WO2013040873A1 - 一种治疗肠道疾病的药物缓控释微粒制剂及其制备方法 - Google Patents

一种治疗肠道疾病的药物缓控释微粒制剂及其制备方法 Download PDF

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WO2013040873A1
WO2013040873A1 PCT/CN2012/071756 CN2012071756W WO2013040873A1 WO 2013040873 A1 WO2013040873 A1 WO 2013040873A1 CN 2012071756 W CN2012071756 W CN 2012071756W WO 2013040873 A1 WO2013040873 A1 WO 2013040873A1
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drug
coating
layer
release
controlled release
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PCT/CN2012/071756
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English (en)
French (fr)
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赵建成
石宗丰
慕晓军
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贝沃特医药技术(上海)有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a controlled release micropellet or a microparticle preparation of a medicament for treating intestinal diseases (5-aminosalicylic acid); in addition, the invention also relates to the preparation of the above-mentioned slow application by using a multi-layer coating technique.
  • a method of controlled release pellets or microparticle formulations is also provided.
  • Mesalazine ie 5-aminosalicylic acid
  • Mesalazine is mainly used clinically for the treatment of Chron's disease and ulcerative colitis.
  • the dosage is higher (4g is often used in the prescription), and there is some stimulation to the stomach, and the treated site is in the colon.
  • oral products on the market are prepared by slow release and controlled release. Products to reduce the number of doses and stimulation of the human body, improve the efficacy.
  • most of the products and technologies involved in the invention can not achieve the intended purpose, mainly because the dosage is too high, resulting in a relatively low application space of the auxiliary materials in the preparation process, and it is difficult to achieve the effects of sustained release and intestinal positioning at the same time.
  • Pellets are a new type of multi-drug delivery system, which has less physiological impact than conventional preparations; large gastrointestinal tract distribution area can improve bioavailability and reduce local irritation; release behavior is easy to control (such as colon positioning, slowing Interpretation, etc., the advantages of small individual differences.
  • the ideal process for the preparation of mesalazine (ie 5-aminosalicylic acid) sustained-release pellets includes mixing, granulating, extruding, spheronizing and drying of the main drug and the sustained-release polymer material and other auxiliary materials. Then, the obtained pellets are enteric coated, so that the drug does not release in the gastric juice in advance, and then enters the intestinal tract before releasing the drug, which is beneficial to reducing the stimulation of the main drug to the stomach and increasing the lesion site (colon). Drug concentration.
  • the Chinese patent with the patent number CN00808889.6 also has the above-mentioned defects and cannot achieve the purpose of intestinal positioning release;
  • the Chinese patent No. CN200410020455.6 discloses a colon-positioned pellet system, but its sustained release function. And the apparent increase in drug loading is not sufficient; and the disclosure of the CN200480010790.6 patent does not solve the problem of early release in gastric juice;
  • the CN200810232858.5 patent discloses a colon-targeted tablet preparation technique, and the beauty salad Qin takes a higher dose, and the size of the tablets produced is generally larger (if the tablet is small, the number of tablets that the patient needs to take will be greatly increased). From a clinical point of view, the large-sized tablets are subjected to gastric emptying after taking them. The impact is greater (especially when passing through the pylorus), so it is easy to cause individual differences and affect the efficacy.
  • the technical problem to be solved by the present invention is to provide a drug controlled release microparticle preparation for treating intestinal diseases and a preparation method thereof, which use a multi-layer coating technology to uniformly disperse a drug and a sustained-release coating material in pellets or small
  • the surface of the beads can effectively solve the problem of uniformity of mixing of the auxiliary materials and the main drug.
  • the present invention provides a drug controlled release microparticle preparation for treating intestinal diseases, wherein the main active ingredient of the preparation is 5-aminosalicylic acid, and the preparation comprises:
  • a) medicated pellet core containing 5-aminosalicylic acid and auxiliary materials;
  • Isolation layer The main function of this layer is to make the surface of the small particles tend to be smooth and round, and prevent the drug from infiltrating into the sustained release coating layer to affect the release effect.
  • the layer mainly uses materials including one or more kinds of water-soluble polymers and suitable anti-adhesive agents; the water-soluble polymer refers to a strongly hydrophilic polymer material, which can dissolve or swell in water to form an aqueous solution or dispersion. a system; the anti-adhesive agent is a substance that prevents adhesion during the coating process;
  • Sustained release coating layer The main function of this layer is to release the drug slowly and slowly.
  • the thickness of the layer can be adjusted by spraying different coating liquids (generally 0.5 ⁇ 12%).
  • Enteric coating layer The main function of this layer is to avoid the early release of the main drug in the gastric juice, reduce the stimulation of the main drug on the stomach, and improve the local concentration of the drug in the lesion; the layer mainly uses the polymer enteric material.
  • the polymer enteric material is a kind of pH-dependent polymer material in a sustained-release material, which is insoluble in gastric juice (pH ⁇ 5), and can be quickly dissolved under higher pH conditions (such as in intestinal juice).
  • the drug-containing pellet core is prepared by a pellet core medicine process or an extrusion spheronization process;
  • the auxiliary material comprises one or more of the following excipients: povidone PVP, hypromellose HPMC, sodium carboxymethyl cellulose CMC-Na, methyl cellulose MC, hydroxypropyl cellulose HPC, Hypromellose phthalate HPMCP, microcrystalline cellulose, starch, dextrin, lactose, magnesium stearate, water.
  • the drug-containing pellet core is prepared by a pellet core medicine process
  • the accessory material comprises one or more of the following auxiliary materials: sucrose, microcrystalline cellulose, starch, povidone PVP, hydroxypropyl cellulose HPC, Hypromellose phthalate HPMCP, hypromellose HPMC, talc.
  • the medicated pellet core is prepared by an extrusion spheronization process comprising a forming agent or diluent, a binder, and a lubricant, preferably microcrystalline cellulose, povidone PVP, and magnesium stearate.
  • the content of 5-aminosalicylic acid in the drug-containing pellet core is 50 ⁇ 99%, preferably 70 ⁇ 85%, microcrystalline cellulose content is 5% ⁇ 40%, preferably 10 ⁇ 22%, povidone PVP content is 1 ⁇ 15%, preferably 4 ⁇ 9%
  • the magnesium stearate content is 0 to 8%, preferably 0.1 to 1.5%.
  • the material used for the release layer includes one or more of the following: talc, titanium dioxide, kaolin, povidone PVP, hypromellose HPMC, hydroxypropyl cellulose HPC, polyvinyl alcohol PVA, Hypromellose phthalate HPMCP, polyethylene glycol PEG.
  • the material for use of the sustained-release coating layer includes one or more of the following: cellulose derivatives, acrylic resin derivatives, and other useful sustained-release materials.
  • the cellulose derivative refers to a product obtained by esterification or etherification reaction of a hydroxyl group in a cellulose polymer with a chemical reagent; the acrylic resin derivative means a methacrylic acid copolymer and a methacrylate A general term for copolymers.
  • the polymer enteric material used in the enteric coating layer comprises one or more of the following: an acrylic resin, shellac, cellulose acetate phthalate CAP, and other usable enteric materials, and Selected anti-adhesives, plasticizers, solvents.
  • the acrylic resin-based polymer is also referred to as an acrylic resin derivative, and is a generic term for a methacrylic acid copolymer and a methacrylate copolymer.
  • the anti-adhesive agent is a kind of substance for preventing adhesion in the coated medicine during the preparation coating process;
  • the plasticizer refers to a kind of compound for improving the flexibility of the coated film;
  • the shellac is an enteric package
  • One kind of clothing material is the gum secreted by the lac insect insect lac insect on the branches.
  • the auxiliary layer used in the separation layer is talc powder and povidone PVP, and the weight ratio thereof is 1:2 ⁇ 5:1
  • the coating level reaches a weight gain of 0 to 15%, preferably 2 to 5%
  • the main auxiliary material used for the sustained-release coating layer is ethyl cellulose and talc
  • the solid weight ratio is 2:1.
  • the coating level reaches 0.5 to 12%, preferably 1 to 4%
  • the auxiliary material used for the enteric coating layer is acrylic resin, preferably 5:1 to 7:1.
  • the present invention also provides a preparation method of a drug controlled release microparticle preparation for treating intestinal diseases, comprising the following steps:
  • the drug-containing pellet core obtained in the step (1) is placed in a coating device, and a release layer coating, a sustained-release coating layer coating, and an enteric coating layer coating are sequentially performed.
  • the preparation of the drug-containing pellet core adopts a pellet core medicine process or an extrusion spheronization process;
  • the pellet core medicine process is specifically: the components of the pellet core material are sufficiently stirred uniformly to prepare a solid content of 10 -20% of the suspension is ready for use; the pellet core is loaded Coating equipment And preheating, when the bed temperature is higher than 35 ° C, the suspension of the drug is pumped until the end, the container and the pipe are rinsed with a small amount of water, and dried to obtain a pill core;
  • the extrusion spheronization process is specifically: The components of the drug-containing core material are thoroughly mixed, and then an appropriate amount of water is added to prepare a soft material, and the obtained soft material is further extruded and granulated, and then spheronized by a rounding machine to obtain a suitable size wet pulp core. Further drying and sieving, the pellet core is obtained.
  • the step (3) is specifically: placing the drug-containing pellet core prepared in the step (1) into a fluidized bed, preheating with hot air to make the bed temperature greater than 35 ° C, and starting to spray the separation layer coating liquid for coating the separation layer.
  • the flow rate of the coating liquid is about 1.5 ⁇ 3.5g/min, the atomization pressure is 0.7 ⁇ 2.5kg/m 2 , and the bed temperature is kept at 25 ⁇ 35°C.
  • the hot air is dried for 20min, and the sustained release layer is sprayed.
  • the coating liquid is coated with a slow release layer.
  • the flow rate of the coating liquid is about 1.5 ⁇ 3.5g/min, the atomization pressure is 0.7 ⁇ 2.5kg/m 2 , the bed temperature is kept at 25 ⁇ 35°C, and the drying is continued for 20min after the coating is completed. Then, spraying the enteric layer coating liquid to coat the enteric layer, the flow rate of the coating liquid is about 1.5-3.5 g/min, the atomization pressure is 0.7-2.5 kg/m 2 , and the bed temperature is maintained at 25-45 ° C, then Continue to dry until the product moisture is below 3%.
  • the present invention has the following beneficial effects: the drug controlled release microparticle preparation for treating intestinal diseases of the present invention and the preparation method thereof, so that the main medicine and the functional auxiliary material in the preparation product can be effectively
  • the uniform distribution of the pellets or beads on the surface and the release of the drug in a controlled manner can further ensure the homogeneity of any component in the product, mainly in:
  • a uniform content of the drug-containing pellet core can be prepared by using a coating technique or an extrusion spheronization process
  • Coating layer is coated on the surface of the drug-containing core with a coating technology to ensure that the drug in the core does not penetrate into the sustained-release coating layer, and the surface of the pellet tends to be smooth and round;
  • the prepared drug can achieve the purpose of intestinal positioning and sustained release at the same time without increasing the drug loading ratio of the auxiliary materials;
  • each pellet is administered as a pellet, which is less affected by physiological factors and can enter the intestine quickly. After entering the intestine, each pellet can be slowly released as a release unit, achieving a long-term mechanism, reducing the number of medications and increasing the number of medications. Compliance when the patient takes the medicine;
  • Fig. 1 is a graph showing the results of in vitro release curves of pellets in Example 6 under simulated pH conditions of the gastrointestinal tract.
  • the preparation method of the pellet core taking the above-mentioned drug-containing pellet core prescription components 1, 3, 4 and stirring well, preparing a suspension having a solid content of 10-20% for use; and loading the component 2 blank pellet core into the coating equipment and preheating When the bed temperature is higher than 35 °C, the suspension of the drug is pumped until the end, and the container and the pipe are rinsed with a small amount of water, and dried to obtain a qualified immediate release drug-containing pellet core.
  • the povidone and talc powder are dispersed in an aqueous solution ( components 1, 2, and 3 in the coating formulation), and the coating liquid of the separation layer is prepared by using a 60-mesh sieve.
  • Ethylcellulose and talc are dispersed in an aqueous solution ( component 6 in the coating formulation), mixed and stirred evenly, and passed through a 60 mesh sieve to prepare a slow-release coating solution;
  • Component 7 was dispersed in component 8 and sieved through a 60 mesh screen to form an enteric layer coating solution.
  • Coating process placing the prepared drug-containing immediate release pellet core into a fluidized bed or other coating equipment, preheating with hot air to make the bed temperature greater than 35 ° C, starting to spray the isolation layer coating liquid coating isolation layer, coating
  • the liquid flow rate is about 1.5g / min, the pressure is 0.7kg / m 2 (the bed temperature is kept at 25 °C), after the coating is finished, continue to blow dry air for 20min, continue to carry out the sustained release coating (spray release layer coating liquid)
  • the flow rate of the coating liquid is about 1.5g / min, the pressure is 0.7kg / m 2 (the bed temperature is kept at 25 ° C)), the drying is continued for 20 minutes after the coating is completed, and then the enteric coating is applied (spraying the enteric layer coating solution,
  • the flow rate of the coating liquid is about 1.5 g / min, the pressure is 0.7 kg / m 2 (the bed temperature is maintained at 25 ° C)), and then drying is continued until the product moisture is less than 3%.
  • the preparation method of the pellet core the above components are thoroughly mixed, and different types of mixing equipment or a high shear wet granulator can be used, and then an appropriate amount of water is added to prepare the soft material.
  • the obtained soft material is further extruded and granulated, and then spheronized by a rounding machine to obtain a wet pellet core of a suitable size, which is further dried and sieved to obtain a qualified drug-containing instant release pellet core.
  • the povidone and talc powder are dispersed in an aqueous solution ( components 1, 2, and 3 in the coating formulation), and the coating liquid of the separation layer is prepared by using a 60-mesh sieve.
  • the components 4 and 5 in the prescription are dispersed in the aqueous solution of the prescription component 6 , mixed and dispersed uniformly, and passed through a 60 mesh sieve to prepare a sustained release layer coating liquid for use; and the components 7 , 8 , and 9 are dispersed in the component 10 In the water, and through a 60 mesh sieve to make an enteric coating solution for use.
  • Coating process placing the prepared drug-containing immediate release pellet core into a fluidized bed or other coating equipment, preheating with hot air to make the bed temperature greater than 35 ° C, starting to spray the isolation layer coating liquid coating isolation layer, coating
  • the liquid flow rate is about 3.5g / min, the pressure is 2.5kg / m 2 , (the bed temperature is maintained at 35 ° C), after the coating is finished, continue to blow dry air for 20min, continue to carry out the sustained release coating (spray release coating) Liquid, coating liquid flow rate of about 3.5g / min, pressure 2.5kg / m 2 , (the bed temperature is maintained at 35 ° C)), after the coating is completed, continue to dry for 20min and then enteric coating (spraying the enteric layer coating
  • the liquid, the coating liquid flow rate is about 3.5g / min, the pressure is 2.5kg / m 2 , (the bed temperature is maintained at 35 ° C)), and then continue to dry until the product moisture is less than 3%.
  • the preparation method of the pellet core the above components are thoroughly mixed, and different types of mixing equipment or a high shear wet granulator can be used, and then an appropriate amount of water is added to prepare the soft material.
  • the obtained soft material is further extruded and granulated, and then spheronized by a rounding machine to obtain a wet pellet core of a suitable size, which is further dried and sieved to obtain a qualified drug-containing instant release pellet core.
  • the povidone and talc powder are dispersed in an aqueous solution ( components 1, 2, and 3 in the coating formulation), and the coating liquid of the separation layer is prepared by using a 60-mesh sieve. Disperse the components 4 and 5 in the coating formulation in an aqueous solution ( component 6 in the coating formulation), mix and stir evenly, and pass through a 60 mesh sieve to prepare a sustained release layer coating solution for use; component 7 and components 8 Disperse in component 9 and disperse well, and pass through a 60 mesh sieve to make an enteric coating solution.
  • Coating process the prepared drug-containing immediate release pellet core is placed in a fluidized bed or other coating equipment, preheated with hot air to make the bed temperature greater than 35 ° C, and the separation layer is started, and the flow rate of the coating liquid is about 2 g / min.
  • the preparation method of the pellet core the above components are thoroughly mixed, and different types of mixing equipment or a high shear wet granulator can be used, and then an appropriate amount of water is added to prepare the soft material.
  • the obtained soft material is further extruded and granulated, and then spheronized by a rounding machine to obtain a wet pellet core of a suitable size, which is further dried and sieved to obtain a qualified drug-containing instant release pellet core.
  • Preparation of the coating liquid firstly disperse hypromellose and talc in an aqueous solution ( components 1, 2, 3 in the coating formulation), and pass through a 60 mesh sieve to form a barrier coating solution;
  • the coating prescription components 4 and 5 are dispersed in the aqueous solution of the prescription component 6 , mixed and stirred uniformly, and passed through a 60 mesh sieve to prepare a sustained release layer coating liquid for use; and component 7 is dispersed in 2/3 of the component 10
  • the enteric coating solution was prepared by using a 60 mesh sieve.
  • Coating process the prepared drug-containing immediate release pellet core is placed in a fluidized bed or other coating equipment, preheated with hot air to make the bed temperature greater than 35 ° C, and the isolation layer is started, and the flow rate of the coating liquid is about 3 g / min.
  • the preparation method of the pellet core the above components are thoroughly mixed, and different types of mixing equipment or a high shear wet granulator can be used, and then an appropriate amount of water is added to prepare the soft material.
  • the obtained soft material is further extruded and granulated, and then spheronized by a rounding machine to obtain a wet pellet core of a suitable size, which is further dried and sieved to obtain a qualified drug-containing instant release pellet core.
  • the povidone and talc powder are dispersed in an aqueous solution ( components 1, 2, and 3 in the coating formulation), and the coating liquid of the separation layer is prepared by using a 60-mesh sieve.
  • the coating formulation of the components 4, 5, 6 are dispersed in an aqueous solution (component in the coating formulation 7), mixed and stirred uniformly, through a 60 mesh sieve sustained release layer coating liquid reserve;
  • Components 8 and Component 9 was dispersed in component 10 and thoroughly dispersed, and passed through a 60 mesh sieve to prepare an enteric coating solution.
  • Coating process the prepared drug-containing instant release pellet core is placed in a fluidized bed or other coating equipment, preheated with hot air to make the bed temperature greater than 35 ° C, and the spray coating layer is sprayed, and the flow rate of the coating liquid is about 3g /min, pressure 2kg / m 2 , (the bed temperature is maintained at 30 ° C), after the coating is finished, continue to blow dry air for 20min, continue to carry out the sustained release coating (spray release layer coating solution, coating liquid
  • the flow rate is about 3g / min, the pressure is 2kg / m 2 , (the bed temperature is kept at 30 ° C)), the drying is continued for 20 minutes after the coating is completed, and then the enteric coating is applied (spraying the enteric layer coating liquid, the flow rate of the coating liquid is about 3g / min, pressure 2kg / m 2 , (the bed temperature is maintained at 30 ° C)), and then continue to dry until the product moisture is less than 3%, that is.
  • Example 2 The pellets of Example 2 were subjected to a release test for simulating the pH change of each segment of the gastrointestinal tract, and the release conditions were: USP basket method, rotation speed 100 rpm, 900 mL of dissolution medium at 37 ⁇ 0.5 °C. 0 ⁇ 2h
  • the dissolution medium is pH HCl solution, and the dissolution medium is replaced in the third hour.
  • Table 1 and Figure 1 show the results of the release of the pellets of Example 2 at different pH conditions in the simulated gastrointestinal tract, SD
  • Table 1 and Figure 1 show the results of the release of the pellets of Example 2 at different pH conditions in the simulated gastrointestinal tract, SD
  • the advantages of the pellet release system prepared by the method in enteric and drug release stability can be illustrated:
  • Example 2 Three batches of Example 2 The product was cumulatively released at different times and pH conditions.
  • the experimental design in the above examples requires that the pellets release less than 5% in the gastric juice for 2 h and 0.5 h in the intestinal fluid. 10-30%, release 30-50% at 1h, release 60-80% at 2h, and release at least 80% within 7 hours.
  • the invention discloses a drug controlled release microparticle preparation for treating intestinal diseases and a preparation method thereof, so that the main medicine and the functional auxiliary material in the preparation product can be effectively distributed on the surface of the pellet or bead, and the medicine is made. Release in a controlled manner can ensure the uniformity of any component content in the product, mainly in:
  • a uniform content of the drug-containing pellet core can be prepared by using a coating technique or an extrusion spheronization process
  • Coating layer is coated on the surface of the drug-containing core with a coating technology to ensure that the drug in the core does not penetrate into the sustained-release coating layer, and the surface of the pellet tends to be smooth and round;
  • the prepared drug can achieve the purpose of intestinal positioning and sustained release at the same time without increasing the drug loading ratio of the auxiliary materials;
  • each pellet is administered as a pellet, which is less affected by physiological factors and can enter the intestine quickly. After entering the intestine, each pellet can be slowly released as a release unit, achieving a long-term mechanism, reducing the number of medications and increasing the number of medications. Compliance when the patient takes the medicine;

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Abstract

一种治疗肠道疾病的缓控释微粒制剂及其制备方法。所述缓控释微粒制剂包括：a）包含5-氨基水杨酸和辅料的含药丸芯；b）包含水溶性高分子和抗黏剂的一种或几种的隔离层；c）使用缓释材料的缓释包衣层；和d）使用高分子肠溶材料的肠溶包衣层。

Description

一种治疗肠道疾病的药物缓控释微粒制剂及其制备方法 技术领域
本发明属于药物制剂领域，尤其涉及一种治疗肠道疾病的药物（5-氨基水杨酸）的缓控释微丸或微粒制剂；此外，本发明还涉及运用多层包衣技术制备上述缓控释微丸或微粒制剂的方法。
背景技术
美沙拉秦（即5-氨基水杨酸）在临床上主要用于克罗恩氏（Chron's）病和溃疡性结肠炎的治疗。但是其服用剂量较高（处方中常常会用至4g），并且对胃有一定的刺激，而且所治疗的发病部位在结肠，目前市场上的口服产品多采用缓释、控释的方法制备该产品，以减少服用次数和对人体的刺激，提高疗效。但大多数产品和发明所涉及的技术都不能达到预想的目的，原因主要是剂量太高而导致在制剂工艺中的辅料应用空间比较低，难以同时达到缓释和肠道定位的目的。
微丸是一种新型的多元给药系统，与常规制剂相比受生理影响小；胃肠道分布面积大，可提高生物利用度和减少局部刺激；释药行为易于控制（如结肠定位、缓释等），个体差异小等优点。
目前比较理想的美沙拉秦（即5-氨基水杨酸）缓释微丸制剂采用的常规工艺包括主药与缓释高分子材料和其他辅料进行混合、制粒、挤出、滚圆以及干燥等，然后对得到的微丸进行肠溶包衣，使得药物不会在胃液中提前释放，并继而进入肠道后才开始释药，有利于降低主药对胃的刺激以及增加病灶部位（结肠）的药物浓度。
然而， 上述工艺运用在以5-氨基水杨酸为活性成分的制剂生产过程中存在明显不足。在大生产过程中，保证主药和辅料的混合均匀是确保产品质量的关键因素。如果处方中主药比例比较高，所使用辅料的比例较低，而这些辅料中又包括了对药物控制释放起关键作用的材料，那么主药与辅料混合的均匀度就成了生产工艺中的关键。在一般的制剂生产工艺中，很难保证缓释高分子材料与主药以及其他辅料混合均匀，因而容易影响药物的释放效果，影响药品的质量。
专利号为CN00808889.6的中国专利亦存在上述缺陷，并且无法达到肠道定位释放的目的；专利号为CN200410020455.6的中国专利公开了一种结肠定位的微丸系统，但是其在缓释功能和提高载药量方面明显不足；而CN200480010790.6的专利所公开的内容亦不能解决胃液中的提前释放问题；CN200810232858.5的专利公开了一种结肠靶向的片剂制备技术，而美沙拉秦服用剂量较高，所生产的片剂规格一般较大（若是小片则病人需要服用的片数就会大大增加），从临床角度说，由于大规格片剂在服用之后所受到胃排空的影响较大（尤其在通过幽门时），所以很容易引起个体差异较大，影响疗效。
技术问题
本发明要解决的技术问题是提供一种治疗肠道疾病的药物缓控释微粒制剂及其制备方法，其运用多层包衣技术，使得药物和缓释包衣材料均匀地分散在小丸或小珠(beads)表面，可以有效地解决辅料与主药混合均一性的问题。
技术解决方案
为了解决上述技术问题，本发明提供一种治疗肠道疾病的药物缓控释微粒制剂，该制剂的主要活性成份为5-氨基水杨酸，该制剂包括：
a) 含药丸芯：包含5-氨基水杨酸及辅料；
b) 隔离层：本层主要作用是使小粒表面趋于光滑圆整，并阻止药物渗透到缓释包衣层影响释放效果 ，增加药物的稳定性 ，该层主要使用材料包括水溶性高分子和合适的抗黏剂的一种或几种；所述水溶性高分子指强亲水性的高分子材料，能溶解或溶胀于水中形成水溶液或分散体系；所述抗黏剂为防止在包衣过程中产生粘连的一类物质；
c) 缓释包衣层：本层主要作用是使药物持续缓慢地释放，可以通过喷洒不同包衣液的量来调节本层的厚度（一般在0.5 ~ 12% 的包衣增重水平）以达到不同的释药水平；该层主要使用缓释材料；所述缓释材料指一些 高分子 材料 以不同方式组合到制剂中，起到控制药物的释放速率、释放时间以及释放部位的作用。
d) 肠溶包衣层：本层主要作用是避免主药在胃液中的提前释放，减少主药对胃的刺激，提高药物在病灶部位的局部浓度；该层主要使用高分子肠溶材料。所述高分子肠溶材料是缓释材料中的一类pH依赖型高分子材料，在胃液中（pH<5）不溶解，而在较高pH条件下（如肠液中）可以快速溶解。
所述含药丸芯采用丸芯上药工艺或者挤出滚圆工艺制得；所述辅料包括以下辅料的一种或几种：聚维酮PVP、羟丙甲纤维素HPMC、羧甲基纤维素钠CMC-Na、甲基纤维素MC、羟丙基纤维素HPC、 羟丙甲纤维素邻苯二甲酸酯 HPMCP 、微晶纤维素、淀粉、糊精、乳糖、硬脂酸镁、水。
优选的，所述含药丸芯采用丸芯上药工艺制备，所述辅料包括以下辅料的一种或几种：蔗糖、微晶纤维素、淀粉、聚维酮PVP、羟丙基纤维素HPC、 羟丙甲纤维素邻苯二甲酸酯 HPMCP 、羟丙甲纤维素HPMC、滑石粉。
所述含药丸芯采用挤出滚圆工艺制备，所述辅料包括成型剂或稀释剂、粘合剂以及润滑剂，优选为微晶纤维素、聚维酮PVP和硬脂酸镁。所述含药丸芯中5-氨基水杨酸含量为50 ~ 99% ，优选为70 ~ 85% ，微晶纤维素含量为5% ~ 40% ，优选为10 ~ 22% ，聚维酮PVP含量为1 ~ 15% ，优选为4 ~ 9% ，硬脂酸镁含量为0 ~ 8% ，优选为0.1 ~ 1.5% 。
所述隔离层的使用材料包括以下的一种或几种：滑石粉、二氧化钛、高岭土、聚维酮PVP、羟丙甲纤维素HPMC、羟丙基纤维素HPC、 聚乙烯醇 PVA 、 羟丙甲纤维素邻苯二甲酸酯 HPMCP 、 聚乙二醇 PEG 。
所述缓释包衣层的使用材料包括以下的一种或者几种：纤维素类衍生物、丙烯酸树脂类衍生物，以及其他可用的缓释材料。所述纤维素类衍生物是指纤维素高分子中的羟基与化学试剂发生酯化或醚化反应后的生成物；所述丙烯酸树脂类衍生物是指甲基丙烯酸共聚物和甲基丙烯酸酯共聚物的总称。
所述肠溶包衣层使用的高分子肠溶材料包括以下的一种或者几种：丙烯酸树脂类聚合物、虫胶、醋酸纤维素酞酸酯CAP、及其他可用的肠溶材料、以及可选择的抗黏剂、增塑剂、溶剂。所述丙烯酸树脂类聚合物也称为丙烯酸树脂类衍生物，是指甲基丙烯酸共聚物和甲基丙烯酸酯共聚物的总称。所述抗黏剂为制剂包衣工艺过程中防止在包药丸生粘连的一类物质；所述增塑剂是指为提高包衣膜柔韧性的一类化合物；所述虫胶是肠溶包衣材料的一种，为紫胶虫科昆虫紫胶虫在树枝上所分泌的胶质。
优选的，所述隔离层使用的辅料为滑石粉和聚维酮PVP，其重量比例为1:2 ~ 5:1 ，优选3:1，包衣水平达到增重0 ~ 15% ，优选2 ~ 5% ；所述缓释包衣层主要使用的辅料为乙基纤维素和滑石粉，固体重量比例为2:1 ~ 10:1 ，优选5:1 ~ 7:1 ，包衣水平达到增重0.5 ~ 12% ，优选1 ~ 4% ；所述肠溶包衣层主要使用的辅料为丙烯酸树脂、 柠檬酸三乙酯、滑石粉、乙醇、丙酮、水，优选辅料为 丙烯酸树脂，包衣水平达到增重5 ~ 32% ，优选11 ~ 28% 。
此外，本发明还提供一种治疗肠道疾病的药物缓控释微粒制剂的制备方法，包括如下步骤：
（1）制备含药丸芯；
（2）将各层辅料溶于水中混匀制成隔离层包衣液、缓释包衣层包衣液、肠溶包衣层包衣液；
（3）将步骤（1）制得的含药丸芯置入包衣设备，依次进行隔离层包衣、缓释包衣层包衣和肠溶包衣层包衣。
步骤（1）中，所述制备含药丸芯采用丸芯上药工艺或者挤出滚圆工艺；所述丸芯上药工艺具体为：取含药丸芯材料各组分充分搅拌均匀，制备固含量10-20%的混悬液备用；将丸芯装入 包衣设备 并预热，床层温度高于35℃时进行泵入药物的混悬液直至结束，用少量的水润洗容器和管道，干燥，即得含药丸芯；所述挤出滚圆工艺具体为：取含药丸芯材料各组分充分混匀，然后加入适量的水制备软材，将得到的软材进一步挤出制粒，然后使用滚圆机滚圆即可得到合适大小的湿丸芯，此丸芯进一步干燥并筛分，即得含药丸芯。
步骤（3）具体为：将步骤（1）制备的含药丸芯置入流化床内，用热空气预热使得床层温度大于35℃， 开始喷洒隔离层包衣液进行隔离层包衣，包衣液流速约1.5~3.5g/min，雾化压力0.7~2.5kg/m2 ，床层温度保持在25~35℃，包衣结束后，继续吹热空气干燥20min，继续喷洒缓释层包衣液进行缓释层包衣，包衣液流速约1.5~3.5g/min，雾化压力0.7~2.5kg/m2，床层温度保持在25~35℃，包衣完成后继续干燥20min，然后喷洒肠溶层包衣液进行肠溶层包衣，包衣液流速约1.5~3.5g/min，雾化压力0.7~2.5kg/m2 ，床层温度保持在25~45℃，然后继续干燥至产品水分低于3%，即得。
 有益效果
本发明与现有技术相比，有如下有益效果：本发明的一种治疗肠道疾病的药物缓控释微粒制剂及其制备方法，使制剂产品中的主药和功能性辅料可以有效地在小丸或小珠(beads)表面均匀分布，并使药物以缓控方式释放，可以更加确保产品中的任何组成成分含量的均一性，主要体现在：
1. 通过使用包衣技术或者挤出滚圆工艺，可以制备含量均匀的含药丸芯；
2. 使用包衣技术在含药丸芯表面包裹一层隔离层，以保证丸芯中的药物不会渗透到缓释包衣层，并使得小丸表面趋于光滑圆整；
3. 使用包衣技术，通过重复地在所制备的小丸表面喷洒起缓释作用的高分子溶液，可使得这些材料可以均匀地包裹在所制备的小丸表面；
4. 将起肠溶作用的各种成分喷洒在小丸上，以保证每种成分都能均匀地包裹在小丸表面；
5. 在不增加辅料使用比例的高载药量情况下，所制备的药品同时可以达到肠道定位和缓释目的；
6. 避免药物在胃液中的提前释放，一方面减少药物对胃的刺激，另一方面增加药物由于胃酸引起的不稳定性；
7. 以小丸的方式给药，受到生理因素影响较小而可以很快进入肠道；进入肠道后，每个小丸可单独作为一个释药单位缓慢释药，达到长效机制，减少服药次数，提高病人服药时的依从性；
8. 与普通的混合搅拌方法相比，可以更加确保产品中的任何组成成分含量的均一性和释药的稳定性；
9.本发明所公开的方法和工艺，亦可以用于其他类似治疗目的的药物（如肠道局部疾病、一些不耐酸的药物等）。
 附图说明
图1是实施例6中微丸在模拟的胃肠道不同pH条件下体外释放曲线结果示意图。
本发明的最佳实施方式
本发明的实施方式
下面的实施例进一步说明本发明，但本发明并不限于以下所列实施例：
实施例 1
含药丸芯的处方：
1 美沙拉秦 750 g
2 微晶纤维素空白丸芯 195 g
3 聚维酮 45 g
4 水 适量
丸芯制备方法：取以上含药丸芯处方组分 1 、 3 、 4 充分搅拌均匀，制备固含量 10-20% 的混悬液备用；将组分 2 空白丸芯装入包衣设备并预热，床层温度高于 35 ℃ 时进行泵入药物的混悬液直至结束，用少量的水润洗容器和管道，干燥，即得合格的速释含药丸芯。
包衣处方：
1 聚维酮 20.0 g
2 滑石粉 7.5 g
3 水 270 g
4 乙基纤维素 20.0 g
5 滑石粉 2.5 g
6 水 175 g
7 甲基丙烯酸和甲基丙烯酸甲酯 1 ： 1 共聚物 215.0 g
8 95% 乙醇 860 g
包衣液的配制：首先将聚维酮和滑石粉分散在水溶液中（包衣处方中组分 1 、 2 、 3 ），过 60 目筛制成隔离层包衣液备用。将乙基纤维素和滑石粉（处方中组分 4 、 5 ）分散在水溶液（包衣处方中组分 6 ）中，混合并搅拌均匀，过 60 目筛制成缓释包衣液备用；将组分 7 分散在组分 8 中，并过 60 目筛 制成肠溶层包衣液 备用。
包衣工艺：将制备的含药速释丸芯置入流化床或者其他包衣设备，用热空气预热使得床层温度大于 35 ℃ ，开始喷洒隔离层包衣液包隔离层，包衣液流速约 1.5g /min ，压力 0.7kg /m2 （床层温度保持在 25 ℃ ），包衣结束后，继续吹热空气干燥 20min ，继续进行缓释包衣（喷洒缓释层包衣液，包衣液流速约 1.5g /min ，压力 0.7kg /m2 （床层温度保持在 25 ℃ ）），包衣完成后继续干燥 20min 然后进行肠溶包衣（喷洒肠溶层包衣液，包衣液流速约 1.5g /min ，压力 0.7kg /m2 （床层温度保持在 25 ℃ ）），然后继续干燥至产品水分低于 3% ，即得。
实施例 2
含药丸芯的处方：
1 美沙拉秦 750 g
2 微晶纤维素 195 g
3 聚维酮 45 g
4 硬脂酸镁 10 g
5 水 适量
丸芯制备方法：取以上各组分充分混匀，可使用不同类型的混合设备或者高剪切湿法制粒机，然后加入适量的水制备软材。将得到的软材进一步挤出制粒，然后使用滚圆机滚圆即可得到合适大小的湿丸芯，此丸芯进一步干燥并筛分，即得合格的含药速释丸芯。
包衣处方：
1 聚维酮 25.0 g
2 滑石粉 8.0 g
3 水 270 g
4 乙基纤维素 16.9 g
5 滑石粉 4.1 g
6 水 185.0 g
7 甲基丙烯酸和丙烯酸乙酯 1:1 共聚物 150 g
8 柠檬酸三乙酯 30 g
9 滑石粉 50 g
10 水 1200 g
包衣液的配制：首先将聚维酮和滑石粉分散在水溶液中（包衣处方中组分 1 、 2 、 3 ），过 60 目筛制成隔离层包衣液备用。将处方中组分 4 、 5 分散在处方组分 6 的水溶液中，混合并分散均匀，过 60 目筛制成缓释层包衣液备用；将组分 7 、 8 、 9 分散在组分 10 水中，并过 60 目筛制成肠溶包衣液备用。
包衣工艺：将制备的含药速释丸芯置入流化床或者其他包衣设备，用热空气预热使得床层温度大于 35 ℃ ，开始喷洒隔离层包衣液包隔离层，包衣液流速约 3.5g /min ，压力 2.5kg /m2 ，（床层温度保持在 35 ℃ ），包衣结束后，继续吹热空气干燥 20min ，继续进行缓释包衣（喷洒缓释层包衣液，包衣液流速约 3.5g /min ，压力 2.5kg /m2 ，（床层温度保持在 35 ℃ ）），包衣完成后继续干燥 20min 然后进行肠溶包衣（喷洒肠溶层包衣液，包衣液流速约 3.5g /min ，压力 2.5kg /m2 ，（床层温度保持在 35 ℃ ）），然后继续干燥至产品水分低于 3% ，即得。
实施例 3
含药丸芯的处方：
1 美沙拉秦 950 g
2 微晶纤维素 40 g
3 羟丙甲纤维素 5 g
4 硬脂酸镁 5 g
5 水 适量
丸芯制备方法：取以上各组分充分混匀，可使用不同类型的混合设备或者高剪切湿法制粒机，然后加入适量的水制备软材。将得到的软材进一步挤出制粒，然后使用滚圆机滚圆即可得到合适大小的湿丸芯，此丸芯进一步干燥并筛分，即得合格的含药速释丸芯。
包衣处方：
1 聚维酮 15.0 g
2 滑石粉 7.5 g
3 水 210 g
4 乙基纤维素 15.9 g
5 滑石粉 2.1 g
6 水 165 g
7 甲基丙烯酸和甲基丙烯酸甲酯 1:2 共聚物 250 g
8 柠檬酸三乙酯 50 g
9 丙酮 1000 g
包衣液的配制：首先将聚维酮和滑石粉分散在水溶液中（包衣处方中组分 1 、 2 、 3 ），过 60 目筛制成隔离层包衣液备用。将包衣处方中组分 4 、 5 分散在水溶液（包衣处方中组分 6 ）中，混合并搅拌均匀，过 60 目筛制成缓释层包衣液备用；将组分 7 和组分 8 分散在组分 9 中并充分分散，过 60 目筛制成肠溶包衣液备用。
包衣工艺：将制备的含药速释丸芯置入流化床或者其他包衣设备，用热空气预热使得床层温度大于 35 ℃ ，开始包隔离层，包衣液流速约 2g /min ，压力 1kg /m2 ，（床层温度保持在 30 ℃ ），包衣结束后，继续吹热空气干燥 20min ，继续进行缓释包衣（喷洒缓释层包衣液，包衣液流速约 2g /min ，压力 1kg /m2 ，（床层温度保持在 30 ℃ ）），包衣完成后继续干燥 20min 然后进行肠溶包衣（喷洒肠溶层包衣液，包衣液流速约 2g /min ，压力 1kg /m2 ，（床层温度保持在 30 ℃ ）），然后继续干燥至产品水分低于 3% ，即得。
实施例 4
含药丸芯的处方：
1 美沙拉秦 550 g
2 微晶纤维素 355 g
3 聚维酮 45 g
4 硬脂酸镁 50 g
5 水 适量
丸芯制备方法：取以上各组分充分混匀，可使用不同类型的混合设备或者高剪切湿法制粒机，然后加入适量的水制备软材。将得到的软材进一步挤出制粒，然后使用滚圆机滚圆即可得到合适大小的湿丸芯，此丸芯进一步干燥并筛分，即得合格的含药速释丸芯。
包衣处方：
1 羟丙甲纤维素 22.5 g
2 滑石粉 6.5 g
3 水 270 g
4 乙基纤维素 15.9 g
5 滑石粉 3.8 g
6 水 166.45 g
7 甲基丙烯酸和丙烯酸乙酯 1:1 共聚物 125 g
8 1 mol/L NH3 70 g
9 柠檬酸三乙酯 62.5 g
10 水 932.5 g
包衣液的配制：首先将羟丙甲纤维素和滑石粉分散在水溶液中（包衣处方中组分 1 、 2 、 3 ），过 60 目筛制成隔离层包衣液备用；将处方中包衣处方组分 4 、 5 分散在处方组分 6 的水溶液中，混合并搅拌均匀，过 60 目筛制成缓释层包衣液备用；将组分 7 分散在 2/3 的组分 10 中，然后加入组分 8 并搅拌 1h 以上形成丙烯酸树脂混合液；然后将组分 9 与余下的 1/3 的组分 10 混合均匀然后加入丙烯酸树脂混合液继续搅拌 1h ，将混悬包衣液过 60 目筛制成肠溶包衣液备用。
包衣工艺：将制备的含药速释丸芯置入流化床或者其他包衣设备，用热空气预热使得床层温度大于 35 ℃ ，开始包隔离层，包衣液流速约 3g /min ，压力 2kg /m2 ，（床层温度保持在 30 ℃ ），包衣结束后，继续吹热空气干燥 20min ，继续进行缓释包衣（喷洒缓释层包衣液，包衣液流速约 3g /min ，压力 2kg /m2 ，（床层温度保持在 30 ℃ ）），包衣完成后继续干燥 20min 然后进行肠溶包衣（喷洒肠溶层包衣液，包衣液流速约 3g /min ，压力 2kg /m2 ，（床层温度保持在 30 ℃ ）），然后继续干燥至产品水分低于 3% ，即得。
实施例 5
含药丸芯的处方：
1 美沙拉秦 900 g
2 微晶纤维素 90 g
3 聚维酮 5 g
4 硬脂酸镁 5 g
5 水 适量
丸芯制备方法：取以上各组分充分混匀，可使用不同类型的混合设备或者高剪切湿法制粒机，然后加入适量的水制备软材。将得到的软材进一步挤出制粒，然后使用滚圆机滚圆即可得到合适大小的湿丸芯，此丸芯进一步干燥并筛分，即得合格的含药速释丸芯。
包衣处方：
1 聚维酮 15.0 g
2 滑石粉 7.5 g
3 水 210 g
4 丙烯酸乙酯，甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯 1 ： 2 ： 0.1 共聚物 105.0 g
5 柠檬酸三乙酯 15.0 g
6 滑石粉 10.0 g
7 水 585 g
8 甲基丙烯酸和甲基丙烯酸甲酯 1:2 共聚物 250 g
9 柠檬酸三乙酯 50 g
10 丙酮 1000 g
包衣液的配制：首先将聚维酮和滑石粉分散在水溶液中（包衣处方中组分 1 、 2 、 3 ），过 60 目筛制成隔离层包衣液备用。将包衣处方中组分 4 、 5 、 6 分散在水溶液（包衣处方中组分 7 ）中，混合并搅拌均匀，过 60 目筛制成缓释层包衣液备用；将组分 8 和组分 9 分散在组分 10 中并充分分散，过 60 目筛制成肠溶包衣液备用。
包衣工艺：将制备的含药速释丸芯置入流化床或者其他包衣设备，用热空气预热使得床层温度大于 35 ℃ ，开始喷洒隔离层包衣液，包衣液流速约 3g /min ，压力 2kg /m2 ，（床层温度保持在 30 ℃ ），包衣结束后，继续吹热空气干燥 20min ，继续进行缓释包衣（喷洒缓释层包衣液，包衣液流速约 3g /min ，压力 2kg /m2 ，（床层温度保持在 30 ℃ ）），包衣完成后继续干燥 20min 然后进行肠溶包衣（喷洒肠溶层包衣液，包衣液流速约 3g /min ，压力 2kg /m2 ，（床层温度保持在 30 ℃ ）），然后继续干燥至产品水分低于 3% ，即得。
实施例 6
对实施例 2 的微丸进行模拟胃肠道各区段的 pH 变化的释放度实验，释放条件： USP 转篮法，转速 100rpm ， 900mL 溶出介质，温度为 37 ± 0.5 ℃ 。 0~2h 溶出介质为 pH1.0 的 HCl 溶液，第 3 小时溶出介质更换为 pH6.8 的磷酸盐缓冲液，结果如表 1 和图 1 所示：
表 1 和图 1 为实施例 2 的微丸在模拟的胃肠道不同 pH 条件下释放结果， SD 可说明本方法所制备的微丸释药系统在肠溶和释药稳定性方面的优势：
表 1. 三批实施例 2 所制备的产品在不同时间和 pH 条件累积释放
时间 /pH 2h/
pH 1.0 		2.5h/ pH 6.8 3h/
pH 6.8 		4h/
pH 6.8 		7h/
pH 6.8 		9h/
pH 6.8 		11h/
pH 6.8
批 1 0.8 22.2 41.8 66.9 90.5 100.6 102.4
批 2 0.7 25.8 45.9 69.5 91.6 100.4 101.4
批 3 0.8 20.4 40.6 64.9 87.0 99.9 100.8
平均 0.8 22.8 42.8 67.1 89.7 100.3 101.5
SD 0.1 2.7 2.8 2.3 2.4 0.3 0.8
以上实施例中的实验设计要求为小丸在胃液中 2h 释放低于 5% ，在肠液中 0.5h 释放 10-30% ， 1h 释放 30-50% ， 2h 释放 60-80% ， 7 小时内释放不低于 80% 。
一般情况下，在制剂工艺过程中，为了证明工艺的稳定性，会使用相同的工艺进行生产若干批次（即表1中三批产品），所生产出来的产品批次间差异越小（本实验用标准差SD表示），说明工艺越稳定。从表1中可以看出，各点释放标准差SD均小于3，说明该工艺是非常稳定的，也就从侧面说明，主药和辅料混合是非常均匀的。
 工业实用性
本发明的一种治疗肠道疾病的药物缓控释微粒制剂及其制备方法，使制剂产品中的主药和功能性辅料可以有效地在小丸或小珠(beads)表面均匀分布，并使药物以缓控方式释放，可以更加确保产品中的任何组成成分含量的均一性，主要体现在：
1. 通过使用包衣技术或者挤出滚圆工艺，可以制备含量均匀的含药丸芯；
2. 使用包衣技术在含药丸芯表面包裹一层隔离层，以保证丸芯中的药物不会渗透到缓释包衣层，并使得小丸表面趋于光滑圆整；
3. 使用包衣技术，通过重复地在所制备的小丸表面喷洒起缓释作用的高分子溶液，可使得这些材料可以均匀地包裹在所制备的小丸表面；
4. 将起肠溶作用的各种成分喷洒在小丸上，以保证每种成分都能均匀地包裹在小丸表面；
5. 在不增加辅料使用比例的高载药量情况下，所制备的药品同时可以达到肠道定位和缓释目的；
6. 避免药物在胃液中的提前释放，一方面减少药物对胃的刺激，另一方面增加药物由于胃酸引起的不稳定性；
7. 以小丸的方式给药，受到生理因素影响较小而可以很快进入肠道；进入肠道后，每个小丸可单独作为一个释药单位缓慢释药，达到长效机制，减少服药次数，提高病人服药时的依从性；
8. 与普通的混合搅拌方法相比，可以更加确保产品中的任何组成成分含量的均一性和释药的稳定性；
9.本发明所公开的方法和工艺，亦可以用于其他类似治疗目的的药物（如肠道局部疾病、一些不耐酸的药物等）。
 序列表自由内容

Claims (1)

1. 一种治疗肠道疾病的药物缓控释微粒制剂，该制剂的主要活性成份为5-氨基水杨酸，其特征在于，该制剂包括：
a) 含药丸芯：包含5-氨基水杨酸及辅料；
b) 隔离层：本层主要作用是使小粒表面趋于光滑圆整，并阻止药物渗透到缓释包衣层影响释放效果 ，增加药物的稳定性 ，该层主要使用材料包括水溶性高分子和抗黏剂的一种或几种；
c) 缓释包衣层：本层主要作用是使药物持续缓慢地释放， 可以通过调节本层的厚度达到不同的释药水平 ；该层主要使用缓释材料；
d) 肠溶包衣层：本层主要作用是避免主药在胃液中的提前释放，减少主药对胃的刺激，提高药物在病灶部位的局部浓度；该层主要使用高分子肠溶材料。
2. 如权利要求1所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述含药丸芯采用丸芯上药工艺或者挤出滚圆工艺制得；所述辅料包括以下辅料的一种或几种：聚维酮PVP、羟丙甲纤维素HPMC、羧甲基纤维素钠CMC-Na、甲基纤维素MC、羟丙基纤维素HPC、 羟丙甲纤维素邻苯二甲酸酯 HPMCP 、微晶纤维素、淀粉、糊精、乳糖、硬脂酸镁、水。
3. 如权利要求2所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述含药丸芯采用丸芯上药工艺制备，所述辅料包括以下辅料的一种或几种：蔗糖、微晶纤维素、淀粉、聚维酮PVP、羟丙基纤维素HPC、 羟丙甲纤维素邻苯二甲酸酯 HPMCP 、羟丙甲纤维素HPMC、滑石粉。
4. 如权利要求2所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述含药丸芯采用挤出滚圆工艺制备，所述辅料包括成型剂或稀释剂、粘合剂以及润滑剂。
5. 如权利要求4所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述辅料包括微晶纤维素、聚维酮PVP和硬脂酸镁。
6. 如权利要求1所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述隔离层的使用材料包括以下的一种或几种：滑石粉、二氧化钛、高岭土、聚维酮PVP、羟丙甲纤维素HPMC、羟丙基纤维素HPC、聚乙烯醇PVA、羟丙甲纤维素邻苯二甲酸酯HPMCP、聚乙二醇 PEG 。
7. 如权利要求1所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述缓释包衣层的使用材料包括以下的一种或者几种：纤维素类衍生物、丙烯酸树脂类衍生物，以及其他可用的缓释材料。
8. 如权利要求1所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述肠溶包衣层使用的高分子肠溶材料包括以下的一种或者几种：丙烯酸树脂类聚合物、虫胶、 醋酸纤维素酞酸酯 CAP 、及其他可用的肠溶材料、以及可选择的抗黏剂、增塑剂、溶剂。
9. 如权利要求1所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述隔离层使用的辅料为滑石粉和聚维酮PVP，所述缓释包衣层主要使用的辅料为乙基纤维素和滑石粉，所述肠溶包衣层主要使用的辅料为丙烯酸树脂、 柠檬酸三乙酯、滑石粉、乙醇、丙酮、水 。
10. 如权利要求5所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述含药丸芯中5-氨基水杨酸含量为50 ~ 99% ，微晶纤维素含量为5% ~ 40% ，聚维酮PVP含量为1 ~ 15% ，硬脂酸镁含量为0 ~ 8% 。
11. 如权利要求10所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述含药丸芯中5-氨基水杨酸含量为70 ~ 85% ；所述微晶纤维素含量为10 ~ 22% ；聚维酮PVP含量为4 ~ 9% ；硬脂酸镁含量为0.1 ~ 1.5% 。
12. 如权利要求9所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述隔离层使用的辅料聚维酮PVP和滑石粉，重量比例为1:2 ~ 5:1 ；包衣水平达到增重0 ~ 15% ；所述缓释包衣层使用的辅料乙基纤维素和滑石粉，固体重量比例为2:1 ~ 10:1 ，包衣水平达到增重0.5 ~ 12% ；所述肠溶包衣层使用的辅料为丙烯酸树脂，包衣水平达到增重5 ~ 32% 。
13. 如权利要求12所述的治疗肠道疾病的药物缓控释微粒制剂，其特征在于，所述隔离层使用的辅料聚维酮PVP和滑石粉，比例为3:1；包衣水平达到增重2 ~ 5% ；所述缓释包衣层使用的辅料乙基纤维素和滑石粉，固体重量比例为5:1 ~ 7:1 ，包衣水平达到增重1 ~ 4% ；所述肠溶包衣层使用的辅料为丙烯酸树脂，包衣水平达到增重11 ~ 28% 。
14. 一种如权利要求1-13任一项所述的治疗肠道疾病的药物缓控释微粒制剂的制备方法，其特征在于，包括如下步骤：
（1）制备含药丸芯；
（2）将各层辅料溶于水中混匀制成隔离层包衣液、缓释包衣层包衣液、肠溶包衣层包衣液；
（3）将步骤（1）制得的含药丸芯置入包衣设备，依次进行隔离层包衣、缓释包衣层包衣和肠溶包衣层包衣。
15. 如权利要求14所述的治疗肠道疾病的药物缓控释微粒制剂的制备方法，其特征在于，步骤（1）中，所述制备含药丸芯采用丸芯上药工艺或者挤出滚圆工艺；所述丸芯上药工艺具体为：取含药丸芯材料各组分充分搅拌均匀，制备固含量10-20%的混悬液备用；将丸芯装入 包衣设备 并预热，床层温度高于35℃时进行泵入药物的混悬液直至结束，用少量的水润洗容器和管道，干燥，即得含药丸芯；所述挤出滚圆工艺具体为：取含药丸芯材料各组分充分混匀，然后加入适量的水制备软材，将得到的软材进一步挤出制粒，然后使用滚圆机滚圆即可得到合适大小的湿丸芯，此丸芯进一步干燥并筛分，即得含药丸芯。
16. 如权利要求14所述的治疗肠道疾病的药物缓控释微粒制剂的制备方法，其特征在于，步骤（3）具体为：将步骤（1）制备的含药丸芯置入流化床内，用热空气预热使得床层温度大于35℃， 开始喷洒隔离层包衣液进行隔离层包衣，包衣液流速为 1.5~3.5g/min ，雾化压力为 0.7~2.5kg/m2 ，床层温度保持在 25~35℃，包衣结束后，继续吹热空气干燥20min ，继续喷洒缓释层包衣液进行缓释层包衣，包衣液流速为 1.5~3.5g/min ，雾化压力为 0.7~2.5kg/m2 ，床层温度保持在 25~45℃，包衣完成后继续干燥20min ，然后喷洒肠溶层包衣液进行肠溶层包衣，包衣液流速为 1.5~3.5g/min ，雾化压力为 0.7~2.5kg/m2 ，床层温度保持在 25~35℃，然后继续干燥至产品水分低于3% ，即得。
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