution but are insoluble or hardly soluble in water The higher the compatibility, the lower the amount of the above-mentioned polymer film which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water, and the lower the amount of the water-soluble pharmaceutical additive before coating; When the film polymer which is soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water is selected from a polymer which is completely compatible with the controlled release film polymer, the above is soluble in the stomach and/or The amount of the polymer film of the intestinal digestive solution which is insoluble or hardly soluble in water is from 3 to 50% by weight, preferably from 5 to 30%, before the coating of the above water-soluble pharmaceutical additive. (weight); when the film polymer which is soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water is selected from a polymer which is partially compatible with the controlled release film polymer, the above is soluble in the stomach. And/or the amount of the polymer film which is insoluble or hardly soluble in the intestinal digestive juice and the above The amount of the water-soluble medicinal additive before coating may be relatively large, such as 5~80% by weight, preferably 10~50%, before the coating of the water-soluble medicinal additive. (weight), more preferably 15 to 30% by weight.

The method for judging the compatibility between polymers will be described below. There is also a "similar compatibility" principle for interpolymer compatibility and can therefore be used to evaluate the compatibility of polymer blends. For example, Eudragit E. Eudragit L. Eudragit S Eudragit FS has good compatibility with Eudragit RL and Eudragit RS.

Since the solubility parameter can characterize the amount of cohesive force between polymer molecules, it can be used to evaluate the compatibility of polymer blends. 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 system has 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. At different polymer concentrations, the viscosity is plotted against the percent composition of the polymer, as the relationship is linear, indicating that the polymer is Complete compatibility at the molecular level; if the relationship is non-linear, it is partially compatible; when it is completely incompatible, the relationship is S-shaped. 4), thermal method and dynamic mechanical analysis method (measuring glass transition temperature Tg), the method is particularly recommended by the present invention, and there are three Tg change trends in the polymer alloy system, assuming that the Tg of the two polymers in the binary alloy system are respectively For Tg^BT _g2 (T _gl < Tg ₂ ), (1), fully compatible system: only one Tg appears, T _gl <Tg<Tg ₂ ; (2), completely incompatible system: two Tg appear, Respectively and _2; (3), partially compatible system: two T _gl ', 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.

The polymer suitable for use in the controlled release coating of the present invention may be a pharmaceutically acceptable block polymer or copolymer which is insoluble or hardly soluble in water and gastric and intestinal digestive juices, typically a hydrophobic polymer. Suitable polymers which are insoluble or hardly soluble in water and stomach and intestinal digestive juices may be selected from, but not limited to, cellulose esters, acrylic polymers which are insoluble or hardly soluble in water and stomach and intestinal digestive juices. , polyvinyl acetates, polyvinyl chlorides and combinations thereof. 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, nitrocellulose, triam Acid cellulose, cellulose tridodecanoate, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, polyvinyl acetate, methacrylic acid a polymer, a terpolymer of vinyl chloride-vinyl alcohol-vinyl acetate, a vinyl chloride-ethylene acetate copolymer, a polycarbonate, a polymethyl methacrylate, an ethyl acrylate, a methyl acrylate polymer, Polyvinyl chloride, polyethylene, polyisobutylene, poly(ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride) and combinations thereof.

Commercially available latex, pseudo-latex and emulsion-controlled release coatings of the above polymers, such as ethyl cellulose (EC) are available: Aquacoat® and Surelease®, acrylics are: Eudragit® RS30D, Eudragit® RE30D And Eudragit® RL30D, cellulose acetate (CA): CA398-10 latex, polyvinyl acetate: Kol l icoat SR 30 D and K0LLID0N SR.

5〜19%的聚乙烯酯和为例如。 The other example of the polymer which is insoluble or hardly soluble in water and the digestive juice of the stomach and the intestines is 80.95. 0. 5~10% aqueous dispersion of polyvinyl alcohol terpolymer (body) coating liquid.

Another useful example of a polymer that is insoluble or hardly soluble in water and stomach and intestinal digestive juices is an aqueous dispersion containing 50 to 100% polyvinyl chloride and 0 to 50% polyvinyl acetate copolymer. ) Coating liquid.

The ratio of the controlled release 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. It is from 5% to 95% by weight, preferably from 10% to 75%, more preferably from 15% to 60%, based on the dry weight of the controlled release coating component. Other general additives that can be added to the film are described below.

In order to improve or enhance the mechanical properties and drug release stability of the controlled release film, especially when the temperature is lower than its glass transition temperature (Tg), the glassy toughness and impact resistance of the polymer and/or high temperature increase The high dimensional stability and strength of the polymer at its glass transition temperature (Tg), the present invention can be incorporated into a controlled release coating film to add a polymer reinforcing agent and/or a toughening agent and other mechanical property improving agent.

The mechanical property improving agent is usually used in an amount of from 0.5 to 40% by weight, preferably from 1% to 25%, more preferably from 2% to 15%, based on the dry weight of the film component.

In order to obtain a film having excellent properties, the present invention may add two or more kinds of water-insoluble polymers as a mixed film forming agent. In order to make these film-forming polymers have better compatibility, the adhesion between the polymers is increased, a stable structure is formed, the dispersed phase and the continuous phase are made uniform, and phase separation is less likely to occur, and the present invention can be coated. A compatibilizing agent which is compatible by the action of blocking or grafting or the like is added to the liquid. The amount of the compatibilizer is usually from 0.1% to 40% by weight of the film-forming polymer, preferably from 0.5% to 25%, more preferably from 1% to 10%.

A general additive material may be added to the coating liquid of the present invention. The amount and application of the universal 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-adhesives (separators), stabilizers, pigments, defoamers, antioxidants, penetration enhancers, shine 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 advantageous properties imparted to pharmaceutical dosage forms. 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.

The coatings which are soluble in the stomach and/or intestinal digestive juice but which are insoluble or hardly soluble in water and the additives commonly used in the controlled release coatings are described below.

• Plasticizer

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. A suitable glass transition temperature (Tg) is usually in the range of 0 to 70 ° C, preferably 10 to 50 ° C, and most preferably 15 to 40 ° C.

If necessary, plasticizers of different properties such as water-soluble, water-insoluble or water-insoluble plasticizers can be utilized to adjust the release rate of the controlled release coating film.

The plasticizer is generally 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 C _{1 () to} C ₁₆ ) an aliphatic or aromatic mono- to tricarboxylic acid with ~ (: ₈ (preferably C _{2 to} C ₆ , special) Preference is given to c ₂ c ₅ ) lipophilic esters formed by aliphatic alcohols. Examples of such plasticizers are dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, triethyl citrate, acetyl citrate Ethyl ester, triacetin, tributyl alginate, sorbitan ester, sucrose ester. Examples of other useful plasticizers are 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 50% by weight, preferably 10 40% by weight, particularly preferably 10 30% by weight, based on the dry weight of the film component.

•Anti-adhesive (separator)

Anti-adherents (separators) are generally beneficial hydrophobic materials and are typically added to the spray suspension. They prevent the accumulation of nuclei during the 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 38. The amount of the polymer in the coating layer of the present invention is 0.55% by weight (by weight). In a particularly advantageous embodiment, the separating agent is added as a final coating in concentrated form. The coating is carried out in powder form or by spraying from a suspension of 5 30% solids. The amount of the dosage of the pharmaceutical dosage form is 0.12%.

•stabilizer

The stabilizer is preferably an emulsifier or a surfactant, that is, a certain interface active material, which stabilizes the dispersion (body). 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 content of the stabilizer is 1 15% by weight, preferably 5 10% by weight, based on the wet weight of the component of the dispersion liquid.

• Pigments

Usually used in controlled release coatings. Rarely added as a soluble pigment. Alumina or an iron oxide pigment is generally dispersed and added. Titanium dioxide is used as a white pigment. The amount of the pigment added in the coating layer of the present invention is 20 60% by weight of the polymer mixture. However, due to the high pigment binding ability, the addition amount can be as high as 100% by weight.

• Defoamer

The antifoaming agent is generally dimethicone.

All additives used in the film must in principle be pharmaceutically acceptable, non-toxic and not dangerous to the patient in the drug. The following is a description of the core material.

Core materials useful in the coatings of the present invention include, but are not limited to, regular, irregular forms of tablets, granules, pellets, crystals, drug-loaded resins. The granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules, the granules Other pharmaceutical auxiliaries.

The active ingredient (or drug or biologically active substance) used in the present invention is generally not particularly limited. The active ingredient to be used in the present invention may be any of the above-mentioned pharmaceutically or nutritionally therapeutic or preventive substances. The active ingredients which can be used in the present invention are as follows: central stimulant, analgesic, antipyretic analgesic, anti-inflammatory analgesic, anti-gout, anti-shock palsy, antipsychotic, anti-anxiety, antidepressant , antiepileptic drugs, sedatives, hypnotics, anticonvulsants, autonomic nervous system drugs, calcium antagonists, drugs for the treatment of chronic heart failure, antiarrhythmic drugs, angina pectoris, peripheral vasodilators, blood pressure lowering drugs, Regulating blood lipids and anti-atherosclerotic drugs, respiratory drugs, antacids and peptic ulcer drugs, gastrointestinal antispasmodics, digestive drugs, antiemetics, emetics and gastrointestinal drugs, hepatobiliary diseases Medication, urinary system drugs, drugs that affect blood and hematopoietic system, antihistamines, allergic reaction medium release agents, adrenocortical hormones and adrenocorticotropic hormones, sex hormones and gonadotropins, islet hormones and other drugs that affect blood sugar, thyroid gland Hormone drugs and antithyroid drugs, penicillins, cephalosporins, beta-lactamase inhibitors, ammonia Glycosides Classes, tetracyclines, macrolides, antituberculosis drugs, antifungals, antivirals, antitumor drugs, drugs that affect the body's immune function, vitamins and nutrients, diet pills or herbal extracts.

Since the osmotic pump type preparation can simultaneously push out various components of the Chinese herbal medicine extract into the preparation, there is no problem that the release of the active ingredient is not synchronized due to the different nature of the ingredients, and therefore, the present invention is particularly suitable for the need for controlled release of Chinese herbal medicines. A controlled release formulation of the extract, especially an osmotic pump formulation.

Examples of drugs which are particularly suitable for the preparation of gastric-soluble membrane-controlled release preparations in the present invention include, but are not limited to, ciprofloxacin, captopril, furosemide, ursodeoxycholic acid, compound digestive enzymes, traditional Chinese medicine gynecological daughters, and irbes Sartan, glimepiride, leflunomide, medimycin, irbesartan, amoxicillin, cefuroxime, ceftriaxone, cefpodoxime, clarithromycin, chlorocephalosporin, azithromycin, cephalosporin Gram, cefadroxil, acyclovir, diltiazem, captopril, simvastatin, lovastatin, etodolac, ketorolac, ranitidine, famotidine, fenbutin Phenazepine, pseudoephedrine, phenylpropanolamine, dextromethorphan, dextrophene, bromocriptine, cyclosporine, baxyphene, allopurinol, (+) alpha-aminomethyl-2-methoxy Sulfonic acid benzyl benzyl alcohol (patent application EP842148 Example 3. 6 disclosed) or 3'-(2 amino-l-hydroxyethyl- 4' fluoromethanesulfonate aniline (NS49) other examples such as benzamides, Specific examples such as metoclopramide, verapride, alibidine, clopiride, more special It is amisulpride, thiophene, sulpiride and its salts; in addition, there are α ΐ-antagonists, specific examples such as terazosin and alfuzosin and their salts, especially alfuzosin hydrochloride.

Examples of drugs which are particularly suitable for the preparation of enteric membrane controlled release formulations in the present invention include, but are not limited to, 5-aminosalicylic acid and salts thereof such as zinc salts, calcium acamprosate, adipinepine, alendronate, Azithromycin, azinamide and its combination preparations, aspirin, esomeprazole and its salts such as magnesium, sodium, strontium, ilaprazole, citrate, dexamethasone, omeprazole and Salts such as magnesium salts, sodium salts, oxaprozin, pimeprazole, benzoyl metronidazole, bisacodyl, piroxicam, propylthiouracil, bromelain and its combination, hepatocyte growth factor, Aceclofenac, cephalexin trimethoprim, allicin, elastase, citicoline sodium, dirithromycin, adenosine succinate, succinate thioadenosine methionine, tosy gland Glycosylmethionine, adenosylmethionine, sodium p-aminosalicylate, faropenem sodium, fenoprofen calcium, nitrofurantoin, coenzyme Q10, bovine fetal liver extract and its combination preparation, glutamine and its compound preparation, double acetylene loss Carbon ester and its compound preparation, compound phosphoric acid Enzyme, glipizide metformin compound preparation, glutathione, reduced glutathione, bone peptide, diammonium glycyrrhizinate, guimeixin, cyclophosphamide and its compound preparation, erythromycin, pentoxifylline Thiamphenicol, guitarmycin, methimazole, mefenamic acid, arginine ketoprofen, clarithromycin, matrine, recombinant B subunit/bacterial cholera vaccine preparation, Bacillus subtilis II Combination of live bacteria, bifid triple live bacteria, lysine, rabeprazole sodium, ranitidine, tiopronin, gentamicin sulfate, ferrous sulfate glycine complex, norfloxacin, Rufloxacin, lomefloxacin, chlorocrometol, sulfasalazine, hexamethyl melamine, roxithromycin, mycophenolate sodium, fosfomycin and its salts such as calcium salts, mepacrol, melo Xikang, mazakavir, metacycline, magnesium aspartate, paroxetine, mifepristone, misoprostol, papain, naproxen, brain protein hydrolysate, nimesulide, Uracil tegafur combination preparation, patrazole, pantoprazole and its salts such as sodium , sodium aescinate, troxerutin brain protein hydrolysate compound preparation, didanosine, lysozyme, adenosine triphosphate, tribendimidine, serrapeptase, sparfloxacin, telmisartan, diclofenac sodium, Ketoprofen, sodium sulphate, cytochrome C, thymosin, duloxetine, doxycycline, metformin, fluoxetine, sinomenine, acetyl-L-carnitine, acetylspiramycin, levamisole, pancreas Kininogenase, trypsin, insulin, acetylsalicylic acid, pentoxifylline, simvastatin, erythropolis, colloidal pectin, taurine, calf blood deproteinized extract, rasasin,蚓 kinase, dexketoprofen, zaltoprofen, neutral protease, levonorgestrel, levonorgestrel ethinyl estradiol, sodium chlorophyll sodium, iriparazole, etodolac, magnesium isoglycyrrhizinate, vitamin E nicotinate.

Examples of traditional Chinese medicine preparations which are particularly suitable for the preparation of enteric film controlled release preparations include, but are not limited to, garlic extract, saponin extract, bear bile, cordyceps mycelium, dragon blood, and Aspergillus oryzae trypsin. (慷彼申), Zhiling Mycelium, Myrtle Oil, Huachansu or the trade name is Biyuanshu, Xiaoyan Lidan, Futongning, Longjing Tieshu, Cidan, Fupu cold, compound Eucommia, Compound berberine, cold flu, Huixuesheng, Jiangxieling, Jiangtangjia, Leiwan, Liquor and lipid-lowering, Longxiang Pingchuan, Naomaitai, Asthma and anti-inflammatory, Qishengjing, Qishengli, Xinnaokang, Maixuekang, Paju Pill, Qipi, Qianlieping, 芩Redness and Cough, Yexiazhu, Yiyin Xiaoke, Cushen, Zhimaikang, Ji Ruxin, Xiaolong, Sanqitongshu, male treasure, Spring blood, good governance, sputum, curcuma, Baibao Dan, Dan Huangqi, Compound Eucommia ulmoides, Gengnian, Kangxi, Liuwei Dihuang, Liuweimuxiang, Thrombolytic Brain, Shenan, Xuesaitong, Cough, Compound Yew, Xiaoshuan, Cold Chinese patent medicine for clearing heat, Qilian, Keji Gutai, Naoliqing or Yunzhi Gantai.

Representative examples of drugs that are particularly suitable in the present invention for making colon-soluble membrane-controlled release formulations include, but are not limited to, balsalazide, sulfasalazine, azosalicylic acid, 5-aminosalicylic acid, and salts thereof. Such as zinc salt, ibuprofen, hydrogenated prednisone, dexamethasone, budesonide, beclomethasone, fluticasone, tioxocortal, hydrocortisone, metronidazole, tinidazole, metronidazole Carbazole, cyclosporine, methotrexate, piperidinone, 5-fluorouracil, bisacetoxyphenylmethylpyridine, senna, thymosin, insulin, vasopressin, growth hormone, Colony stimulating factor, calcitonin, immunoglobulin, glibenclamide, diltiazem, verapamil, nifedipine, thiomethionine, benazepril, enalapril, theophylline , naproxen, cycloflurazine, acyclovir, omeprazole, lovastatin, alendronate, desmopressin, metformin, methoxybenzamine, cisapride, tetrahydroamino Acridine, their mixture and microbial regulator (probioti _CS ).

Examples of drugs which are particularly suitable in the present invention for the preparation of controlled release formulations for extended release include, but are not limited to, Gepirone, risedronate, paroxetine and its salts, moxonidine, a-lipoic acid and Its derivatives, biguanides (such as metformin and its salts) drugs, gabapentin, 1R, 2S-methoxyamine, clarithromycin, proton pump inhibitors and their salts (such as lansoprazole, omeprazole, 泮托Lazosole, rabeprazole, esomeprazole, tetoprazole).

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

The core material may contain other pharmaceutical auxiliary agents besides the active substance, such as slow release materials, porogens, fillers, binders, disintegrants, disintegrators, lubricants (including flow aids, anti-adhesives). ) an essential component such as an osmotic active substance (ie, an osmotic pressure promoter) or a permeation-promoting polymer (a penetration enhancer). In addition, it may also contain solubilizers, suspending agents, sweeteners, fragrances, pigments, absorbents and surfactants (such as wetting, dispersing, solubilizing, emulsifying, etc.). The pharmaceutical auxiliaries and their amounts 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. Method for preparing controlled release preparation

Another object of the present invention is to provide a method for preparing a controlled release preparation having improved properties. The following is a detailed description of each of the basic steps in the preparation method of the controlled release preparation.

1), preparing a core material containing a drug

The method of preparing the core material containing one drug is not particularly limited. Usually, the preparation method is to directly pulverize the components of the pharmaceutically active substance, the pharmaceutical auxiliary, etc. by direct extrusion, dry, wet or sintered granules, extrude and subsequently round, wet or dry granulation or direct pelleting ( For example, on a disc) or a powder (powder layer) is bonded to an inactive material sphere (particle) or an active substance-containing particle, or the above-mentioned particles are further formed into a sheet in a certain manner such as pressing.

2), preparing a porogen, that is, the particles of the water-soluble medicinal additive are coated with a pharmaceutically acceptable plasticizer or a plasticizer-free soluble in the stomach and/or intestinal digestive juice. Polymer film that is insoluble or almost insoluble in water

In one embodiment, the water-soluble pharmaceutical additive is dispersed and suspended in a gastric or/or intestinal digestive solution containing or containing no pharmaceutically acceptable plasticizer, but is insoluble in Or an (organic or aqueous) solution or (organic or aqueous) dispersion of a polymer that is substantially insoluble in water (wherein the particle size of the polymer in the organic dispersion should generally be comparable to the particle size of the polymer in the aqueous dispersion or Finer) Medium (add other additives such as plasticizer if necessary) and mix well. The coating layer is prepared from the core material by a coating method such as casting, dipping, painting or spraying using the solution or suspension obtained above. It is preferably carried out by spraying.

In another embodiment, the water-soluble pharmaceutical additive is suspended in the air, and the suspended particulate matter is sprayed with a pharmaceutically acceptable plasticizer or a plasticizer-free soluble stomach and/or intestine (organic or water) solution or (organic or water) dispersion of a digestive liquid but insoluble or almost insoluble in water (additional coating additives such as plasticizer if necessary), by spraying Coating.

In a particular embodiment, the water-soluble pharmaceutical additive and the polymer coated with it soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water can be digested in water or in vivo. a chemical reaction occurs, in which case non-water is used (not The organic solvent containing water is used as a solvent or dispersant for the polymer, and the above operation is carried out. Otherwise, the two are reacted in advance in an aqueous medium.

The content of the polymer in the (organic or water) solution is usually from 1 to 15%, preferably from 2 to 10%, more preferably from 3 to 8%. The content of the polymer in the (organic or water) dispersion (body) is usually 2 to 30%, preferably 5 to 20%, more preferably 8 to 15%. The aqueous dispersion (body) may also contain a certain amount of an organic solvent, and its content is usually from 1 to 20%, preferably from 1 to 10%, more preferably from 2 to 5%. The particle size of the polymer in the dispersion, especially in the organic dispersion, should generally be no greater than 50 μm, typically no greater than 10 μm, preferably no greater than 1 μm, more preferably no greater than 300 calendars, more preferably It is not more than 100 calendars, more preferably not more than 30 nm, and most preferably not more than 10 nm.

Whether the particulate matter of the water-soluble medicinal additive is coated with the above-mentioned polymer film soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water is completely covered depending on whether the two can Whether a chemical reaction occurs in water or in vivo digestive juice and whether an aqueous medium is used in the following controlled release coating film coating process, that is, if the two can be chemically reacted in water or in vivo digestive juice and the controlled release film coating process is employed Water as a dispersing agent for a controlled release coating film polymer or an aqueous organic solvent as a solvent or dispersing agent for a controlled release coating film polymer, generally requiring the above-mentioned soluble coating of particles of a water-soluble pharmaceutical additive The polymer film of the stomach and/or intestinal digestive juice but which is insoluble or hardly soluble in water must be intact, and the permeability of the film to water must be 0, as by the healing treatment described below, otherwise Reacting in an aqueous medium in advance; if the controlled release film coating process uses a non-aqueous organic solvent as a solvent or dispersant for the controlled release coating film polymer, generally no particulate matter is required for the water-soluble pharmaceutical additive. Above soluble coating the stomach and / or intestine digestive juice but insoluble or hardly water-soluble film coating polymer must be complete.

The film formation process is carried out by energy input independent of the coating method and can be done by convection (heat), radiation (infrared or microwave) or conduction. The solvent used as a solvent or suspending agent for the coating is thus evaporated off, and if necessary, vacuum evaporation may be applied. This process requires higher drying efficiency, so the present invention often employs high efficiency coating equipment (e.g., fluidized bed).

Water-soluble pharmaceutical additive using the above-mentioned solution containing a pharmaceutically acceptable plasticizer or a plasticizer-insoluble solution which is soluble in the stomach and/or intestinal digestive solution but which is insoluble or hardly soluble in water. After the dispersion is coated, the amount of the polymer film is usually not more than 700% (weight/weight) of the water-soluble pharmaceutical additive before coating, preferably not more than the water-soluble drug. 300% (weight/weight) of the amount before the coating with the additive, more preferably from about 2 to about 200% (weight/weight) of the water-soluble pharmaceutical additive before coating, more preferably 2 to about 100% (weight/weight), more preferably about 3 to about 50% (weight/weight), most preferably about 3 to about 30% (weight/weight).

The temperature for coating 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 and fused. Film formation). The temperature for coating is usually higher than the minimum film forming temperature of 10 to 20 °C. If the temperature is too low, cracks may occur in the film; if the temperature is too high, the polymer will be excessively softened, resulting in adhesion of the film.

When coating, it is usually preheated to 20~90 ° C, preferably 30~70 ° C, more preferably 30~50 ° C, first coated at a lower spray rate, until the surface of the core material has been coated After the thin film is coated, the spray rate is increased until the end of the coating.

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. For example, fluidized bed coating, such as coating temperature, fluidizing volume, atomization pressure and spray rate, can be optimized according to the actual situation.

3), coated controlled release film

In a preferred embodiment, the porogen is the above water-soluble pharmaceutical additive coated with the above-mentioned polymer film which is soluble in the stomach and/or intestinal digestive solution but which is insoluble or hardly soluble in water. The particulate matter is dispersed and suspended in the above (organic or aqueous) dispersion containing a pharmaceutically acceptable plasticizer or a polymer which is insoluble or hardly soluble in water and stomach and intestinal digestive juices. In particular, in the aqueous dispersion (body), if necessary, other controlled release film additive bases may be added to the dispersion (body) and mixed uniformly. The pH of the above aqueous dispersion (body) should be within the pH range in which the porogen coating film is insoluble or degraded or hardly dissolved or degraded, so the pH of the aqueous dispersion (body) should generally be The porogen is adjusted to a pH range in which the porogen coating film does not dissolve or degrade before it is added. The above-mentioned polymer which is insoluble or hardly soluble in water and stomach and intestinal digestive juice is usually contained in the dispersion (body) in an amount of 2 to 30%, preferably 5 to 20%, more preferably 8 to 15%. The dispersion (body) may further contain a certain amount of other solvent which is insoluble in the gastric or/or intestinal digestive solution but insoluble or hardly soluble in water, and the content thereof is usually from 1 to 20%, preferably. Ground 1 to 10%, more preferably 2 to 5%. The above organic dispersion (body) should not dissolve or degrade or hardly dissolve or hardly degrade the above porogen coating film, that is, the above-mentioned soluble in the stomach and/or intestinal digestive solution but insoluble or almost insoluble A polymer film of water.

The coating layer is prepared from the core material by a coating method such as casting, dipping, painting or spraying by using the suspension of the dispersion 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. The water used as a suspending agent for the coating is thus evaporated off, 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).

In another embodiment, the controlled release coating film polymer can be dissolved in a suitable organic solvent, and a plasticizer (if necessary, other additives can be added to the coating film), and a controlled release coating film can be prepared according to the above method. It is pointed out that the solvent should not dissolve or degrade or hardly dissolve or hardly degrade the above-mentioned porogen coating film, that is, the above-mentioned soluble in the stomach and/or intestinal digestive solution but insoluble or almost insoluble in water. Polymer film.

In a particular embodiment, the porogen in which the core material can be chemically reacted with the polymer coating the polymer in the aqueous solution is preferably dispersed in the water-free of the controlled release coating polymer. In an organic solvent or dispersant, and the non-aqueous organic solvent or dispersant does not dissolve or degrade or hardly dissolves or hardly degrades the above-mentioned porogen coating film, that is, the above-mentioned soluble in stomach and/or intestine digestion A liquid, but insoluble or nearly water-insoluble polymeric film.

The amount of the controlled release film material is usually 0.5 to 50% by weight, preferably 5 to 30% by weight, most preferably 10 to 20% by weight; The thickness of the coating layer is usually 5 to 500 μm, preferably 50 to 300 μm, more preferably 100 to 200 μm.

When coating, the surface temperature of the core should be higher than the minimum film forming temperature (MFT) of the dispersion (minimum film forming temperature refers to the lowest temperature at which the dispersion (body) forms a continuous film, below the minimum film forming temperature. The polymer particles cannot be deformed and fused to form a film). The surface temperature of the core material is generally higher than the minimum film forming temperature of 10 to 20 ° C in the present invention. If the surface temperature of the core material is too low, cracks may occur in the coating film, which may affect the release characteristics of the preparation; if the surface temperature of the core material is too high, the polymer will be excessively softened, resulting in adhesion of the coating film.

When the aqueous dispersion is coated, the core material is usually preheated to 20 to 90 ° C, preferably 30 to 70 ° C, more preferably 30 to 50 ° C, and first coated at a lower spray rate. After the surface of the core material has been coated with a thin layer of film, the spray rate is increased to the end of the coating. This operation prevents moisture from penetrating into the core material and causes changes in the properties of the core material during storage.

Aqueous dispersion (body) Before coating, the core material can be coated with a barrier layer according to the actual conditions, which helps to: 1 avoid water-sensitive drugs from hydrolyzing during the coating process; 2 avoid water-soluble drugs evaporating with water Migrate to the film; 3 improve the surface flatness of the core material, reduce the porosity, ensure the continuity of the film; 4 improve the hydrophobicity of the core material to facilitate the spreading of the aqueous coating liquid; 5 improve the brittleness of the core material, Avoid breakage during the coating process. Depending on the actual situation, a water-soluble material (such as a solution of hydroxypropylmethylcellulose and hydroxypropylcellulose) or a polymer organic 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.

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.

4), healing (aging) treatment of controlled release film

After the end of the above two coatings, the polymer particles in the film are often not fully fused and have a certain permeability. This is particularly disadvantageous for the porogen in which the above-mentioned core material can be chemically reacted with the polymer coating the same in the aqueous solution, which is disadvantageous in the next step of controlling the release film by the aqueous dispersion, since moisture may permeate therein, They react during the preparation process and lose their proper function.

Further fusion occurred during the storage of the controlled release film. 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.

Therefore, in the present invention, the healing treatment is performed after the completion of the coating. In the present invention, the curing treatment for the controlled release coating film comprises the following processes: after the solvent or dispersing agent in the controlled release coating film is substantially evaporated, the coated controlled release polymer coating is applied in a closed environment. The core of the film is placed at a temperature higher than the glass transition temperature of the film to be long enough to reach the end point, so that the polymer particles in the controlled release film of the above formulation are completely or substantially completely fused, eliminating or substantially eliminating the coating process. The micropores formed in the middle form a completely dense or substantially intact dense film, and 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 controlled release coating formulation is healed at a temperature above the glass transition point of the controlled release coating film until the formulation is at a temperature of, for example, about 40 ± 2 ° C and a relative humidity of 70% to 80%. The dissolution characteristics were left unaffected for 3 months and/or 6 months or longer under accelerated storage conditions. Or in other words, the in vitro dissolution of the bioreactive material immediately after healing is placed for 3 months and/or 6 under accelerated storage conditions at a temperature of about 40 ± 2 ° C and a relative humidity of 70% to 80%. The wound treatment of the healing treatment has stable dissolution characteristics compared to the in vitro dissolution of the biologically active substance of the month. 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, etc., determines that it is substantially unaffected by accelerated storage conditions that are affected by accelerated storage conditions.

In a particular embodiment of the invention, for the porogen in which the core material can chemically react with the polymer coating the polymer in the aqueous solution, the polymerization of the controlled release coating containing the porogen is used in the next step. The aqueous dispersion of the substance (body) before the release of the film, the film of the porogen should be cured to the end of the state in which the permeability of the film of the porogen to water is 0, the healing The treatment comprises the following process: after the solvent or dispersant of the film of the above porogen is substantially evaporated, in the closed environment, the porogen (that is, the above-mentioned soluble in the stomach and/or intestinal digestive solution but insoluble) Or a water-insoluble polymer coating film coated with a water-insoluble polymer film) is placed at a temperature higher than the glass transition temperature of the above film for a sufficient time until the porogen film is water-repellent The end point of the state where the permeation performance is 0, the polymer particles in the porogen coating film are completely fused, the micropores formed during the coating process are eliminated, and a complete and dense film is formed, and at the end of the above state, hole The agent does not undergo a chemical reaction in the above aqueous dispersion of the polymer which is insoluble or hardly soluble in water and the digestive juice of the stomach and intestine, at least in the next aqueous dispersion (body) coated controlled release No chemical reaction takes place during the filming process.

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 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 after heat treatment is relatively low. Therefore, the present invention preferably employs an oven heat treatment method.

At higher heat treatment temperatures, in order to prevent the low-melting-point drugs (such as ibuprofen) from migrating into the film, causing problems such as accelerated drug release and mechanical properties of the film, the drug-loading core may be provided with a barrier layer. Clothing, or reduce the heat treatment temperature.

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.

If the coating has healed completely during the coating process, no healing (aging) treatment, such as a formulation coated with Surelease (EC) aqueous dispersion (body).

Formulations prepared by any of the above methods may be coated with a thin layer of coating material to improve the surface integrity of the formulation or to prevent the formulations from sticking to one another during storage. 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. The pharmaceutical dosage form prepared by any of the above methods can be used substantially directly, such as directly orally. Small pieces, pellets, and granules prepared by the above method may also be loaded into a capsule, a pouch (small sachet) or a suitable multi-metering container by means of a metering device. If possible, the pellets or granules prepared by the above method are mixed with other auxiliaries and then obtained by a suitable method such as pressing to obtain a new preparation such as a tablet, which is decomposed after administration, and most or all of the coated small units are released. . It is also contemplated to embed a controlled release formulation prepared by the above method in polyethylene glycol or a lipid or other matrix to prepare a suppository or vaginal dosage form. The coated tablets are packaged in hemispherical containers or multi-dose containers and taken directly before the patient takes them.

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. The present invention has the following technical advantages over the prior art:

1), drug release reproducibility or stability;

2), the effect of in vivo factors on drug release is reduced;

3), the influence of in vitro factors on drug release is reduced, such as preventing water-soluble substances from being easily precipitated from the polymer film, overcoming the "pan-cream" phenomenon;

4), the time lag of drug release is reduced, drug release is advanced, drug release is accelerated, and bioavailability is improved;

5), the mechanical properties of the controlled release film are enhanced;

6), can achieve drug release in the gastrointestinal tract controlled release release, such as gastric, intestinal, colon controlled release release;

7), can achieve delayed release of drug release in the gastrointestinal tract, gap or pulsed controlled release. Bright

1 Example 1 and control 1 simvastatin in vitro release test results

2 Example 2 and control 3 in vitro release test results of diltiazem hydrochloride

3 Example 3 and control 5 in vitro release test results of metformin hydrochloride

4 Example 4 and control 7 Budesonide in vitro release test results

5 Example 5 and control 8 in vitro release test results of diclofenac sodium

6 Example 6 and reference 9 Qubitipide external release test results Example

The following non-selective examples further describe preferred embodiments within the scope of the invention. Many variations of these embodiments are possible within the scope of the invention. Example 1 and Comparative Example 1-2

1. Prepare samples and sample samples

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

Mg/tablet

Simvastatin 40

CABB0P0L 974P 26. 7

Sodium dihydrate citrate 26. 7

(grinding, allowing it to pass through a 100 00 mesh screen)

Hydrated lactose (spray drying) 26. 6

Povidone (K29/32) 6

Tert-butyl-p-methoxyphenol (BHA) 0. 04

Magnesium stearate 0. 6

Total 126. 64

Mix simvastatin, CABB0P0L 974P, ground sodium dihydrate, lactose and polyvinylpyrrolidone, Granulation with 10% (by weight) aqueous solution of ethanol (containing the desired BHA); the wet granulated material is forced through a 18 mesh sieve and dried for 24 hours; after granulation, the magnesium stearate is added and mixed. The sheet was pressed with a 1/4 inch standard concave circular die, using a pressing force of 800 to 1000 pounds. The thickness of the tablet after pressing is 3.89 mm, and the hardness is 8 to 10 kg.

2), preparing enteric coating film coated granules

Coating liquid prescription

Component %

Carboxymethylethylcellulose (CMEC) ^# 6. 5

Distillation of acetylated glycerol -acid fat 0. 75

Hydrogenated castor oil 0. 75

Anhydrous ethanol: acetone (8: 2) 92

Total 100

Description, # : The test carboxymethyl ethyl cellulose is compatible with the following controlled release coating polymer cellulose acetate.

A coating solution of carboxymethylethylcellulose was prepared in accordance with the above-mentioned coating liquid formulation. To a centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10), sodium hydrogencarbonate particles (particle size: 300 to 400 mesh, 38 to 48 μm) were added. The inlet gas temperature and the outlet gas temperature were respectively controlled at 60 to 80 ° C and 30 to 40 ° C, and sodium hydrogencarbonate powder was sprayed with the spray liquid prepared above, and the sodium hydrogencarbonate particles were increased in weight by about 100%. Dry and heal (temperature is 55 ° C, healing time is not less than 72 hours, until the sodium ions do not ooze out, no water seepage occurs and the chemical reaction is reached), and the obtained granules are passed through a 240 mesh circular sieve (61 μ πι And sieving with a 300-mesh circular sieve (48 μm) to obtain enteric coating film-coated granules (particle size 48 to 61 μ πι) containing a sodium hydrogencarbonate core.

3), preparation of controlled release coating film coating solution:

Adding 5% solution of acetic acid acetate to ethyl acetate monoacetate (95:5) as the 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.

4), packet-controlled release film:

The core-coated controlled release film has a moisture barrier protective coating on the front and back sides. The coating for the moisture barrier protective coating is a suspension containing 4.5% hydroxypropylmethylcellulose (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. The moisture barrier coating has a weight gain of about 1%.

An enteric coating film-coated granule and a diacetin used as a plasticizer are added to the cellulose acetate aqueous dispersion obtained above, wherein cellulose acetate: enteric coating film-coated granule: diacetic acid 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 ~4. 0. The core film was coated with a release coating film using the prepared coating liquid. The controlled release film coating weight gain was 16%.

Coating with a timed automatic film coating machine, the coating condition parameters are: spraying time of about 20 seconds, blasting time of about 30 to 40 seconds, blasting temperature of 50 to 70 ° C, core temperature of 40 to 50 ° C.

5), healing controlled release film

The healing treatment is carried out in a closed oven. The healing temperature was 65 ° C and the healing time was 30 hours.

6), preparation of comparative examples

To the cellulose acetate aqueous dispersion obtained above, granules of carboxymethylethylcellulose (particle size 48 to 61 m) and diacetin used as a plasticizer, wherein cellulose acetate is added : Carboxymethylethylcellulose particles: diacetin was 1:2:1 (weight ratio), and the coating liquid was prepared by diluting with water to a suspension containing 3% cellulose acetate. Then, Comparative Example 1 containing a carboxymethylethylcellulose particle as a controlled release coating film was prepared as described above.

Adding sodium bicarbonate particles (particle size 48~61 μ πι) and diacetin as a plasticizer to the acetone solution of cellulose acetate, wherein cellulose acetate: sodium hydrogencarbonate: diacetin A coating liquid was prepared by diluting with acetone to a suspension containing 3% cellulose acetate at a ratio of 1:2:1 (by weight). Then, Comparative Example 2 in which the controlled release coating film contained sodium hydrogencarbonate particles was prepared as described above. 2, in vitro release test

It was determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The speed is 50r/min, the temperature is (37±1) V, and the transmitter is artificial gastric juice (pH 1.2 hydrochloric acid) and artificial intestinal juice containing 0.4% sodium decyl sulfate (pH 6. 0 phosphate buffer). Liquid), artificial intestine (pH 7.4 phosphate buffer) containing 0.4% sodium decyl sulfate, 900 mL each. The release of the drug was monitored using a flow-through ultraviolet spectrophotometer. Figure 1 shows the release of the drug from the controlled release coated tablets and Comparative Example 1.

The results showed that the drug in the sample of the example was released faster in the artificial intestinal juice, less affected by the pH and less time delay, while in the control case, the drug was released relatively slowly in the artificial intestinal juice, which was relatively affected by the pH. Large, time lag is also relatively large; both drugs are basically not released in artificial gastric juice. Example 2 and Comparative Example 3-4

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

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 granulation, stearic acid is added. The magnesium was mixed and pressed with a 12 mm standard concave circular die. The pressing force was 1200 to 2000 kg, and the pressing time was 1 to 2 s. The hardness is 6~10kg.

2), preparation of gastric coating film coated granules

Coating liquid prescription

EUDRAGIT E100 25g

Sodium dihydrogen citrate granules (particle size 45~53 μ πι) 50g

Anhydrous ethanol 633g

Acetone 632g

Total 1370g

Description, *: Tested EUDRAGIT E100 is compatible with the following controlled release coating polymers EUDRAGIT® RS 30 D, EUDRAGIT® RL 30 D, with a high degree of compatibility.

A solution of EUDRAGIT E100 was prepared as described above for the coating solution. Using a spray dryer (TCSD: Japanese vehicle), the solution was spray-dried at an inlet temperature of 80 ° C, a hot air flow rate of 34 to 38 mm H ₂ 0, a spray rate of 2 g/min, and the solvent was distilled off to increase the weight of the particles by about 50%, and dried. Healing (temperature is 45 Ό, healing time is not less than 60 hours, until the sodium ions do not ooze out, no water seepage occurs and the chemical reaction is reached). After the particles pass through the 230 and 270 mesh sieve, the stomach coating film package is obtained. Coating of gastric coated film coated with sodium dihydrogen citrate core (particle size 53~62 μ m).

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

Coating liquid prescription (1000 tablets):

~Έ content (g) dry weight g

EUDRAGIT® RS 30 D 54. 6 16. 38

EUDRAGIT® RL 30 D 15. 4 4. 62

Gastro-coated film coated granules 49 49

Deionized water 331.1 Total 452. 5 72. 4

The aqueous dispersion (body) has a solids content of 16% by weight.

The core was coated on a Hi coater/Fruend coater. Coating conditions parameters: inlet temperature, 50~60 °C; outlet temperature, 30~35 °C; core temperature 31~36 °C; core weight gain 12. 63%.

4), healing controlled release film

The healing treatment is carried out in a closed oven. The healing temperature was 45 °C and the healing time was 24 hours.

5), prepare a control article.

Replace the gastric coating film coated sodium dihydrogen citrate pellets in the coating solution with the coated EUDRAGIT E 100 pellets (particle size 53~62 μm) or uncoated sodium dihydrogen citrate pellets. (particle size 53 to 62 μm), a control article 3 or 4 was prepared according to the above method and conditions.

2, in vitro release test

It was determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The rotational speed is 100r/min, the temperature is (37±1) V, the transmitter uses artificial gastric juice I (pH 6.0 in hydrochloric acid), artificial gastric juice II (pH 4.0 in hydrochloric acid) and artificial intestinal juice (pH 7. 5 phosphate). Buffer) 1000 mL each. The sample of Example 2 and the control sample 3 were directly placed in a dissolution cup, and 5 mL was sampled at regular intervals, and the same volume of dissolution transmitter was added. It was filtered through a 0.8 μm microporous membrane, and the filtrate was taken and diluted with water to prepare a solution containing about 8 μg per 1 ml. In addition, accurately weigh the appropriate amount of diltiazem hydrochloride which was dried at 105 °C for 2 hours, dissolve it with water and quantitatively dilute it to make a solution containing about 8 g per lml. Taking the above two solutions, the absorbance was measured by spectrophotometry (Chinese Pharmacopoeia 2005 edition Appendix IV A), and the absorbance was measured at a wavelength of 240 nm, and the dissolution amount of each tablet at different times was calculated. The results are shown in Figure 2.

The results showed that the drug in the sample of the example was released faster in the artificial gastric juice, less affected by the pH and less time lag, while in the control case, the drug was released slowly in the artificial gastric juice, which was greatly affected by the pH. The time lag is also large; the two drugs are basically released in artificial intestinal fluid. Example 3 and Comparative Example 5-6

1. Prepare samples and sample samples

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

Component mg/tablet

Metformin hydrochloride 500

Sodium decyl sulfate 25. 8

Povidone * 36

Magnesium stearate 2. 8

Total 564. 6

Povidone *, molecular weight of 10,000, 000; dynamic viscosity (10% w / v, 20 ° C) is 300 ~ 700mPas.

Metformin hydrochloride and sodium dodecyl sulfate were repeatedly passed through a 40 mesh sieve and mixed; the povidone K-90-F was dissolved in pure water; and the mixed powder of metformin hydrochloride and sodium dodecyl sulfate was placed in the stream. In the chemical bed; granulation of the solution sprayed with povidone; inlet temperature 50~70 °C, pressure 1~3bars, spray rate 10~100ml/min. After the granules were dried, they were passed through a sieve of 18 mesh, mixed with magnesium stearate, and pressed with a 12 mm standard concave circular die. The pressing force was 1200 to 2000 kg, and the pressing time was 1 to 2 s. The hardness is 6~10kg.

2), preparation of gastrointestinal two coat film coated particles

Coating liquid prescription:

Component % ―

2-methyl-5-vinylpyridine/methacrylic acid 2

Methyl/methacrylic acid copolymer ※

Mannitol (particle size 15~25 μ πι) 2. 5

Triacetin 0. 2 , -

47. 7

47. 6

100

Note: ※: The 2-methyl-5-vinylpyridine/methyl methacrylate/methacrylic acid copolymer was tested to be almost completely compatible with the following controlled release coating polymer polyvinylacetic acid.

The gastrointestinal two-coated film-coated granule coating suspension was prepared according to the above-mentioned coating liquid prescription. The obtained coating suspension was spray-dried with a spray dryer (TCSD: Japanese vehicle), and the weight gain of the pellet was about 80%, and mannitol particles coated with the gastrointestinal two coating film (particle size: 18 to 30 μ πι) were obtained. .

3), packet-controlled release film:

Core coating solution (1000 tablets):

Component content (g) dry weight

Kol l icoat SR 30 D (polyvinyl acetate 111. 1 30

Aqueous dispersion (body)

Gastrointestinal two-coated film particles 70 45

Triacetin 1. 8 1. 8

Titanium dioxide (particle size 20nm) 2 2

Deionized water 463. 81

Total 648. 7 78. 8

Prepare the coating solution according to the above prescription, and if necessary, adjust the pH to about 5. 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 13. 96%.

3), healing controlled release film

The healing treatment is carried out in a closed oven. The healing temperature was 45 ° C and the healing time was 24 hours.

4) Prepare a control article.

The gastrointestinal two-coated film coated granules in the coating solution are replaced by 2-methyl-5-vinylpyridine/methacrylic acid methyl/methacrylic acid copolymer particles (particle size 18~30 μ πι The control article 5 containing the copolymer was prepared according to the above method and conditions.

The above-mentioned tablet core was subjected to the above-described method and conditions using the following coating liquid to prepare a mannitol-containing control article 6. Coating liquid prescription: 1000 tablets dosage: Polyvinyl acetate 30g, mannitol particles (particle size 18~30 μ πι) 45g, triacetin 1. 8g, titanium dioxide (particle size 20nm) 2g, ethanol 1000ml.

2, in vitro release test

It was determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The rotation speed is 75r/min, the temperature is (37 ± 1) °C, and the transmitter is pH mL. 0 hydrochloric acid solution and PH 7. 4 phosphate buffer solution each 1000 mL. The examples and the comparative examples were directly placed in a dissolution cup, and 5 mL was sampled at regular intervals, and the same volume of dissolved transmitter was added. The absorbance was measured spectrophotometrically at a wavelength of 235 nm, and the degree of release was calculated. The results are shown in Figure 3.

The results showed that the release of the drug in the sample of the example was faster and the time lag was also small; in the control case, the release of the drug was relatively slow and the time lag was relatively large. Example 4 and Comparative Example Ί

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

Component mg/tablet

Budesonide (micronized) 2 Sugar Pills (Suglets®, 60 80 mesh) 321

Aquacoat ECD 30 (ethyl cellulose) 6. 6

Acetyl tributyl citrate 0. 5

Polysorbate 80 0. 1

Polyethylene oxide (PE0-K100) 196

Granulac® 140 (Lactose) 100

Magnesium stearate 1. 8

Micronized silica gel 2

Total 630 (dry weight)

Disperse budesonide (micronized) in Aquacoat ECD 30 aqueous dispersion (body) containing acetyl tributyl citrate and polysorbate 80, and mix to prepare a coating liquid; In the chemical bed; sprayed into the above coating liquid to granulate. After the granules were dried, they were mixed with lactose, polyethylene oxide, magnesium stearate and micronized silica gel, and pressed with a 12 mm standard concave circular die. The pressing force was 1200 2000 kg, and the pressing time was l 2 s. Hardness is 6 10kg

2) Preparation of water-soluble fine particles coated with a colon coating film

Colon coating film coating solution: pectin

Guar gum

N3⁄4C0 _{3 is} suitable for 1^·

Water 1⁄2 4 quantity G

Total

Prepare a solution of pectin-guar in accordance with the above-mentioned coating solution, and adjust the pH to 8 with ₂ (:0 _3). Centrifugal fluidized coating granulator (Powrex Corp. (Japan), MP-10) Add sucrose pellets (particle size 80 113 μm, containing 20% microcrystalline cellulose). Spray the sucrose powder with the spray solution prepared above, and increase the sucrose pellet by about 10%. Then dry, the obtained granules are passed through a 175 mesh circular sieve (aperture). A sieve of 86 μπι) and 120 mesh (pore size 120 μπι) was sieved to obtain 120 175 mesh particles having a colon coating film coated sugar core.

3), on the core of the film according to the following prescription and process control release film:

Coating liquid prescription:

Cellulose acetate butyric acid vinegar CAB381-20 64g

Cellulose acetate CA435-75S 16g

Colon coated film coated sugar pills 160g

Diethyl phthalate 8g

Dichloromethane 3000ml

Methanol 1000ml

Total 100

The core film was coated with a release coating film using the prepared coating liquid. A Freund type HCT micro high performance coater (8 inch disc) was used to apply a 250 micron thick coating to the tablet with the coating solution.

5), preparation of control supplies

A solution of pectin-guar prepared above was cast on a Teflon plate to form a film having a thickness of 250 500 μm, dried and pulverized at a temperature of 40 30 ° C, and the obtained granules were passed through a 175 mesh circular sieve. And 120 mesh circular sieves were sieved to obtain 120 175 mesh pectin-guar particles.

Preparation of granules containing pectin-guar gum using the obtained pectin-guar granules according to the above methods and conditions 7

2, in vitro release test It was determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The rotational speed was 75r/min, the temperature was (37 ± 1) °C, and the transmitter was artificial gastric juice (SGF) *, artificial intestinal fluid (SIF) ** and artificial colon fluid (SCF) *** 1000mL. The examples and the comparative examples were directly put into the dissolution cup, and the sample was changed to SIF after being kept in SGF for 2 hours, replaced with SCF in SIF for 4 hours, and then subjected to a release test in SCF, and 5 mL was sampled at regular intervals. And supplement the same volume of dissolved transmitter. The release of budesonide was determined by HPLC (HP-1100, Hewlett-Packard, column: μ Bondapak C-18). The result is shown in Figure 4.

The results showed that the release of the drug in the sample of the example was faster and the time lag was also small; in the control case, the drug was released slowly and the time lag was also large.

Note: Artificial gastric juice (SGF) *: This refers to a solution of pH 1.2. Each 1000 ml of this solution contains 2 g of NaCl, 3. 2 g of pepsin dissolved and an appropriate amount (about 7 ml) of HCl.

The artificial potassium sulphate (SIF) **: Here, a potassium phosphate buffer solution containing 0.1% of pancreatin at pH 7.5, the preparation of the solution is as follows, 6.8 g of monovalent alkali potassium phosphate is dissolved in 250 ml of water 5。 Then, 190ml of 0. 2N NaOH, 400ml of water and 10g of pancreatin, and finally added 0. 2N NaOH, the pH was adjusted to 7.5, and then diluted to 1000ml with water.

Artificial Colonic Fluid (SCF) herein refers to a buffer containing 50 mM phosphate, 26 pg/ml Pectinex Ultra SPL (Novo Nordisk) and 20 unit/ml galactomannanase (Novo Nordisk). Example 5 and Comparative Example 8

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

Component mg/"

Diclofenac sodium 150

Hydroxypropyl methylcellulose (Methocel K15 M) 60

Mannitol 50

Povidone (K29/32) 20

Magnesium stearate 3

Colloidal silica 2

Total 285

Diclofenac sodium, hydroxypropyl methylcellulose, mannitol 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; Magnesium stearate and colloidal silica were added, mixed, and pressed with a 9 mm standard concave circular die, using a pressing force of 200 to 2000 kg, and a pressing time of l 2 s. The hardness is 5~10kg.

2) Preparation of water-soluble fine particles coated with a colon coating film

Colon coating film coated granule coating solution prescription:

Component %

Shellac (acid value 70) (pH greater than 7.5 dissolved) 13. 5

Triacetin 1. 5

Water 85

Total 100

A colon coating film-coated granule coating suspension is prepared according to the above coating liquid formulation. To the centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10), sucrose powder (particle diameter: 48 to 58 μm) was added. The sucrose powder was sprayed with the coating liquid prepared above, and the sucrose powder gained about 20% by weight. After drying, the obtained granules were sieved through a 270 mesh circular sieve (53 μm) and a 230 mesh circular sieve (62 μm) to obtain a 230-270 mesh powder containing a powdered sugar core (particle size 53 to 62 μ πι). .

Coating liquid prescription:

~m- content (g) dry weight (g)

Surelease E-7-19050 (ethyl cellulose 45. 6 ΪΪΛ Aqueous dispersion (body)

Colon coated film coated particles 22.2 22.2

Nano-alumina dispersion (average particle size 10nm) 0.6 0.6

Deionized water 146.6

Total 215 34.2

The coating liquid was prepared according to the above prescription, and the pH was adjusted to 5 to 5.5 as necessary. The aqueous dispersion (body) had a solids content of 16 (the core was coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50 to 60 ° C; outlet temperature, 40 to 42 ° C; The core temperature is 40 ° C; the core weight gain is 12%. The core is not heat treated after coating.

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%.

6), preparation of control supplies

The shellac coating liquid prepared above is cast on a polytetrafluoroethylene sheet to form a film having a thickness of 250 to 500 μm, dried and pulverized at a temperature of 40 to 30 ° C, and the obtained granules are passed through a 270 mesh circular sieve ( 53 μπι) and a 230 mesh circular sieve (62 μm) were sieved to obtain particles of 53 to 62 μm.

Using the obtained granules, a shellac-containing granule control article 8 was prepared in accordance with the above methods and conditions.

2, in vitro release test

It was determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The rotation speed is 100r/min, the temperature is (37±1) V, and the transmitter is artificial gastric juice (pH1.2 hydrochloric acid solution, no enzyme), artificial intestinal juice (pH 6.8 potassium phosphate buffer, no enzyme) and phosphoric acid. Salt buffer (pH 7.8) 1000 mL. The examples and the control examples were directly put into the dissolution cup, and the sample was kept in artificial gastric juice for 2 hours, then replaced with artificial intestinal juice, and kept in artificial intestinal juice for 4 hours, then changed to phosphate buffer solution (pH 7.8), and then in phosphoric acid. The release test was carried out in a salt buffer (pH 7.8). The absorbance was measured spectrophotometrically at a wavelength of 287 nm, and the amount of dissolution per tablet at different times was calculated. The result is shown in Figure 5.

The results showed that the release of the drug in the sample of the example was faster and the time lag was also small; in the control case, the drug was released slowly and the time lag was also large. Example 6 and Comparative Example 9

1), press

Tripidil 150

Hydroxypropyl methylcellulose (Methocel K4) 30

Mannitol 98.3

Povidone (K9/32) 3.7

Magnesium stearate 2

Colloidal silica 1

Total 285

Mix the pirimidol, hydroxypropyl methylcellulose and mannitol uniformly, and granulate with a solution of povidone in ethanol; force the wet granulated material through a 25 mesh sieve and dry for 24 hours; Add magnesium stearate and colloidal silica, mix, and compress the sheet with a 9-concave standard concave circular die. The pressing force is 1200~2000kg, and the pressing time is l~2s. The hardness is 6~10kg.

2) Preparation of water-soluble fine particles coated with a delayed release coating film

Delayed release film coating solution (inner layer):

Component% Poly( ε -caprolactone) 1

(molecular weight is 160,000)

Dichloromethane 49.5

Acetone 49.5

Total 100

Enteric film encapsulation prescription (outer coat):

Έ"minute %"

HP50 5

Triacetin 0.5

Dichloromethane 47.25

Denatured alcohol 47.25

Total 100

A solution of the polymer poly (ε-caprolactone) and HP-50 was prepared according to the above coating liquid formulation. The sucrose powder (particle size: 53 61 μπι) is placed in a centrifugal fluidized granulator to be tumbling, and the above poly( ε - _ca p _ro l _ac t ₀ n _e ) solution is sprayed while blowing hot air. The solution, the thickness of the coating layer was 27 29 μm (the weight gain of the particles was about 700%); and the solution of the above HP-50 solution was sprayed to a thickness of about Ιμπι (particle weight gain of about 5%). After drying, a sugar pill containing a delayed release film was obtained.

3), packet-controlled release film:

The controlled release film is coated with a moisture barrier protective coating before and after coating. The coating for the moisture barrier protective coating was 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. The weight of the moisture barrier protective coating before coating is about 1%, and the weight of the moisture barrier coating after coating is about 2%.

In the cellulose acetate aqueous dispersion prepared by the method of Example 1, a sugar pellet containing a delayed release coating film and a diacetin used as a plasticizer are added, wherein the cellulose acetate: package delay The release film of the sugar film: diacetin is 1:2:1 (weight ratio), diluted with water to a suspension containing 3% cellulose acetate to prepare a coating liquid, if necessary, adjust the cellulose acetate suspension The pH is up to 4.0 4.5. The core film was coated with a release coating film using the prepared coating liquid. The controlled release film coating weight gain is 16%. It is coated with a timed automatic film coating machine. The coating conditions are as follows: spraying time is about 20 seconds, blasting time is about 30 40 seconds, blast temperature is 50 70 ° C, film Core temperature 40 50 ° C

5), healing controlled release film

6), preparation of control supplies

The poly-caprolactone coating solution prepared above was cast on a polytetrafluoroethylene plate to form a film having a thickness of 250 500 μm, dried and pulverized at a temperature of 40 30 ° C, and the obtained granules were passed through a 180-mesh circular sieve (80 μ m) and 170 mesh circular sieve (90 μ m) sieve, prepare 80 90 μ m particles, and then spray the above solution of HP-50 solution by the above process, the thickness of the coating layer is about Ιμπι (particle weight gain about 5%). Using the obtained granules to prepare a granular control article containing poly( ε -caprolactone) according to the above method and conditions 9

2, in vitro release test

It was determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The rotation speed is 100r/min and the temperature is (37±1)V. The transmitter is used for artificial intestinal juice (pH 6.8 potassium phosphate buffer, no enzyme) 1000mL. The examples and the comparative examples were directly introduced into the dissolution cup. The absorbance was measured by spectrophotometry (Chinese Pharmacopoeia 2005 edition Appendix IV A) at a wavelength of 300 nm, and the amount of dissolution of each tablet at different times was calculated. The result is shown in Figure 6.

The results showed that the sample of the sample was released faster and the time lag was appropriate, and the delayed release of 56 hours could be achieved, which could meet the clinical needs. However, the release of the control substance was extremely slow and the time lag was too long. It took 30-32 to start. Release medicine, can not be used clinically. Example 7

The sodium bicarbonate particles (particle size 300-400 mesh, 38-48 μm) in Example 1 gained about 300%, and the obtained particles were dried and healed by a 200-mesh circular sieve (75 μm) and 240. The mesh was sieved through a circular sieve (61 μm) to obtain particles (particle size: 61 to 75 μm) containing a sodium hydrogencarbonate core. The granules (particle diameter 61 to 75 μm) obtained above were prepared in accordance with the formulation and process described in Example 1. Example 8

The sodium bicarbonate particles (particle size 300-400 mesh, 38-48 μm) in Example 1 gained about 700% by weight, and the obtained particles were dried and healed by a 160-mesh circular sieve (96 μm) and 200. The mesh was sieved through a circular sieve (75 μm) to obtain particles (particle size 75 to 96 μm) containing a sodium hydrogencarbonate core. The pellets (particle size 75 to 96 μm) obtained above were prepared in accordance with the formulation and process described in Example 1. Example 9

The mannitol particles (particle diameter: 15 to 25 μm) in Example 3 were weight-increased by about 200% to obtain granules coated with two coats of gastrointestinal coating (particle diameter: 23 to 38 μm). The pellets obtained by the above (particle diameter 23 to 38 μm) were prepared in accordance with the formulation and process described in Example 3. Example 10

The sucrose pellets of Example 4 gained about 2%. Otherwise, the granules obtained above were prepared in accordance with the formulation and process described in Example 4. Example 11 and Comparative Example 10

Preparation of water-soluble fine particles coated with enteric coating film according to the following prescriptions and processes

Coating liquid prescription

Component %

Eudragit L** 6.5

Triglyceride acetate 1.5

Anhydrous ethanol: acetone (5: 5) 92

Total 100

Description, #: Tested Eudragit L is partially compatible with the controlled release coating polymer cellulose acetate.

The coating solution of Eudragit L was prepared according to the above formulation of the coating solution. Sodium carbonate particles (particle size: 240 to 150 mesh, 61 to 106 μm) were added to a centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10). The inlet gas temperature and the outlet gas temperature were respectively controlled at 60 to 80 ° C and 30 to 40 ° C, and the sodium carbonate powder was sprayed with the spray liquid prepared above, and the sodium carbonate particles were increased by about 100%. Dry and heal (temperature is 45 ° C, healing time is not less than 60 hours, until the sodium ions do not ooze out, no water seepage occurs and the chemical reaction is reached), the obtained granules are passed through a 200 mesh circular sieve (75 μπι) and A 115-mesh circular sieve (125 μm) was sieved to obtain an enteric coating film-coated granule (particle diameter: 75 to 125 μm) containing a sodium carbonate core.

Example 11 and Comparative Example 10 were prepared according to the formulation and process of Example 1 and Comparative Example 1, wherein Example 11 encapsulated release film of cellulose acetate: enteric coating film coated granules: diacetin was used. 1:1.5:1 (weight ratio), Comparative Example 10 Cellulose acetate in a controlled release coating film: Eudragit L particles (particle size 75 to 125 μm) _: diacetin is 1:1.5:1 (weight ratio) Example 12 and Comparative Example 11

Coating liquid prescription

Component % ― Vinyl acetate-maleic anhydride copolymer 6. 5

Distillation of acetylated glycerol -acid fat 0. 75

Diethyl phthalate (DEP) 0. 75

Anhydrous ethanol: acetone (8: 2) 92

Total 100

A coating liquid of a vinyl acetate-maleic anhydride copolymer was prepared in accordance with the above coating liquid formulation. To a centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10), glucose particles (particle diameter: 300 to 400 mesh, 38 to 48 μm) were added. The inlet gas temperature and the outlet gas temperature were respectively controlled at 60 to 80 ° C and 30 to 40 ° C, and the glucose particles were sprayed with the spray liquid prepared above, and the glucose particles were weighted by about 100%, and the obtained particles were passed through a 240-mesh circular sieve ( The 61 μm) and 300-mesh circular sieves (48 μm) were sieved to obtain enteric coating film-containing granules (particle size 48 to 61 μ πι) containing a glucose core.

Example 12 was prepared according to the formulation and process of Example 1; the carboxymethylethylcellulose particles (particle size 48~61 μπι) in Comparative Example 1 were replaced with vinyl acetate-maleic anhydride copolymer particles ( Comparative Example 11 was prepared according to the formulation and process of Comparative Example 1 with a particle size of 48 to 61 μm. Example 13 and Comparative Example 12

Coating liquid prescription

Component %

Polyvinyl phthalate 6. 5

Diethyl phthalate (DEP) 1. 25

Triglyceride acetate 1. 25

Anhydrous ethanol: acetone (5: 5 ) 91

Total 100

A coating liquid of polyvinyl alcohol phthalate was prepared according to the above coating liquid formulation. To a centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10), trisodium citrate particles (particle diameter: 150 to 100 mesh, 106 to 150 μm) were added. The inlet gas temperature and the outlet gas temperature were respectively controlled at 60 to 80 ° C and 30 to 40 ° C, and the trisodium citrate particles were sprayed with the spray liquid prepared above, and the trisodium citrate particles were weighted by about 80%. Dry and heal (temperature is 55 ° C, healing time is not less than 72 hours, until the sodium ions do not ooze out, the water does not seep and the chemical reaction is reached), the obtained particles are passed through a 115 mesh circular sieve (125 μ πι And sieving with an 80-mesh circular sieve (180 μm) to obtain enteric coating film-coated granules (particle diameter: 125 to 180 μm) containing a trisodium citrate core.

Example 13 and Comparative Example 12 were prepared according to the formulation and process of Example 3 and Comparative Example 5, wherein Comparative Example 5 encapsulated 2-methyl-5-vinylpyridine/methacrylic acid methyl group in the release film. The methacrylic acid copolymer particles (particle size 18 to 30 m) were replaced with polyvinyl phthalate (particle size 125~180 μ πι), and the others were unchanged. Example 14 and Comparative Example 13

1), according to the embodiment 2 core prescription and process preparation core

2), according to the following prescription and process to prepare water-soluble fine particles coated by gastric coating film

Coating liquid prescription

Component %

Cellulose acetate diethylaminoacetate 6. 5

Distillation of acetylated glycerol -acid fat 1. 75

Hydrogenated castor oil 1. 75

Anhydrous ethanol: acetone (6: 4) 90

Total 100 A coating liquid of cellulose acetate diethylaminoacetate was prepared in accordance with the above coating liquid formulation. To a centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10), citric acid particles (particle diameter: 300 to 400 mesh, 38 to 48 μm) were added. The inlet gas temperature and the outlet gas temperature were respectively controlled at 60 to 80 ° C and 30 to 40 ° C, and the tannic acid particles were sprayed with the spray liquid prepared above, and the tannic acid particles were increased in weight by about 100%. Dry and heal (temperature is 55 Ό, healing time is not less than 72 hours, until the water is not neutralized and the chemical reaction is reached). The obtained granules are passed through a 240 mesh circular sieve (61 μ πι) and a 300 mesh circular sieve (48 μ Πι) sifting to obtain particles containing a niobate core (particle size 48~61 μ πι).

3), in the cellulose acetate aqueous dispersion obtained by the method of Example 1, the above-mentioned gastric coating film-coated citric acid granules and diacetin used as a plasticizer, wherein acetic acid is added Cellulose: guar granule coated with gastric coating film: diacetin is 1: 2: 1 (weight ratio), diluted with water to a suspension containing 3% cellulose acetate to prepare a coating liquid, necessary 5。 8. The pH of the cellulose acetate suspension was adjusted to 6. 5-7. The core film was coated with a release coating film using the obtained coating liquid. The controlled release coating film coating weight gain was 16%.

5), healing controlled release film

The healing treatment is carried out in a closed oven. The healing temperature was 65 ° C and the healing time was 36 hours.

6), a comparative example 13 was prepared as described above, wherein the citrate particles coated with the gastric coating film were replaced with cellulose acetate diethylaminoacetate (particle size 48 to 61 μ πι), and the others were unchanged. Example 15 and Comparative Example 14

Coating liquid ^

Component %

Ethyl piperidinyl-acetyl acetal ethylene copolymer 6 ~~

Triethyl acetyl citrate 1. 25

Triglyceride acetate 0. 75

Anhydrous ethanol: acetone (5: 5 ) 92

Total 100

A coating liquid of ethylene piperidinyl-acetyl acetal ethylene copolymer was prepared in accordance with the above coating liquid formulation. To the centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10), sucrose particles (particle diameter: 150 to 100 mesh, 106 to 150 μm) were added. The inlet gas temperature and the outlet gas temperature were respectively controlled at 60 to 80 ° C and 30 to 40 ° C, and the sucrose particles were sprayed with the spray liquid prepared above, and the sucrose particles were weighted by about 80%, and the obtained granules were passed through a 115-mesh circular sieve ( Immersed in a 125-mesh sieve (180 μm) and an 80-mesh circular sieve (180 μm) to obtain a vinyl piperidinyl-acetylacetal ethylene copolymer-coated granule (particle size: 125 to 180 μm) containing a sucrose core.

3), packet-controlled release film:

Core coating solution (1000 tablets):

Component content (g) dry weight

Kol l icoat SR 30 D (polyvinyl acetate 111. 1 30

Aqueous dispersion (body)

Gastric coating film coated sucrose particles 70 45

Triacetin 1. 8 1. 8

Titanium dioxide (particle size 20nm) 2 2

Deionized water 463. 81

Total 648. 7 78. 8

Prepare the coating solution according to the above prescription, and if necessary, adjust the pH to about 5. The core is coated in Hicoater/Fruend Coating on board. The coating temperature parameters: inlet temperature, 50~60 ° C; outlet temperature, 35~37 ° C; core temperature 36~38 ° C; core weight gain 13.96%.

3), healing controlled release film

The healing treatment is carried out in a closed oven. The healing temperature was 45 ° C and the healing time was 36 hours.

6) A comparative example 14 was prepared as described above, wherein the sucrose particles coated with the gastric coating film were replaced with ethylene piperidinyl-acetyl acetal ethylene copolymer (particle size 48 to 61 μ πι), and the others were unchanged. Example 16 and Comparative Example 15

Preparation of water-soluble fine particles coated with two coats of gastrointestinal coating according to the following prescriptions and processes

Coating liquid prescription

Component %

Carboxymethylbenzylaminocellulose 6. 5

Distillation of acetylated glycerol -acid fat 0. 75

Dibutyl sebacate 0. 75

Anhydrous ethanol: acetone (6: 4) 92

Total 100

A coating liquid of carboxymethylbenzylaminocellulose was prepared in accordance with the above coating liquid formulation. To a centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10), sorbose granules (having a particle size of 300 to 400 mesh, 38 to 48 μm) were added. The inlet gas temperature and the outlet gas temperature were respectively controlled at 60 to 80 ° C and 30 to 40 ° C, and the sorbose granules were sprayed with the spray liquid prepared above, and the sorbose granules were weighted by about 100%, and the obtained granules were rounded by 240 mesh. Sieves (61 μm) and 300 mesh circular sieves (48 μm) were sieved to obtain granules containing sorbose core (particle size 48 to 61 μ πι).

Example 16 was prepared according to the formulation and process of Example 3; the carboxymethylethylcellulose particles (particle size 48-61 μπι) in Comparative Example 5 were replaced with carboxymethylbenzylaminocellulose particles (granules). Comparative Example 15 was prepared according to the formulation and process of Comparative Example 1, except that the diameter was 48 to 61 μm. Example 17 and Comparative Example 13

Coating liquid ^

Component %

Chitosan (granules, 5_30 calendar) 8. 5

Distilled acetylated glycerol -acid fat 0. 85

Hydrogenated castor oil 0. 85

Span 40 1. 3

Anhydrous ethanol: acetone (5: 5) 88. 5

Total 100

A suspension coating solution of chitosan was prepared according to the above formulation of the coating solution. To a centrifugal fluidized coating granulator (manufactured by Powrex Corp. (Japan), MP-10), citric acid particles (particle diameter: 300 to 400 mesh, 38 to 48 μm) were added. The inlet gas temperature and the outlet gas temperature were respectively controlled at 70 to 80 ° C and 40 to 50 ° C, and the tannic acid particles were sprayed with the spray liquid prepared above, and the tannic acid particles were increased in weight by about 100%. The obtained granules were sieved through a 240-mesh circular sieve (61 μm) and a 300-mesh circular sieve (48 μm) to obtain granules having a niobic acid core (particle diameter: 48 to 61 μm).

Coating liquid prescription j

~ Ϊ Cellulose acetate butyrate CAB381-20 48g

Cellulose acetate CA435-75S 12g

Gastrointestinium coated particles 120g

Diethyl phthalate 6g

Dichloromethane 2250ml

Methanol 750ml

Total 100

The core film was coated with a release coating film using the prepared coating liquid. A Freund-type HCT micro-high performance coater (8-inch disc) was used to apply a 250 μm thick coating to the tablet with the coating solution. Test Example 1 Drug release stability test

The samples in the examples 1 to 6 and the control were tested for stability. The in vitro release test was carried out in the same manner as in the examples. The results are shown in Tables 1 to 6.

Table 1 Example 1 sample and control article Drug release amount at pH 6.8 Time start amount (%) March ※ (%) March ^# (%) June ※ (%) June ^# (%) Example 1 ~~ 2h 23^2 22^5 22?0 2L9 207

6h 57.3 55.8 55.4 54.7 54.2

10h 83.6 82.1 81.8 80.3 79.4

12h 93.3 92.7 91.2 90.6 89.5 Reference 1 ~~ 2h Ϊ3Λ ΓΤ7Ί 9^5 9^2 6?8

6h 38.5 34.9 31.4 30.5 22.3

10h 61.4 56.5 50.2 43.2 33.2

12h 78.6 70.3 63.3 58.2 48.9

Reference 2 ~~ 2h 26?9 202 25^2 23?8

6h 60.5 48.1 55.3 36.5 52.2 lOh 86.4 73.8 83.5 57.9 78.2

12h 97.8 81.3 90.8 66.6 87.4

* Indicates an environment with a temperature of 25 ° C and a relative humidity of 90% (the same applies below);

# indicates the temperature of 40 ° C, the relative humidity of 50% of the environment (the same below). Example 2 Sample and Control Supplies Drug Release at pH 2.5

Time start amount (%) March ※ (%) March ^# (%) June ※ (%) June ^# (%) Example 2 2h 27.8 26.6 26.2 25.7 25.2

8h 71.3 70.9 69.3 68.3 67.7

12h 91.5 89.2 88.9 88.3 87.3

16h 98.2 97.1 96.9 95.3 94.7 For comparison 3 ~~ 2h Ϊ08 βΓθ ~1

8h 46.8 42.6 36.3 38.1 23.2

12h 70.1 66.5 55.1 61.8 38.5

16h 82.2 77.6 68.6 72.2 51.7 Reference 4 ~~ 2h 305 22^2 29?7 Ϊ3Λ 28^2

8h 74.6 61.2 71.8 46.2 70.3

12h 95.3 77.7 90.4 60.8 88.8

16h 101.4 87.7 100.8 73.2 98.7 Table 3 Drug release amount of the sample of Example 3 and the control article (pH 6.8)

Time start amount (%) March ※ (%) March ^# (%) June ※ (%) June ^# (%) Example 3 2h 17. 3 17. 0 16. 8 16. 5 15. 1

4h 37. 2 36. 4 36. 6 35. 6 35. 0

8h 68. 6 67. 8 67. 5 65. 7 65. 3

10h 87. 3 84. 8 84. 4 82. 3 81. 7 Control 2h 5. 4 3. 6 3. 2 2. 0 1. 4

4h 21. 6 19. 2 16. 8 16. 5 11. 4

8h 49. 2 47. 7 42. 9 44. 6 36. 6 lOh 67. 5 64. 7 58. 1 61. 4 47. 6 Control 3⁄4 6 2h 21. 4 15. 6 20. 9 9. 3 19. 3

4h 40. 3 32. 8 38. 7 24. 2 35. 4

8h 71. 4 57. 3 67. 5 41. 6 62. 0 lOh 89. 7 71. 2 80. 4 56. 7 73. 9 Table 4 Example 4 Drug release from samples and control supplies

Time start amount (%) March ※ (%) March ^# (%) June ※ (%) June ^# (%) Example 4 8h 19. 8 19. 0 18. 5 18. 2 17. 1

12h 52. 4 51. 8 50. 9 51. 3 50. 2

16h 79. 5 78. 7 78. 2 77. 4 77. 3

20h 96. 5 95. 1 94. 9 94. 7 94. 1 Reference substance 7 8h 1. 2 1 0. 6 0. 8 0. 3

12h 35. 3 32. 5 27. 7 30. 2 21. 8

16h 66. 1 62. 8 53. 2 56. 5 43. 7

20h 81. 2 78. 1 70. 2 73. 7 57. 7 Table 5 Example 5 Drug release from samples and control supplies

Time start amount (%) March ※ (%) March ^# (%) June ※ (%) June ^# (%) Example 5 8h 22. 9 21. 3 21. 5 20. 3 20. 7

12h 65. 7 64. 5 63. 9 63. 1 63. 0

16h 96. 2 95. 7 95. 4 94. 1 94. 6 Reference 8 ~~ 8h 0 7 0 5 0 4 0 3 0 3

12h 43. 9 40. 8 35. 6 36. 3 27. 1

16h 80. 4 76. 9 70. 4 71. 1 56. 7

The test results show that the sample samples containing the water-soluble particles coated with the digested liquid soluble but water-insoluble polymer have good drug release stability, and contain uncoated water in the controlled release film. The drug release stability of the examples was improved in the control of the granules and the lysate-soluble but water-insoluble polymer.

In addition, in the stability test under the environment of 90% relative humidity, it was observed that the controlled release film containing the uncoated water-soluble particles (2, 4, 6) showed some samples of "pancrea" "Phenomenon, that is, water-soluble porogens precipitated from the controlled release coating film; this phenomenon was not observed in the example samples. Test example 2 Mechanical properties test of controlled release film

The controlled release film coating liquid prepared in Examples 1-3 and Controls 2, 4, and 6 was cast on a polytetrafluoroethylene plate to form a thickness. For a film of 150 μm, the film was cut into a size of IX 7 cm. The tensile strength was then measured under an INSTRON tensile strength tester. The results are shown in Table 7.

Table 7 Measurement results of tensile strength of polymer film

Film breaking load (g) maximum strain (%)

Example 1 303 146

Control 2 182 77

Example 2 173 73

Reference 4 53 24

Example 3 385 152

Reference 6 194 88

The results show that the mechanical properties of the examples are better than those of the control. The water-soluble particles (porogen) in the controlled release film coating liquid are coated with the polymer and the mechanical properties of the controlled release film film relative to the uncoated particles. Improved. Test Example 3 In vivo drug release test

12 male healthy subjects, one oral sample (1-3, 7-9) and one control sample (1, 3, 5) were randomly crossed for in vivo drug release test (bioavailability study) The blood concentration is determined by liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (HPLC-MS/MS). The results are shown in Tables 8, 9, and 10.

Table 8 Test results of simvastatin release in vivo (average SD, n=6)

Test article

(h) ( μ g / L) ( g / L · h) (h) Example 1 3.2 ± 1 · 1 11.8 ± 2 · 4 45.5 ± 10.6 0.4 ± 0 · 2 Example 7 4.2 ± 1 · 4 8.7 ± 2· 6 38.8±11· 5 0.7±0· 3 Example 8 5.0±1· 9 6.8±2· 7 31.5±12· 3 1.2±0· 3 Reference substance 1 6.5±3· 3 5.3±4· 3 23.5 ±16.5 2.5±1·3 Example 11 3.5±1·3 11.3±2·8 48.6±13· 2 0.3±0· 2 Comparative Example 10 6.2±2·1 5.2±2· 7 21.5±10.5 1.4±0· 5 Example 12 4.8±1·3 9.2±2·3 36.6±12·7 0.8±0·4 Comparative Example 11 7.2±2·6 5.0±2·3 19.5±8·8 1.6±0·6 Table 9 Hydrochloric acid Diltiazem in vivo release test results (mean ± SD, n = 6)

Test article

(h) ( μ g / L) ( g / L · h) (h) Example 2 3.4 ± 1 · 2 113.3 ± 38 · 9 2374.5 ± 762 · 6 0.5 ± 0 · 2 Reference 3 6.0 ± 3. 6 52.6±35.6 1023.5±642·6 1.8±1·4 Example 14 3.8±1·4 107.8±34·3 2276.2±715.9 0.5±0·3 Comparative Example 13 6.5±3·3 43.5±16.7 976.7 ±302.5 2.1± 1· 6 Example 15 4.5±1· 6 83.8±31· 6 1725.8±667· 4 0.7±0· 3 Comparative Example 14 6.8 ± 3.6 48.1 ± 15 · 3 997.7 ± 347 · 2 2.3 ± 1 · 2 Table 10 in vivo release test results of metformin hydrochloride (mean ± SD, n = 6)

Test article

(h) ( μ g / L) ( g / L · h) (h) Example 3 3.6 ± 1 · 0 622.4 ± 137 · 3 4963 ± 1235 0.6 ± 0 · 3 Example 9 4.8 ± 1 · 6 486.8 ± 152· 7 3607±1338 1.1±0· 7 Reference 5 6.3±3· 2 349.8 ±193.2 2556±1546 2.3±1· 5 Example 13 2.2±1· 1 945.6 ±332.5 6242±1343 0.4±0· 2 Example 12 5.6±2·1 323.4±112·7 2245±857 2.5±1·3 Example 16 4·1±1·3 741.5±245.8 3849±1021 0.8±0· 3 Comparative Example 15 5.8±2· 2 356.6 ±124· 8 2376±825 2.1±1· 1 The results showed that the in vivo release behavior of the examples was better than that of the control, and the degree of influence in the body was lower than that of the control; the dissolution time of the sample was smaller, especially in the case of A porogen for in vivo reactions.

Claims

Claim

A controlled release preparation having improved properties, characterized in that the controlled release preparation comprises:

a) a core containing a drug;

b) a controlled release coating film overlying the core, wherein the controlled release film comprises a pharmaceutically acceptable plasticizer, pharmaceutically acceptable insoluble or almost insoluble in water, and gastric and intestinal digestive juices And a pharmaceutically acceptable soluble or non-plasticizer-containing pharmaceutically acceptable plasticizer or a plasticizer which is embedded in the stomach and/or intestinal digestive solution but is insoluble as a porogen Or a particle of a water-soluble pharmaceutical additive coated with a polymer film which is hardly soluble in water, the above-mentioned water-soluble pharmaceutical additive and the above-mentioned soluble in stomach and/or intestinal digestive solution but insoluble in Or a polymer that is almost insoluble in water cannot undergo a chemical reaction or chemical reaction in the digestive juice of the body, but does not form a pharmaceutically unacceptable product including a product which is insoluble in water and which is solid or liquid at normal temperature (25 ° C). a product, and the above-mentioned polymer film soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water is used in an amount of not more than about 700% by weight of the above water-soluble pharmaceutical additive (weight)

2. The controlled release preparation according to claim 1, wherein said polymer film soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water is used in an amount not exceeding said soluble amount. About 300% of the amount of pharmaceutical additives used in water

(weight / weight).

3. The controlled release preparation according to claim 1 or 2, characterized in that the amount of the polymer film which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water is as described above. The amount of the pharmaceutically acceptable additive dissolved in water is from about 2 to about 200% (weight/weight).

The controlled release preparation according to any one of the preceding claims, characterized in that the polymer soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water is soluble in said The amount of the gastric and/or intestinal digestive juice but insoluble or hardly water-soluble polymer film is from 35% to 100% (weight/weight) based on the total dry weight of the film.

The controlled release preparation according to any one of the preceding claims, characterized in that the polymer soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water is insoluble or Polymers that are almost insoluble in water and stomach and intestinal digestive juices are compatible or fully compatible.

The controlled release preparation according to any one of the preceding claims, characterized in that the water-soluble pharmaceutical additive is selected from the group consisting of water-soluble amino acids, oligopeptides (2-10 peptides), and is soluble in Water monosaccharide and pharmaceutically acceptable derivative thereof, oligosaccharide (2-6 sugar) and pharmaceutically acceptable derivative thereof, inorganic salt soluble in water of sodium, potassium or ammonium ion, soluble in water An organic acid having a water carbon number of not more than 6 and a water-soluble sodium, potassium or ammonium ion salt thereof, an organic base having a water-soluble carbon number of not more than 6 and a water-soluble salt thereof. A water-soluble nonionic surfactant, a pharmaceutically acceptable water-soluble nonionic polymer, and mixtures thereof.

The controlled release preparation according to any one of the preceding claims wherein the water-soluble pharmaceutical additive is selected from the group consisting of alanine, glycine, serine, proline, asparagine, lysine , glutamine, methionine, arginine, hydroxyproline, proline, dynamite (L-alanyl-L-glutamine), glutathione, D-erythrose, D-erythrulose, erythritol, D-ribose, D-2 deoxyribose, D-xylose, L-arabinose, D-ribulose, D-xylulose, xylitol, glucose , galactose, mannitol, mannose, fructose, sorbose, D-mannoheptulose, D-sedoheptulose, maltose, lactose, sucrose, cellobiose, gentiobiose, melibiose, seaweed Disaccharide, Isomalt, Maltose, Lactuate, Trehalose, Shell Disaccharide, Raffinose, Shell Trisaccharide, Stachyose, Chitosan, Tetras, Maltose, Malt Sugar, adipic acid, trans/maleic acid, malic acid, citric acid, tartaric acid, phytic acid, amber Peric acid and glycolic acid and their soluble sodium, potassium or ammonium ion salts, water-soluble basic amino acids, meglumine and water-soluble salts thereof, chloride, bromide, fluoride, phosphate , sodium hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, bisulfite, pyrosulfite, nitrate, carbonate, bicarbonate, and sodium, potassium or ammonium ion salts of percarbonate, soluble Polyoxyethylene decyl ether surfactant in water, water-soluble polyoxyethylene castor oil surfactant, water-soluble polyoxyethylene stearate surfactant, soluble in water Cyclodextrin and cyclodextrin derivatives, water-soluble oligosaccharides (degree of polymerization 7-20), water-soluble dextran, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, Hydroxypropyl cellulose, hydroxypropylmethyl cellulose, low viscosity methyl cellulose, polyvinyl alcohol, povidone, PEG (polyethylene glycol) having a molecular weight of 2000-20000 and Claim

a mixture of them.

The controlled release preparation according to any one of the preceding claims, characterized in that the water-soluble pharmaceutical additive has an average particle diameter of 5 to 250 μm.

A controlled release preparation according to any one of the preceding claims characterized in that the solubility of the water-soluble pharmaceutical additive in water (temperature 25 ° C) is not less than 100 mg / ml.

A controlled release preparation according to any one of the preceding claims, characterized in that the water-soluble pharmaceutically acceptable additive further contains a disintegrant.

The controlled release preparation according to any one of the preceding claims, characterized in that the polymer soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water is selected from the group consisting of gastric soluble polymers, Enteric polymers, enteric and gastric soluble polymers, biodegradable polymers, enzymes and/or microbial degradable polymers, and mixtures thereof.

12. The controlled release preparation according to claim 11, wherein the stomach-soluble polymer is selected from the group consisting of a cellulose derivative having a mono- or disubstituted amino group, a polyethylene derivative having a mono- or disubstituted amino group, and having a mono-substitution Amino acrylic polymer, chitosan and mixtures thereof.

The controlled release preparation according to claim 11 or 12, wherein the stomach-soluble polymer is selected from the group consisting of benzylaminomethylcellulose, diethylaminomethylcellulose, and piperidinylethylhydroxyethyl Cellulose, cellulose acetate diethylaminoacetate, vinyl diethylamine-vinyl acetate copolymer, ethylene benzylamine-vinyl acetate copolymer, polyacetal diethylaminovinyl acetate, ethylene Piperidinyl-acetylacetal ethylene copolymer, polydiethylaminomethylstyrene, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer (ie Eudragit E, Rohm-Pharma trade name), polydimethylaminoethyl methacrylate, chitosan, and mixtures thereof.

The controlled release preparation according to any one of claims 11 to 13, characterized in that the stomach-soluble polymer is selected from Eudragit E.

The controlled release preparation according to claim 11, wherein said enteric polymer is selected from the group consisting of carboxymethyl cellulose, a cellulose derivative having a monoester bond of a dibasic acid, and a dibasic acid monoester bond Polyvinyl derivatives, maleic acid monovinyl polymer, acrylic polymers, and mixtures thereof.

16. A controlled release formulation according to claim 11 or 15, characterized in that the enteric polymer is selected from the group consisting of carboxymethylcellulose, carboxymethylethylcellulose, phthalate cellulose, amber Cellulose acetate, methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl succinate Monoesters, dibasic acid monoesters of vinyl polymers, polyvinyl alcohol phthalate, polyvinyl butyl phthalate, acetyl acetal phthalate polyvinyl acetate, vinyl acetate Anhydride copolymer, butyl vinyl ether-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, methyl acrylate-methacrylic acid copolymer, styrene-acrylic acid copolymer, methyl acrylate monomethyl Acrylic acid octyl acrylate copolymer, Eudragit L, Eudragit S, Eudragit FS, shellac and mixtures thereof.

17. A controlled release formulation according to claim 11 or 15 or 16, characterized in that the enteric polymer is selected from the group consisting of Eudragit S, Eudragit FS and mixtures thereof.

The controlled release preparation according to claim 11, wherein said enteric and gastric-soluble polymer is selected from the group consisting of a vinylpyridine-acrylic copolymer, a carboxymethyl group having a mono- or disubstituted amino group. Polysaccharides, polyethylene amino acid derivatives and mixtures thereof.

19. A controlled release preparation according to claim 11 or 18, characterized in that the enteric and gastric soluble polymer is selected from the group consisting of 2-methyl-5-vinylpyridine/methyl methacrylate/methyl Acrylic acid copolymer, 2-methyl-5-vinylpyridine/methyl acrylate/methacrylic acid copolymer, 2-vinyl-5-vinylpyridine/methacrylic acid/styrene copolymer, 2-vinyl 5-vinylpyridine/methacrylic acid/methacrylic acid copolymer, 2-vinylpyridine/methacrylic acid/methacrylic acid copolymer, 2-vinylpyridine/methacrylic acid/acrylonitrile copolymer, carboxy Methyl piperidinyl starch, carboxy Claim

Methylbenzylaminocellulose, poly-2-(vinylphenyl)glycine, N-vinylglycine monostyrene copolymer and mixtures thereof.

20. The controlled release preparation according to claim 11, wherein the biodegradable polymer is selected from the group consisting of natural biodegradable polymers, aliphatic polyesters, polyamines and copolymers thereof, polyamino acids, polyphosphates. Acid esters, polycyanoacrylates, polyacrylics, poly(3_hydroxybutyrate) and copolymers thereof, polyanhydries poly (methyl vinyl ether-maleic acid), polyurethanes, and mixtures thereof.

21. A controlled release formulation according to claim 11 wherein said enzyme and/or microbial degradable polymer is selected from the group consisting of polymers containing azo or disulfide bonds, pectin, dextran, galactomannan Sugar, 9-dextrose glucuronide and mixtures thereof.

22. A controlled release formulation according to any one of claims 1 to 5, characterized in that the polymer soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water is selected from the group consisting of gastric soluble The polymer, the water-soluble medicinal additive is selected from the group consisting of the above-mentioned gastric-soluble polymer capable of neutralizing in the body digestive juice but not including water-insoluble and at room temperature (25 ° C). a pharmaceutically acceptable acidic substance in a water-soluble ambient temperature (25 ° C) of a pharmaceutically unacceptable product, such as a solid or liquid product; or soluble in the stomach and/or intestine The polymer of the digestive juice, which is insoluble or hardly soluble in water, is selected from the group consisting of enteric polymers, and the water-soluble pharmaceutical additive is selected from the above-mentioned enteric polymers to be produced in the body digestive juice. Neutralization reaction, but does not produce a pharmaceutically acceptable product which is water-soluble at room temperature (25 ° C) including a pharmaceutically unacceptable product which is insoluble in water and is a solid or liquid product at normal temperature (25 ° C). Acceptable alkaline material.

The controlled release preparation according to claim 22, wherein the acidic substance is selected from the group consisting of organic acids (such as adipic acid) which are solid at room temperature (25 ° C) and have a water-soluble carbon number of not more than 6. , trans/maleic acid, malic acid, citric acid, tartaric acid, succinic acid) or an acidic salt of sodium, potassium or ammonium ion thereof and mixtures thereof; or the basic substance selected from An inorganic alkaline salt of sodium, potassium or ammonium ion soluble in water, and a room temperature of not more than 6 carbon atoms

(25 ° C) is a solid organic base or a salt thereof, a water-soluble organic polybasic acid having not more than 6 carbon atoms, and a salt of a basic sodium, potassium or ammonium ion and their salts mixture.

The controlled release preparation according to any one of claims 1 to 5, 22 to 23, characterized in that the polymer which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water is selected The enteric-soluble polymer, the water-soluble medicinal additive is selected from the group consisting of reacting with the enteric polymer described above in a body digestive solution to produce a gas but not including water-insoluble and at room temperature (25 ° C). A water-soluble pharmaceutical additive which is a pharmaceutically unacceptable product, which is a solid or liquid product.

The controlled release preparation according to any one of claims 1 to 5, 22 to 24, characterized in that the polymer which is soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water is selected An enteric-soluble polymer, said water-soluble pharmaceutical additive selected from the group consisting of sodium, potassium or ammonium salts of hydrogencarbonate, sodium, potassium or ammonium salts of carbonates, carbonates of basic amino acids, amino acids a sodium, potassium or ammonium carbonate, a sodium, potassium or ammonium sugar based carbonate, a sodium, potassium or ammonium salt of sulfite, a sodium, potassium or ammonium salt of hydrogen sulfite, pyrosulfite Sodium, potassium or ammonium salts, sodium, potassium or ammonium percarbonates, and mixtures thereof.

The controlled release preparation according to any one of the preceding claims, characterized in that the porogen is pharmaceutically acceptable in containing or containing a pharmaceutically acceptable plasticizer. The particles of the water-soluble pharmaceutical additive coated with the polymer film of the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water are used in the controlled release film in an amount of 5% to 95%. % (weight ratio or volume ratio) based on the total dry weight or volume of the controlled release film.

27. A controlled release formulation according to any one of the preceding claims wherein the polymer film which is soluble in the stomach and/or intestinal digestive juice but which is insoluble or hardly soluble in water also contains a modulating drug A release rate of an acid or alkaline pharmaceutical additive.

28. A controlled release formulation according to any one of the preceding claims characterized in that it is insoluble or hardly soluble Claim

The water and the polymer of the stomach and intestinal digestive juice are selected from the group consisting of cellulose esters, acrylic polymers, polyvinyl acetates, polyvinyl chlorides, and the like which are insoluble or hardly soluble in water and stomach and intestinal digestive juices. Its composition.

29. A controlled release formulation according to any one of the preceding claims wherein the polymer which is insoluble or hardly soluble in water and the digestive juices of the stomach and intestine is selected from the group consisting of ethyl cellulose, cellulose acetate, propionic acid. Cellulose, cellulose acetate butyrate, cel lulose acetate propionate ^ nitrocellulose, cellulose trivalerate, cellulose tridecanoate, cellulose tripalmitate, cellulose bis succinate, Dipalmitate, polyvinyl acetate, methacrylate polymer, terpolymer of vinyl chloride-vinyl alcohol-vinyl acetate, polycarbonate, polymethyl methacrylate, ethyl acrylate a methyl acrylate polymer, ethylene acetate-vinyl chloride copolymer, polyvinyl chloride, polyethylene, polyisobutylate, poly (ethyl acrylate, me thylmet aery late, tr ime t hylamonioethylmet aery lat chloride ) and combinations thereof Things.

30. A controlled release formulation according to any one of the preceding claims wherein the polymer which is insoluble or hardly soluble in water and the digestive juices of the stomach and intestine is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, acetic acid. a ternary copolymer of cel lulose acetate propionate, containing 80 to 95% of polyvinyl chloride, 0.5 to 19% of polyvinyl acetate, and 0.5 to 10% of polyvinyl alcohol, 50 to 100% polyvinyl chloride and 0 to 50% polyvinyl acetate copolymer and mixtures thereof.

31. A controlled release formulation according to any of the preceding claims, characterized in that the controlled release film further comprises a reinforcing agent and/or a toughening agent of a pharmaceutically acceptable polymer.

A controlled release preparation according to any one of the preceding claims characterized in that said core is selected from the group consisting of a regular or irregular form of a tablet, granule, pellet, crystal or drug-loaded resin.

33. A controlled release formulation according to any one of the preceding claims wherein the drug is selected from the group consisting of central stimulants, analgesics, antipyretic analgesics, anti-inflammatory analgesics, anti-gout agents, anti-tremor Paralysis, antipsychotics, anxiolytics, antidepressants, antiepileptics, sedatives, hypnotics, anticonvulsants, autonomic nervous system drugs, calcium antagonists, drugs for the treatment of chronic heart failure, antiarrhythmias Medicine, prevention and treatment of angina pectoris, peripheral vasodilator, blood pressure lowering medicine, regulating blood lipid medicine and anti-atherosclerosis medicine, respiratory medicine medicine, antacid medicine and treating peptic ulcer medicine, gastrointestinal antispasmodic medicine, digestive medicine , antiemetics, emetics and gastrointestinal drugs, hepatobiliary diseases, urinary system drugs, drugs that affect the 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, blue Classes, cephalosporins, beta-lactamase inhibitors, aminoglycosides, tetracyclines, macrolides, anti-tuberculosis drugs, antifungals, antivirals, antitumor drugs, affecting immune function Drugs, vitamins and nutraceuticals, diet pills or herbal extracts or mixtures thereof.

34. A controlled release formulation according to any one of claims 12 to 14 wherein the drug is selected from the group consisting of alkali-labile, acid-soluble, gastric or gastric proximal, such as duodenal absorption windows. Or a drug that acts locally on the stomach or near the stomach.

The controlled release preparation according to any one of claims 12 to 14 or 34, wherein the drug is selected from the group consisting of ciprofloxacin, captopril, furosemide, ursodeoxycholic acid, and compound digestive enzymes. Traditional Chinese medicine gynecological daughter, irbesartan, glimepiride, leflunomide, medimycin, irbesartan, amoxicillin, cefuroxime, ceftriaxone, cefpodoxime, clarithromycin, C. chlorocephalosporin, azithromycin, cefixime, cefadroxil, acyclovir, diltiazem, captopril, simvastatin, lovastatin, etodolac, ketorolac, ranitidine, Famotidine, fexofenadine, pseudoephedrine, phenylpropanolamine, dextromethorphan, dextromethorphan, bromocriptine, cyclosporine, baxyphene, allopurinol, (+) alpha-carbam A 2-methoxy sulfonylaminobenzyl alcohol or 3'-(2-amino 1-hydroxyethyl-4' fluoromethanesulfon aniline (NS49), metoclopramide, verapride, alibaba , clopiride, amisulpride, sulpride, sulpiride and its salts, terazosin, alfuzosin and their .

The controlled release preparation according to any one of claims 15 to 16 or 24 to 25, characterized in that the medicine Claim

It is selected from the group consisting of acid-labile, alkali-soluble, highly toxic side effects on the stomach, strong stimulating effect on the stomach, and direct treatment in the intestine. A segment is a drug that has a basic absorption site or that requires a delayed release.

The controlled release preparation according to any one of claims 15 to 16 or 24 to 25 or 36, wherein the drug is selected from the group consisting of 5-aminosalicylic acid and a salt thereof, calcium acamprosate, adipine , alendronate, azithromycin, azinamide and its combination, aspirin, esomeprazole and its salts, ilaprazole, lycopene, dexamethasone, omeprazole and their salts, Oxaprozin, pimeprazole, benzoyl metronidazole, bisacodyl, piroxicam, propylthiouracil, bromelain and its compound, hepatocyte growth factor, aceclofenac, cephalexin Acridine, allicin, elastase, citicoline sodium, dirithromycin, adenosine succinate, succinic acid thioalanine methionine, toxin adenosine methionine, adenosylmethionine, p-amino water Sodium salicylate, faropenem sodium, fenoprofen calcium, nitrofurantoin, coenzyme Q10, bovine fetal liver extract and its compound, glutamine and its compound, anordrin and its compound, complex phosphatase, greek Pyrazine metformin compound, glutathione, Prototype glutathione, bone peptide, diammonium glycyrrhizinate, indomethacin, cyclophosphamide and its compound, erythromycin, pentoxifylline, thiamphenicol, guitarmycin, methimazole, mefenac Acid, arginine ketoprofen, clarithromycin, matrine, recombinant B subunit/bacterial cholera vaccine, compound Bacillus subtilis, bifid triple live bacteria, lysine, Rabeprazole sodium, ranitidine, tiopronin, gentamicin sulfate, ferrous sulfate glycinate complex, norfloxacin, rufloxacin, lomefloxacin, cloncloma, sulfasalazine Pyridine, hexamethylene melamine, roxithromycin, mycophenolate sodium, fosfomycin and its salts, mepafloxacin, meloxicam, mazakavir, metacycline, magnesium aspartate, Paroxetine, mifepristone, misoprostol, papain, naproxen, brain protein hydrolysate, nimesulide, uridine tegafur combination, patrazole, pantoprazole and its salts , sodium aescinate, troxerutin brain protein hydrolysate, didanosine, lysozyme, Adenosine phosphate, tribendimidine, serrapeptase, sparfloxacin, telmisartan, diclofenac sodium, ketoprofen, sodium sulfate, cytochrome C, thymosin, duloxetine, doxycycline , metformin, fluoxetine, sinomenine, acetyl-L-carnitine, acetylspiramycin, levamisole, pancreatic kininogenase, trypsin, insulin, acetylsalicylic acid, pentoxifylline, simvastatin , Tremella, colloidal pectin, taurine, calf blood deproteinized extract, rasasixin, lumbrokinase, dexketoprofen, zaltoprofen, neutral protease, levonorgest Ketone, levonorgestrel ethinyl estradiol, copper chlorophyll sodium, iriprazole, etodolac, sinomenine, magnesium isoglycyrrhizinate or vitamin E nicotinate.

The controlled release preparation according to any one of claims 15 to 16 or 24 to 25 or 36, wherein the medicine is selected from the group consisting of garlic extract, saponin extract, bear bile, cordyceps mycelium, Dragon's blood, Aspergillus oryzae trypsin (慷彼申), Zhiling mycelium, Huachansu or the trade name is standard myrtle oil, Biyuanshu, Xiaoyan Lidan, Futongning, Longjing thrombolytic, Cidan, Fupu cold, compound Eucommia, compound berberine, Gankangkang, Huixuesheng, Jiangxieling, Jiangtangjia, Leiwan, Liquor and lipid-lowering, Longxiang Pingchuan, Naomaitai, Asthma and anti-inflammatory, Qishengjing, Qishengli, Xinnaokang, Maixuekang, Pazhu Pill, Qipi, Qianlieping, 芩Redness and Cough, Yexiazhu, Yiyin Xiaoke, Cushen, Zhimaikang, Ji Ruxin, 芪Long, Sanqi Tongshu, male treasure, Chunxue An, Zhizhijia, Qigui Kechuanning, Baibaodan, Danhuangqi, compound Eucommia ulmoides, Gengnian, Kangxi, Liuwei Dihuang, Liuweimuxiang , Thrombolytic cerebral ventricle, Shen'an, Xuesaitong, cough, compound yew, phlegm, cold, heat, phlegm , G Bi bone Thailand, Naoliqing versicolor or Glucurolactone of medicine.

The controlled release preparation according to any one of claims 17 or 21, wherein the drug is selected from the group consisting of digestive enzymes for (local or direct) treatment of diseases of the colon site, and for the upper part of the digestive tract ( Such as the stomach, small intestine) drugs with strong toxic side effects or strong stimulating effects or delayed release.

The controlled release preparation according to any one of claims 17 or 21 or 39, wherein the drug is selected from the group consisting of sulfasalazine, sulfasalazine, azosalicylic acid, 5-aminosalicylic acid and Salt, ibuprofen, hydrogenated prednisone, dexamethasone, budesonide, beclomethasone, fluticasone, _tixoxone (ti _OXOC ort _a l ), hydrocortisone, metronidazole, tinidazole, Metronidazole, cyclosporine, methotrexate, piperidone, 5-fluorouracil, bisacetoxyphenylmethylpyridine, senna, thymosin, insulin, vasopressin, growth Hormone, colony stimulating factor, calcitonin, immunoglobulin, glibenclamide, diltiazem, verapamil, nifedipine, thiomethionine, benazepril, enalapril, Theophylline, naproxen, cycloflurazine, acyclovir, omeprazole, lovastatin, alendronate, desmopressin, metformin, methoxybenzamine, cisapride, tetra Hydrogen amino acridine or probiotics. Claim

41. The controlled release formulation according to claim 20, wherein the drug is selected from the group consisting of drugs that require delayed release.

The controlled release preparation according to claim 20 or 41, wherein the drug is selected from the group consisting of gepirone, risedronate, paroxetine and a salt thereof, moxonidine, a-sulfur Caprylic acid and its derivatives, metformin and its salts, gabapentin, 1R, 2S-methoxyamine, clarithromycin, lansoprazole and its salts, omeprazole and its salts, pantoprazole and its salts, lei Betazolid and its salts, esomeprazole and its salts, tatopyrazole and its salts.

43. A method of preparing a controlled release formulation according to any of the preceding claims, comprising the following basic steps:

1) preparing a core material containing a drug;

2), the particulate matter of the water-soluble medicinal additive is pharmaceutically acceptable in a stomach or/or intestinal digestive solution containing a pharmaceutically acceptable plasticizer or a plasticizer. However, a solution or dispersion of a polymer which is insoluble or hardly soluble in water coats a coating film in an amount within the range;

3), the above-mentioned core material containing a drug is coated with a solution or dispersion of a pharmaceutically acceptable polymer which is insoluble or hardly soluble in water and stomach and intestinal digestive juices containing a pharmaceutically acceptable plasticizer. a coated release film in which a polymer film which is soluble in the stomach and/or intestinal digestive solution but which is insoluble or hardly soluble in water is dispersed as a porogen in the solution or dispersion of the polymer. a particulate material coated with the above-mentioned water-soluble pharmaceutical additive, the solution or dispersion of the polymer is insoluble or non-degradable or hardly dissolved or hardly degraded, and is soluble in the stomach and/or intestinal digestive juice. A polymer that is insoluble or hardly soluble in water.

44. A method of preparing a controlled release formulation according to claim 43, characterized in that the method comprises: said polymer which is soluble in the stomach and/or intestinal digestive juice but which is insoluble or hardly soluble in water The particles of the film-coated water-soluble pharmaceutical additive are dispersed and suspended in the aqueous dispersion of the polymer which is insoluble or hardly soluble in water and stomach and intestinal digestive juice, the aqueous dispersion The pH is in the pH range in which the polymer soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water is insoluble or non-degradable or hardly soluble or hardly degraded.

45. A method of preparing a controlled release formulation according to claim 43, characterized in that the method comprises: said polymer which is soluble in the stomach and/or intestinal digestive solution but which is insoluble or hardly soluble in water The particles of the film-coated water-soluble pharmaceutical additive are dispersed and suspended in an aqueous or non-aqueous organic solvent in which the polymer insoluble or hardly soluble in water and stomach and intestinal digestive juice is dissolved. The aqueous or non-aqueous organic solvent does not dissolve or hardly dissolve the polymer which is soluble in the stomach and/or intestinal digestive juice but which is insoluble or hardly soluble in water.

46. Process for the preparation of a controlled release formulation according to any one of claims 22 to 25, characterized in that it comprises: insoluble or almost insoluble in the digestible juice to be soluble in the stomach and/or intestine The particles of the water-soluble pharmaceutical additive coated with the water-coated polymer film are dispersed and suspended in the insoluble or almost insoluble water and stomach and the pharmaceutically acceptable plasticizer. The aqueous dispersion of the polymer of the intestinal digestive juice, which is coated with the polymer film which is soluble in the stomach and/or intestinal digestive solution but which is insoluble or hardly soluble in water. The particulate matter of the water-soluble pharmaceutical additive is healed at a temperature higher than the glass transition temperature of the coating film until the end point of the state in which the permeation performance of the coating film to water is 0, at the end of the state The polymer soluble in the stomach and/or intestinal digestive solution but insoluble or hardly soluble in water and the water-soluble pharmaceutical additive described below are not in the aqueous dispersion (body) a chemical reaction occurs, or at least contains a drug The core material is coated with a controlled release film by using the aqueous dispersion of the polymer containing a pharmaceutically acceptable plasticizer which is insoluble or hardly soluble in water and a digestive juice of the stomach and intestine. A chemical reaction occurred.

A method of producing a controlled release preparation according to any one of claims 22 to 25, which comprises: using said pharmaceutically acceptable plasticizer or a plasticizer An aqueous, non-aqueous organic solution or dispersion of a polymer of the stomach and/or intestinal digestive juice but which is insoluble or hardly soluble in water, is coated with the water-soluble pharmaceutical additive and will be described a polymer film soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water coated with the water-soluble pharmaceutical additive, the particles are dispersed and suspended in the medicinal An organic, non-aqueous organic solution or dispersion of a polymer which is insoluble or hardly soluble in water and stomach and intestinal digestive juices, which is insoluble or non-degradable or hardly soluble or Almost no degradation of the soluble and soluble in the stomach and / or intestinal digestive juice Claim

A polymer that is or is almost insoluble in water.

The method for preparing a controlled release preparation according to any one of claims 43 to 47, wherein the method further comprises placing the controlled release coating film with a core material containing a drug at a higher level than The controlled release coating film is healed at a temperature at the glass transition temperature until the coated core material has stable dissolution characteristics, and the healing treatment end point is compared with the coating core material just after the healing treatment and at 40 ± 2 ° C The dissolution characteristics of the coated core material placed in the accelerated storage conditions at 70%-80% relative humidity for 3 months and/or 6 months were determined.

49. A method of preparing a controlled release formulation according to any one of claims 43 to 48, characterized in that the prepared controlled release preparation is further filled into a capsule, a pouch (small sachet) or a suitable multi-metering container by means of a metering device Or further into tablets or further prepared as a suppository or further packaged in a hemispherical container or multi-dose container.