WO2012006959A1 - Préparation de régulation de libération - Google Patents

Préparation de régulation de libération Download PDF

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Publication number
WO2012006959A1
WO2012006959A1 PCT/CN2011/077167 CN2011077167W WO2012006959A1 WO 2012006959 A1 WO2012006959 A1 WO 2012006959A1 CN 2011077167 W CN2011077167 W CN 2011077167W WO 2012006959 A1 WO2012006959 A1 WO 2012006959A1
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Prior art keywords
soluble
water
polymer
controlled release
insoluble
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PCT/CN2011/077167
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English (en)
Chinese (zh)
Inventor
钟术光
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Zhong Shuguang
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Publication of WO2012006959A1 publication Critical patent/WO2012006959A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • 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.
  • 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.
  • 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.
  • 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).
  • Aqueous water-insoluble polymer
  • 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.
  • 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
  • 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.
  • the two polymers 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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
  • 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 water-insoluble non-gaseous state ie, solid or liquid at normal temperature (25 ° C)
  • 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.
  • 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.
  • active ingredient means 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.
  • controlled release coating film 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.
  • a as used in the present invention means at least one, and may be one type or two or more types.
  • 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%.
  • 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.
  • 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.
  • the interdiffusion penetration between the polymers 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 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 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.
  • 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:
  • the above formula can be used to obtain different water-soluble medicinal additive coating weight gain W ⁇ Wi particle size increase ⁇ / ⁇ : value, as shown in the following table: 7 100. 0%
  • 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.
  • 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.
  • 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
  • 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.
  • water-soluble pharmaceutical additive 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 ⁇ m, preferably from 5 to 250 ⁇ m, more preferably from 10 to 150 ⁇ m.
  • 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.
  • 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
  • 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).
  • triose
  • 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).
  • disaccharides such as maltose, lactose, sucrose, cellobiose, gentiobiose, melibiose
  • seaweed disaccharide isomalt, maltitol, lactitol, tre
  • 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.
  • 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.
  • 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- ⁇ Polysorbate 61, Polysorbate 65, soluble in water Polyoxyethylene stearate surfactant (such as Polyoxyl 150 di
  • 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- ⁇ -cyclodextrin, hydroxypropyl/ethyl- ⁇ -cyclodextrin, branched- ⁇ -cyclodextrin, glycosyl-cyclodextrin, sulfobutyl ether a ⁇ -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-isomalto
  • 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 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.
  • 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-mannoheptu
  • 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.
  • 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
  • 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 ⁇ -cyclodextrin, ⁇ -cyclodextrin, 2,6-dimethyl- ⁇ -cyclodextrin, hydroxypropyl/ethyl- ⁇ -) Cyclodextrin, branched-chain ⁇ -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), oli
  • 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.
  • 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 ⁇ m.
  • Nonparei l 105 100-200 ⁇ m 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 ⁇ m and spherical cellulose product containing crystalline cellulose (3 parts) and lactose (7 parts) Nonparei l NP-7: 3, 150 ⁇ 250 ⁇ m 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.
  • polymer soluble in the stomach and/or intestinal digestive juice but insoluble or hardly soluble in water 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.
  • (a) include, but are not limited to, benzylaminomethylcellulose, diethylaminomethylcellulose, piperidinylethylhydroxyethylcellulose, cellulose acetate diethylaminoacetate
  • 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
  • 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.
  • (1) include, but are not limited to, carboxymethylcellulose, carboxymethylethylcellulose (CMEC), and mixtures thereof
  • 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
  • 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
  • enteric polymers include carboxymethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, Eudragit. L, Eudragit S, Eudragit FS or shellac.
  • 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.
  • 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.
  • carboxymethyl polysaccharide having a mono- or di-substituted amino group examples include, but are not limited to, carboxymethyl piperidinyl starch, carboxymethylbenzylaminocellulose, and mixtures thereof.
  • polyvinyl amino acid derivative examples include, but are not limited to, poly-2-(vinylphenyl)glycine, N-vinylglycine-styrene copolymer, and mixtures thereof.
  • 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 vinylpyrrolidon
  • 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
  • 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.
  • 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
  • the delayed release of the drug is selected from Eudragit S, Eudragit FS, enzymes in the colon and/or microbial degradable polymers.
  • 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).
  • 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.
  • 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)
  • Acid, tartaric acid, phytic acid, succinic acid) and acidic sodium, potassium or ammonium acid salts thereof are included in the acidic or alkaline water-soluble medicinal additive.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a relatively high level of porogen is beneficial to improve the mechanical properties 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.
  • 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:
  • volume of ⁇ empty release film volume of technical release film
  • 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.
  • 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.
  • an organic acid such as decanoic acid is added to the enteric polymer film to delay dissolution of the film.
  • 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.
  • 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. .
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • solubility parameter can characterize the amount of cohesive force between polymer molecules, it can be used to evaluate the compatibility of polymer blends. 5 ⁇ , ⁇ 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.
  • 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.
  • Tg glass transition temperature
  • 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.
  • 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.
  • ethyl cellulose EC
  • 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.
  • 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.
  • 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.
  • the present invention may add two or more kinds of water-insoluble polymers as a mixed film forming agent.
  • 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.
  • 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.
  • Tg glass transition temperature
  • 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.
  • 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.
  • Mr is about 150 to 800, preferably 300 to 500
  • 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.
  • plasticizers examples include dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, triethyl citrate, acetyl citrate Ethyl ester, triacetin, tributyl alginate, sorbitan ester, sucrose ester.
  • plasticizers examples include 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-adherents 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).
  • 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%.
  • the stabilizer is preferably an emulsifier or a surfactant, that is, a certain interface active material, which stabilizes the dispersion (body).
  • 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.
  • 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.
  • the antifoaming agent is generally dimethicone.
  • 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 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
  • the present invention is particularly suitable for the need for controlled release of Chinese herbal medicines.
  • 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.
  • 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, ⁇ 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.
  • 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.
  • the method of preparing the core material containing one drug is not particularly limited.
  • 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.
  • 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.
  • a pharmaceutically acceptable plasticizer or a plasticizer-free soluble in the stomach and/or intestinal digestive juice a pharmaceutically acceptable plasticizer or a plasticizer-free soluble in the stomach and/or intestinal digestive juice.
  • 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.
  • 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.
  • 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 ⁇ m, typically no greater than 10 ⁇ m, preferably no greater than 1 ⁇ m, 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.
  • 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
  • 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).
  • 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.
  • MFT minimum film forming temperature
  • 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.
  • 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.
  • fluidized bed coating such as coating temperature, fluidizing volume, atomization pressure and spray rate, can be optimized according to the actual situation.
  • 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.
  • aqueous dispersion body
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m, preferably 50 to 300 ⁇ m, more preferably 100 to 200 ⁇ m.
  • 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.
  • MFT minimum film forming temperature
  • 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.
  • 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.
  • a water-soluble material such as a solution of hydroxypropylmethylcellulose and hydroxypropylcellulose
  • a polymer organic solution may be selected for the barrier coating.
  • 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.
  • 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.
  • the healing treatment is performed after the completion of the coating.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • the fluidized bed method 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.
  • the drug-loading core may be provided with a barrier layer. Clothing, or reduce the heat treatment temperature.
  • 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.
  • controlled release release such as gastric, intestinal, colon controlled release release
  • Brightness 7 can achieve delayed release of drug release in the gastrointestinal tract, gap or pulsed controlled release.
  • Example 1 and Comparative Example 1-2 further describe preferred embodiments within the scope of the invention. Many variations of these embodiments are possible within the scope of the invention.
  • 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.
  • a centrifugal fluidized coating granulator manufactured by Powrex Corp. (Japan), MP-10
  • sodium hydrogencarbonate particles particles (particle size: 300 to 400 mesh, 38 to 48 ⁇ m) 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%.
  • 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.
  • 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. .
  • the moisture barrier coating has a weight gain of about 1%.
  • 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 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
  • 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.
  • the healing treatment is carried out in a closed oven.
  • the healing temperature was 65 ° C and the healing time was 30 hours.
  • 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.
  • 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.
  • 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 ⁇ , 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 stomach coating film package is obtained. Coating of gastric coated film coated with sodium dihydrogen citrate core (particle size 53 ⁇ 62 ⁇ m).
  • the core of the film is coated according to the following prescriptions and techniques:
  • 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%.
  • the healing treatment is carried out in a closed oven.
  • the healing temperature was 45 °C and the healing time was 24 hours.
  • 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 ⁇ m microporous membrane, and the filtrate was taken and diluted with water to prepare a solution containing about 8 ⁇ g per 1 ml.
  • 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.
  • 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.
  • 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 ⁇ ⁇ ) were obtained. .
  • Kol l icoat SR 30 D polyvinyl acetate 111. 1 30
  • Aqueous dispersion (body) Aqueous dispersion (body)
  • Titanium dioxide (particle size 20nm) 2 2
  • the healing treatment is carried out in a closed oven.
  • the healing temperature was 45 ° C and the healing time was 24 hours.
  • 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 ⁇ ⁇
  • 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 ⁇ ⁇ ) 45g, triacetin 1. 8g, titanium dioxide (particle size 20nm) 2g, ethanol 1000ml.
  • Granulac® 140 (Lactose) 100
  • 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
  • N3 ⁇ 4C0 3 is suitable for 1 ⁇
  • 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.
  • a solution of pectin-guar prepared above was cast on a Teflon plate to form a film having a thickness of 250 500 ⁇ m, 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.
  • 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.
  • SCF Artificial Colonic Fluid
  • 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.
  • Shellac (acid value 70) (pH greater than 7.5 dissolved) 13. 5
  • a colon coating film-coated granule coating suspension is prepared according to the above coating liquid formulation.
  • sucrose powder particle diameter: 48 to 58 ⁇ m
  • the sucrose powder was sprayed with the coating liquid prepared above, and the sucrose powder gained about 20% by weight.
  • the obtained granules were sieved through a 270 mesh circular sieve (53 ⁇ m) and a 230 mesh circular sieve (62 ⁇ m) to obtain a 230-270 mesh powder containing a powdered sugar core (particle size 53 to 62 ⁇ ⁇ ).
  • the core of the film is coated according to the following prescriptions and techniques:
  • Nano-alumina dispersion (average particle size 10nm) 0.6 0.6
  • 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%.
  • the shellac coating liquid prepared above is cast on a polytetrafluoroethylene sheet to form a film having a thickness of 250 to 500 ⁇ m, dried and pulverized at a temperature of 40 to 30 ° C, and the obtained granules are passed through a 270 mesh circular sieve ( 53 ⁇ ) and a 230 mesh circular sieve (62 ⁇ m) were sieved to obtain particles of 53 to 62 ⁇ m.
  • a shellac-containing granule control article 8 was prepared in accordance with the above methods and conditions.
  • a solution of the polymer poly ( ⁇ -caprolactone) and HP-50 was prepared according to the above coating liquid formulation.
  • the sucrose powder (particle size: 53 61 ⁇ ) is placed in a centrifugal fluidized granulator to be tumbling, and the above poly( ⁇ - 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 ⁇ m (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 ⁇ (particle weight gain of about 5%). After drying, a sugar pill containing a delayed release film was obtained.
  • 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%.
  • 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
  • the healing treatment is carried out in a closed oven.
  • the healing temperature was 65 ° C and the healing time was 30 hours.
  • the poly-caprolactone coating solution prepared above was cast on a polytetrafluoroethylene plate to form a film having a thickness of 250 500 ⁇ m, dried and pulverized at a temperature of 40 30 ° C, and the obtained granules were passed through a 180-mesh circular sieve (80 ⁇ m) and 170 mesh circular sieve (90 ⁇ m) sieve, prepare 80 90 ⁇ m particles, and then spray the above solution of HP-50 solution by the above process, the thickness of the coating layer is about ⁇ (particle weight gain about 5%).
  • a granular control article containing poly( ⁇ -caprolactone) according to the above method and conditions 9
  • Example 8 The sodium bicarbonate particles (particle size 300-400 mesh, 38-48 ⁇ m) in Example 1 gained about 300%, and the obtained particles were dried and healed by a 200-mesh circular sieve (75 ⁇ m) and 240. The mesh was sieved through a circular sieve (61 ⁇ m) to obtain particles (particle size: 61 to 75 ⁇ m) containing a sodium hydrogencarbonate core. The granules (particle diameter 61 to 75 ⁇ m) obtained above were prepared in accordance with the formulation and process described in Example 1.
  • Example 8 Example 8
  • Example 9 The sodium bicarbonate particles (particle size 300-400 mesh, 38-48 ⁇ m) in Example 1 gained about 700% by weight, and the obtained particles were dried and healed by a 160-mesh circular sieve (96 ⁇ m) and 200. The mesh was sieved through a circular sieve (75 ⁇ m) to obtain particles (particle size 75 to 96 ⁇ m) containing a sodium hydrogencarbonate core. The pellets (particle size 75 to 96 ⁇ m) obtained above were prepared in accordance with the formulation and process described in Example 1. Example 9
  • Example 10 The mannitol particles (particle diameter: 15 to 25 ⁇ m) in Example 3 were weight-increased by about 200% to obtain granules coated with two coats of gastrointestinal coating (particle diameter: 23 to 38 ⁇ m). The pellets obtained by the above (particle diameter 23 to 38 ⁇ m) were prepared in accordance with the formulation and process described in Example 3.
  • Example 10 The pellets obtained by the above (particle diameter 23 to 38 ⁇ m) were prepared in accordance with the formulation and process described in Example 3.
  • Example 4 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
  • 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 ⁇ m) 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%.
  • 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 ⁇ m) : diacetin is 1:1.5:1 (weight ratio) Example 12 and Comparative Example 11
  • a coating liquid of a vinyl acetate-maleic anhydride copolymer was prepared in accordance with the above coating liquid formulation.
  • a centrifugal fluidized coating granulator manufactured by Powrex Corp. (Japan), MP-10
  • glucose particles particle diameter: 300 to 400 mesh, 38 to 48 ⁇ m
  • 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 ⁇ m) and 300-mesh circular sieves (48 ⁇ m) were sieved to obtain enteric coating film-containing granules (particle size 48 to 61 ⁇ ⁇ ) containing a glucose core.
  • Example 12 was prepared according to the formulation and process of Example 1; the carboxymethylethylcellulose particles (particle size 48 ⁇ 61 ⁇ ) 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 ⁇ m.
  • a coating liquid of polyvinyl alcohol phthalate was prepared according to the above coating liquid formulation.
  • a centrifugal fluidized coating granulator manufactured by Powrex Corp. (Japan), MP-10
  • trisodium citrate particles particle diameter: 150 to 100 mesh, 106 to 150 ⁇ m
  • 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%.
  • the obtained particles are passed through a 115 mesh circular sieve (125 ⁇ ⁇ And sieving with an 80-mesh circular sieve (180 ⁇ m) to obtain enteric coating film-coated granules (particle diameter: 125 to 180 ⁇ m) 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 ⁇ ⁇ ), and the others were unchanged.
  • a coating liquid of cellulose acetate diethylaminoacetate was prepared in accordance with the above coating liquid formulation.
  • a centrifugal fluidized coating granulator manufactured by Powrex Corp. (Japan), MP-10
  • citric acid particles particle diameter: 300 to 400 mesh, 38 to 48 ⁇ m
  • 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 ⁇ , 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 ⁇ ⁇ ) and a 300 mesh circular sieve (48 ⁇ ⁇ ) sifting to obtain particles containing a niobate core (particle size 48 ⁇ 61 ⁇ ⁇ ).
  • 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.
  • the healing treatment is carried out in a closed oven.
  • the healing temperature was 65 ° C and the healing time was 36 hours.
  • Example 15 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 ⁇ ⁇ ), and the others were unchanged.
  • a coating liquid of ethylene piperidinyl-acetyl acetal ethylene copolymer was prepared in accordance with the above coating liquid formulation.
  • sucrose particles particles (particle diameter: 150 to 100 mesh, 106 to 150 ⁇ m) 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 ⁇ m) and an 80-mesh circular sieve (180 ⁇ m) to obtain a vinyl piperidinyl-acetylacetal ethylene copolymer-coated granule (particle size: 125 to 180 ⁇ m) containing a sucrose core.
  • Kol l icoat SR 30 D polyvinyl acetate 111. 1 30
  • Aqueous dispersion (body) Aqueous dispersion (body)
  • Titanium dioxide (particle size 20nm) 2 2
  • the coating solution is prepared 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%.
  • the healing treatment is carried out in a closed oven.
  • the healing temperature was 45 ° C and the healing time was 36 hours.
  • 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 ⁇ ⁇ ), and the others were unchanged.
  • Example 16 and Comparative Example 15
  • a coating liquid of carboxymethylbenzylaminocellulose was prepared in accordance with the above coating liquid formulation.
  • sorbose granules having a particle size of 300 to 400 mesh, 38 to 48 ⁇ m
  • 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 ⁇ m) and 300 mesh circular sieves (48 ⁇ m) were sieved to obtain granules containing sorbose core (particle size 48 to 61 ⁇ ⁇ ).
  • Example 16 was prepared according to the formulation and process of Example 3; the carboxymethylethylcellulose particles (particle size 48-61 ⁇ ) 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 ⁇ m.
  • a suspension coating solution of chitosan was prepared according to the above formulation of the coating solution.
  • a centrifugal fluidized coating granulator manufactured by Powrex Corp. (Japan), MP-10
  • citric acid particles particle diameter: 300 to 400 mesh, 38 to 48 ⁇ m
  • 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 ⁇ m) and a 300-mesh circular sieve (48 ⁇ m) to obtain granules having a niobic acid core (particle diameter: 48 to 61 ⁇ m).
  • 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 ⁇ m thick coating to the tablet with the coating solution.
  • Test Example 1 Drug release stability test
  • 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
  • Example 2 Sample and Control Supplies Drug Release at pH 2.5
  • 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.
  • 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.
  • 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.
  • 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

Abstract

L'invention porte sur une préparation de régulation de libération ayant des performances améliorées et sur un procédé de préparation de la préparation de régulation de libération. La préparation de régulation de libération comprend un noyau contenant des médicaments et un enrobage de régulation de libération enrobé sur le noyau. L'enrobage de régulation de libération contient un plastifiant, un polymère qui est insoluble dans l'eau et un suc digestif gastro-intestinal, et des particules d'un porogène qui sont incorporées dans le polymère et enrobées par un enrobage de polymère soluble dans un suc gastrique et/ou un suc intestinal mais insoluble dans l'eau. La reproductibilité de la libération de médicaments de l'agent de régulation de libération est améliorée, le retard de libération est réduit, et la biodisponibilité est améliorée. Par conséquent, le positionnement de la libération de médicaments dans le tractus gastro-intestinal est obtenu.
PCT/CN2011/077167 2010-07-16 2011-07-14 Préparation de régulation de libération WO2012006959A1 (fr)

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