WO2016029494A1 - 微晶纤维素在制备美索舒利制剂中的用途及其制备方法 - Google Patents

微晶纤维素在制备美索舒利制剂中的用途及其制备方法 Download PDF

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WO2016029494A1
WO2016029494A1 PCT/CN2014/085783 CN2014085783W WO2016029494A1 WO 2016029494 A1 WO2016029494 A1 WO 2016029494A1 CN 2014085783 W CN2014085783 W CN 2014085783W WO 2016029494 A1 WO2016029494 A1 WO 2016029494A1
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weight
methicillin
parts
tablet
prescription
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PCT/CN2014/085783
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English (en)
French (fr)
Inventor
王学海
李莉娥
许勇
廖娟娟
黄怡
黄璐
涂荣华
杨仲文
乐洋
江曦
张绪文
何震宇
朱垒
余艳平
刘荃
王伟
田华
肖强
范昭泽
杨菁
张毅
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武汉光谷人福生物医药有限公司
湖北生物医药产业技术研究院有限公司
人福医药集团股份公司
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Publication of WO2016029494A1 publication Critical patent/WO2016029494A1/zh

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to the field of pharmacy, and in particular to the use of microcrystalline cellulose in the preparation of methicillin formulations, excipients for methicillin, methicillin formulations and methods for their preparation.
  • Mesoshuli is a new class of 1.1 chemical developed by the Academy of Military Medical Sciences and the People's Medical Group.
  • Mesocycline is a non-steroidal anti-inflammatory drug (NSAID), the main mechanism of action is inhibition of cyclooxygenase (COX-2) activity, thereby inhibiting the final production of arachidonic acid (PGII), prostate PGE1 (PGE2) and thromboxane A2 (TXA2), which reduce the synthesis of inflammatory mediators such as prostaglandins and thromboxane, have a good antipyretic, analgesic, anti-inflammatory and anti-tumor effects.
  • Messocycline is insoluble in water, and there is still no suitable Mesotrophil preparation reported in the report. Therefore, it is very important to develop a methicillin preparation with good curative effect, small side effects, high dissolution rate, high bioavailability and stable quality.
  • the present invention aims to solve at least one of the technical problems in the related art to some extent. To this end, it is an object of the present invention to provide a methicillin preparation having good curative effect, small side effects, high dissolution rate, high bioavailability, and stable quality.
  • the invention provides the use of microcrystalline cellulose for the preparation of a methicillin formulation.
  • the Methosoli preparation is stable in quality, has high dissolution rate of Methosoli, and has high bioavailability.
  • the methicillin formulation is in the form of an oral solid preparation selected from the group consisting of capsules, granules or tablets.
  • an oral solid preparation selected from the group consisting of capsules, granules or tablets.
  • the tablet is at least one selected from the group consisting of a film-coated tablet, an orally disintegrating tablet, a dispersible tablet, and a sustained-release tablet.
  • a film-coated tablet an orally disintegrating tablet, a dispersible tablet, and a sustained-release tablet.
  • the capsule is at least one of a capsule and a sustained release capsule.
  • a capsule and a sustained release capsule are convenient to take and patient compliance is good.
  • the invention provides an adjuvant for mesosomel.
  • the excipients include microcrystalline cellulose as a filler.
  • the excipient according to the embodiment of the present invention can be effectively used for the preparation of the methicillin preparation, and the mesosurcellol preparation is stable in quality, high in dissolution of methicillin, and high in bioavailability.
  • the filler further comprises at least one selected from the group consisting of lactose, dextrin, sucrose, starch, and mannitol, wherein the starch is selected from the group consisting of corn starch, compressible starch, and pre-glue. At least one of the starches.
  • the excipient further comprises: at least one selected from the group consisting of a disintegrant, a binder, a lubricant, a suspending agent, a flavoring agent, a solubilizing agent, a skeleton sustained-release material, a solvent, and a glidant One.
  • the disintegrant is at least one selected from the group consisting of crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and croscarmellose sodium.
  • the methicillin formulation is capable of rapid disintegration and is beneficial for the dissolution of methicillin.
  • the binder is selected from the group consisting of povidone K30, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch syrup, dextrin At least one of them.
  • povidone K30 hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch syrup, dextrin At least one of them.
  • the lubricant is at least one selected from the group consisting of magnesium stearate, micronized silica gel, sodium stearyl fumarate, sodium lauryl sulfate, silica, and polyethylene glycol. .
  • the lubrication effect is good.
  • the suspending agent is at least one selected from the group consisting of povidone, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and microcrystalline cellulose.
  • the flavoring agent is at least one selected from the group consisting of aspartame, orange flavor, sucrose, stevioside, and aspartame.
  • the methicillin preparation has a good taste and the patient has good medication compliance.
  • the solubilizing agent is at least one selected from the group consisting of hydroxypropyl ⁇ -cyclodextrin and poloxamer 188.
  • the solubility of mesosomel can be effectively improved.
  • the sustained release of the skeleton is selected from the group consisting of hydroxypropylmethylcellulose K4M, hydroxypropylmethylcellulose K15M, hydroxypropylmethylcellulose K100M, hydroxypropylmethylcellulose E50, hydroxy At least one of propylmethylcellulose E4M.
  • the methicillin can be slowly released to achieve a 24-hour sustained release effect.
  • the solvent is an ethanol solution having a volume fraction of 75%.
  • the glidant is a micronized silica gel.
  • the glidant is a micronized silica gel.
  • the invention provides a mesosurrol formulation.
  • the Methosoli formulation comprises: mesosomel; and the excipients described above. The inventors have found that the Methosoli preparation of the invention has high dissolution rate, disintegration time period, small side effects and stable quality, and can effectively exert anti-inflammatory, analgesic and antipyretic effects, and has simple preparation process and low cost.
  • the methicillin formulation is in the form of an oral solid preparation selected from the group consisting of capsules, granules or tablets.
  • the tablet is at least one selected from the group consisting of a film-coated tablet, an orally disintegrating tablet, a dispersible tablet, and a sustained-release tablet.
  • a film-coated tablet an orally disintegrating tablet, a dispersible tablet, and a sustained-release tablet.
  • the capsule is at least one of a capsule and a sustained release capsule.
  • a capsule and a sustained release capsule are convenient to take and patient compliance is good.
  • the Methosoli film-coated tablet comprises: the methicillin 25-150 parts by weight; the filler 50-200 parts by weight; the binder 6-12 parts by weight; 5 to 20 parts by weight of the disintegrator; and 0.8 to 4 parts by weight of the lubricant.
  • the inventors have found that the Mesosurrol film of the invention has high dissolution rate, disintegration time period, small side effects and stable quality, and can effectively exert anti-inflammatory, analgesic and antipyretic effects, and has simple preparation process and low cost. .
  • the inventors have unexpectedly found that Messocholide film-coated tablets containing the above-mentioned ratio of raw materials have superior drug properties to other ratios.
  • microcrystalline cellulose is selected as a filler for film-coated tablets, not only the drug has good compressibility, high disintegration speed, high dissolution rate, but also can improve the hardness and surface smoothness of the film-coated tablets. .
  • the inventors have found through a large number of experiments that when lactose is used as a filler alone, cracking can occur in large-scale industrial production, so the present invention is used in a diluent ("diluent” and "filler” are used interchangeably in the present invention). Lactose is not selected separately for excipient selection. Microcrystalline cellulose can not only act as a filler, but also has the performance of a disintegrant. Microcrystalline cellulose can achieve good dissolution.
  • microcrystalline cellulose or a combination of microcrystalline cellulose and lactose is selected as a filler, not only is the drug compressible, the disintegration speed is fast, the dissolution is high, and the hardness of the film-coated tablet can be improved.
  • One-sided finish when povidone K30 is used as a binder and crospovidone is used as a disintegrating agent, the disintegration speed of the mesoxylose film tablet is faster, and the dissolution rate is higher. high.
  • the mesosurrol orally disintegrating tablet comprises: the methicillin 25-125 parts by weight; the mannitol 20-60 parts by weight; the microcrystalline cellulose 30-70 parts by weight 5-40 parts by weight of the binder; 2-30 parts by weight of the disintegrant; 5-20 parts by weight of the flavoring agent; 0.5-10 parts by weight of the lubricant; and the glidant 0.1-0.5 parts by weight.
  • the Mesorizol orally disintegrating tablet of the present invention has a fast disintegration time, a good dissolution rate, and a stable quality.
  • the orally disintegrating tablet is rapidly disintegrated into fine particles or powder in the oral cavity after oral administration, and is especially suitable for patients with dysphagia and elderly patients, and the orally disintegrating tablet has been fine particles or powder before reaching the gastrointestinal tract.
  • Forms exist drug dissolution is accelerated, the area of the gastrointestinal tract is large, and there are many absorption points.
  • poorly soluble drugs such as mesosomel, the bioavailability can be improved.
  • the inventors have unexpectedly discovered that the use of mannitol and microcrystalline cellulose as a filler, the resulting Mesorizol orally disintegrating tablet is convenient to take, has obvious curative effect, good mouthfeel, and is beneficial to Mesoshuli orally disintegrating tablets. Disintegration. Moreover, since the Mesosurrol orally disintegrating tablet of the present invention employs microcrystalline cellulose as an auxiliary filler, the amount of mannitol is reduced, thereby reducing the cost of the entire formulation and overcoming the consumption of mannitol. The resulting resulting orally disintegrating tablets have a high degree of friability and are not suitable for transport storage and use. At the same time, it is suitable for the application of the tableting process, further reducing the cost.
  • the addition of glidant microsilica gel to Mesosurry orally disintegrating tablets can effectively prevent the adhesion of methicillin and excipients, and the addition of a small proportion of micronized silica gel can also effectively eliminate static electricity. It can increase the hydrophilicity of the methicillin drug.
  • the Mesosurry orally disintegrating tablet of the invention not only has a fast disintegration time, has good dissolution rate and stable quality, and has no high brittleness, easy to appear small pieces falling and lobes, and is advantageous for industrial production. Suitable for long-term storage and use as well as extensive promotion and application.
  • the mesosurcellol dispersible tablet comprises: the methicillin 25-125 parts by weight; the flavoring agent 5-20 parts by weight; the filler 60-150 parts by weight; 5-30 parts by weight of the binder; 2-20 parts by weight of the disintegrant; and 0.5-3 parts by weight of the lubricant.
  • the inventors have found that the quality of the methicillin dispersible tablet of the present invention is stable, the disintegration meets the requirements, the dissolution is rapid, the concentration of methicillin rapidly reaches a steady state in the body, the content is uniform, the oral bioavailability is high, and the patient medication compliance is good. .
  • the inventors have used a large number of experiments to realize the preparation of the poorly soluble drug methicillin dispersible tablet in the form of a dispersible tablet, which improves the dissolution rate of the drug, improves the oral bioavailability, and provides a patient with a New clinical medication options.
  • Messocycline dispersible tablets including the above ratio of raw materials have superior drug properties to other ratios.
  • the methicillin sustained-release tablet comprises: 25 to 125 parts by weight of the methicillin; 80 to 127.5 parts by weight of the skeleton sustained-release material; and 5 to 75 parts by weight of the filler;
  • the lubricant is 1.5 to 2.5 parts by weight;
  • the solubilizing agent is 15 to 20 parts by weight;
  • the disintegrant is 3 to 9 parts by weight.
  • the inventors have realized the preparation of the poorly soluble drug methicillin sustained-release tablet by using a technique such as ultrafine pulverization, solid dispersion, cyclodextrin inclusion, etc., in the form of a sustained-release matrix tablet, and improved.
  • the solubility of methicillin in water improves the absorption of the drug in the body, improves oral bioavailability, and provides a new clinical drug option for patients.
  • the Mesosurry sustained-release tablet of the present invention solves the problem of low oral bioavailability of methicillin on the one hand, and the sustained release tablet reduces the number of administrations and improves the compliance of the patient's medication.
  • the invention differs from the fact that the Mesosurril raw material is directly formed into a sustained-release tablet, but the solubility of the methicillin is improved first by the solid dispersion technology, and then it is made into a sustained-release tablet, which not only achieves a slow release.
  • the purpose is also to improve the bioavailability of the drug in the body.
  • the mesosomel granule comprises: the methicillin 25-125 parts by weight; the solubilizing agent 25-500 parts by weight; the filler 125-600 parts by weight; The suspension is 15-75 parts by weight; the flavoring agent is 5-40 parts by weight; the binder is 25-200 parts by weight; and the solvent is 10-200 parts by weight.
  • the inventors have found that the methicillin granules of the present invention can be effectively used for antipyretic, analgesic, anti-inflammatory, and swelling, and have stable quality, good dissolution, good mouthfeel, good medication compliance, and also solve the problem of children. Smaller doses are needed, and tablets and capsules are not conducive to separate deficiencies, especially for elderly, young, and swallowed dysfunction patients.
  • the inventors have found through extensive experiments that in the massophos granules, when the weight ratio of mesosomel to suspending agent is 1: At 0.6-0.8, mesotrophin is in a good suspension state and does not precipitate; in addition, when the weight ratio of mesosomel to flavoring is 1:0.2-0.4, the mouthfeel is the best. Most preferably, the weight ratio of the methicillin, suspending agent, and flavoring agent is 1:0.7:0.3. The above is a good solution to the problem of drug compliance in children and elderly patients.
  • the inventors have experimentally and unexpectedly discovered that the methicillin and the solubilizing agent hydroxypropyl ⁇ -cyclodextrin are mixed, and then subjected to micronization treatment once, and then a filler is added to the micronized particles. , continue to micronize to particles with a particle size of 1-100 microns, and methicillin: hydroxypropyl ⁇ -cyclodextrin: the weight ratio of the filler is 1:1-10:5-16, at this time, The dissolution effect of mesosomel in the granules is good. In particular, when the filler is selected to contain mannitol, the dissolution effect of mesosomel is better.
  • micronized methicillin is mixed with hydroxypropyl ⁇ -cyclodextrin, and in the wet granulation process, hydroxypropyl ⁇ -cyclodextrin is used in the wetness of the aqueous ethanol solution.
  • the inclusion compound has good wettability, so the drug is solubilized.
  • mannitol itself has sweet taste, no hygroscopicity, fast drying, good chemical stability, good granulation property, and water-soluble auxiliary materials. A large amount of mannitol particles are adsorbed around the micronized drug particles, so that the fine drug particles of the methicillin can be prevented from aggregating and stably present in the mixture.
  • the inventors found that when the mixed powder of methicillin, hydroxypropyl ⁇ -cyclodextrin and filler has a particle size of 30-60 ⁇ m, and mesocityl: hydroxypropyl ⁇ -cyclodextrin: filling When the weight ratio of the agent is 1:5:8, the dissolution effect is the best.
  • the methicillin granule obtained by the present invention has good compatibility with the main drug in the prescription, and the auxiliary material has no influence on the stability of the main drug.
  • the granules obtained by the invention have an accelerated 6-month stability test and the quality is stable.
  • the mesosurcellol capsule comprises: the methicillin 25-150 parts by weight; the filler 50-200 parts by weight; the binder 5-20 parts by weight; 5 to 20 parts by weight of the disintegrator; and 0.8 to 4 parts by weight of the lubricant.
  • the inventors have found that the Mesosoli capsule of the present invention can effectively exert anti-inflammatory, analgesic and antipyretic effects, and has high dissolution rate, high bioavailability and small side effects.
  • a combination of lactose and microcrystalline cellulose is preferred as a filler.
  • elution of methicillin can be promoted, and in particular, when a combination of lactose and microcrystalline cellulose is selected, the solubility of mesosomel can be effectively improved, and the dissolution and bioavailability of mesosomel can be improved.
  • the mass ratio of lactose to microcrystalline cellulose is (0.5 to 5): 1, the solubility of methicillin can be effectively improved, thereby improving the dissolution and bioavailability of methicillin.
  • the methicillin sustained release capsule comprises: a sustained release pellet and a hollow capsule, the sustained release pellet comprising a drug-loaded pellet core and a coating layer, the coating layer comprising a barrier layer and a coating layer Release layer, wherein the drug-loaded pellet core comprises:
  • the methicillin is 50 to 100 parts by weight; the disintegrant is 10 to 20 parts by weight; the filler is 100 to 145 parts by weight; and the binder is 30 to 50 parts by weight.
  • the Mesocycline sustained-release capsule of the invention can achieve slow release, and can greatly improve the oral bioavailability of the poorly soluble drug methicillin, and can effectively reduce the dosage and the number of administrations, and has low toxicity and side effects. Good compliance.
  • the Mesosurry sustained-release capsule of the invention is convenient to take, only needs to be administered once or twice a day, and the drug is slowly released, which can effectively prevent the blood drug concentration from undulating excessively and the effective blood drug concentration is high. Low, and the side effects are small.
  • the inventors have carried out a large number of experiments, using ultra-fine pulverization technology, etc., in the form of sustained-release pellets, to achieve the preparation of the poorly soluble drug methicillin sustained-release capsule, and to improve the solubility of methicillin and improve the drug.
  • the absorption in the body improves the dissolution and oral bioavailability of the methicillin drug, and enables the slow release of the methicillin drug, achieving one dose per day, improving the patient's medication compliance, and
  • the quality of the methicillin sustained-release capsule of the present invention is stable, and provides a new clinical drug selection for patients.
  • the sustained-release pellets according to the embodiment of the present invention have a uniform particle size, a stable drug release, and can be continuously released for more than 12 hours.
  • the Mesosurry sustained-release capsule according to the embodiment of the present invention is composed of a plurality of pellets having uniform particle size, and the release behavior is more stable, has better safety, stable blood drug concentration, and reduces patient maladjustment. The probability of reaction.
  • the release layer comprises: a porogen, an anti-adhesive agent, and a barrier coating layer solvent; the sustained release layer comprises a high molecular polymer, a plasticizer, and purified water.
  • the porogen povidone K30 According to an embodiment of the invention, the porogen povidone K30.
  • the anti-tack agent is talc.
  • the barrier layer solvent is anhydrous ethanol.
  • the high molecular polymer is at least one selected from the group consisting of polyacrylic resins and ethyl cellulose.
  • the ethyl cellulose is an aqueous dispersion of ethyl cellulose
  • the plasticizer is at least one selected from the group consisting of propylene glycol, polyethylene glycol 4000, dimethyl benzoate, and triethyl citrate.
  • the invention provides a method of preparing the aforementioned mesosurrol formulation.
  • the method comprises: micronizing the methicillin and mixing the obtained methicillin micronized particles with the excipients described above to obtain a drug mixture; The mixture is made into capsules, granules or tablets.
  • the inventors have found that the method of the invention can be quickly and efficiently prepared to obtain the mesotherapid preparation described above, and is simple and convenient to operate, and is suitable for industrial large-scale production. Among them, by subjecting the methicillin to micronization treatment, the methicillin can be sufficiently dispersed in the excipient, and the dissolution rate of the methicillin can be greatly improved.
  • the Mesosurrol micronized particles have a particle size of from 1 to 100 microns.
  • the dissolution of the mesotherapin preparation prepared from the Messocifine micronized granules of this particle size is significantly better than the other particle sizes.
  • a method of preparing a methicillin preparation may include: (a1) mixing methicillin and a filler, and subjecting the resulting mixture to micronization treatment to obtain a particle diameter of 5 ⁇ m to 100 a micron mixture of fine powder particles, the disintegrating agent, the binder and the lubricant are separately pulverized and passed through an 80 mesh sieve for use; (a2) the binder is mixed with purified water to prepare a mass fraction of 6% to 12 % of the binder aqueous solution aI, spare; (a3) mixing the fine powder particles of the mixture with the added disintegrant to obtain a mixture aII; (a4) adding the aqueous binder aI to the mixture aII, And the obtained mixture is made into a soft material, and the obtained soft material is granulated by 18 mesh stainless steel to obtain wet granules; (a5) the wet granules are dried at 55 ° C to 65 ° C for 1 to
  • the coating solution is subjected to a coating treatment on the methicillin core to obtain the mesotherapine film-coated tablet.
  • the inventors can significantly improve the dissolution rate of Mesocycline film-coated tablets prepared by this method by micronizing the methicillin to make the poorly soluble Mesosuris fully dispersed. .
  • the invention discloses the disintegration agent separately adding a disintegrant and an additional disintegrant in two forms, and adding the disintegrant to promote the disintegration of the particles, and the disintegrating agent can accelerate the particles. Dispersion can greatly improve the dissolution of Messocycline film tablets. It can be seen from the results described in the examples of the present invention that the process using the internal and external addition method of the disintegrator uses only the internal addition method with respect to the disintegrant, and the dissolution degree thereof is remarkably improved. Therefore, the amount of the disintegrant is determined and added in such a manner that the amount of the disintegrant added is 1/2 of the amount of the disintegrant, and the amount added is another 1/2 of the amount of the disintegrant.
  • the tablet weight is controlled within a range of ⁇ 5% of the theoretical tablet weight, and the hardness is controlled at 5 to 7 kg.
  • the obtained Messocycline film-coated sheet has an appearance, a tablet weight, and the like, and has a high disintegration rate and a high dissolution rate.
  • the parameters of the coating treatment may be: an average inlet air temperature of 85 ° C, an average bed temperature of 41 ° C, an atomization pressure of 2.5 bar, an average coating pan speed of 15 to 23 rpm, and an average material.
  • the flow rate is 3 to 4 g/min.
  • the methicillin film tablets prepared by the invention have the properties, hardness, friability and tablet weight difference, and the dissolution rate is high, and both can reach 90%, which meets the requirements.
  • a method of preparing a methicillin preparation may include: (b1) micronizing the methicillin to obtain a methicillin micropowder; (b2) treating the mesoxyl The fine powder is mixed with the glidant and the flavoring agent; (b3) the filler is micronized to obtain a filler fine powder having a particle diameter of 20 to 100 ⁇ m; (b4) obtained in the step (b3) a mixture of the disintegrant and the binder; (b5) mixing the mixture obtained in the step (b4) with the lubricant to obtain a drug mixture; (b6) by direct compression The drug mixture is made into a methicillin orally disintegrating tablet.
  • the inventors discovered that when the methicillyl orally disintegrating tablet is prepared, the specific surface area of the methicillin and the filler is micronized, and the resulting Mesosulide orally disintegrating tablet is obtained. Can quickly disintegrate.
  • the obtained mesoxyl orally disintegrating tablet is prepared. The disintegration speed is faster and the dissolution rate is better.
  • the prescription and the preparation process of the invention can finally ensure that the Mesorizol orally disintegrating tablet has a good mouthfeel and disintegration, and is favorable for the disintegration of the orally disintegrating tablet, the dissolution rate is good, and the quality of the preparation is stable. Conducive to its industrial production.
  • the Mesorizol orally disintegrating tablet prepared by the method has a disintegration time limit of 15 s to 45 s, a hardness of 5-8 kg, a friability of less than 0.5%, and dissolution in a pH 8.8 phosphate buffer solution for 10 minutes. The amount is more than 85% and the quality is stable.
  • the phosphate buffer of pH 8.8 was obtained by dissolving sodium hydroxide and potassium dihydrogen phosphate in water and adjusting the pH to 8.8 with phosphoric acid.
  • a method of preparing a methicillin preparation may include: (c1) dissolving the methicillin in an organic solvent to obtain an organic phase solution; (c2) dispersing the filler and the bonding The agent is dissolved in purified water to obtain an aqueous phase solution; (c3) the organic phase solution is mixed with the aqueous phase solution to obtain a mixed mesosurcellol suspension solution; (c4) the beauty of the mixture is obtained After the soxil suspension solution is homogenized, spray drying is performed to obtain a spray-dried powder; (c5) the spray-dried powder is mixed with the lubricant, the disintegrant, and the flavoring agent so that The drug mixture is obtained; (c6) the drug mixture is sampled and subjected to content determination, and after the test result is passed, the drug mixture is directly powder-pressed to obtain a methicillin dispersible tablet.
  • methicillin is dissolved in an organic solvent to form an organic phase, and then slowly added to an aqueous phase solution in which a filler and a binder are dissolved to obtain a methicillin suspension solution, and then the The suspension solution is homogenized, and the obtained suspension solution particles are pulverized more finely and more uniformly.
  • the obtained spray-dried powder is mixed with a lubricant, a disintegrant and a flavoring agent to obtain a drug mixture.
  • the drug mixture was directly powder-pressed to obtain a methicillyl dispersible tablet.
  • the solubility of the methicillin can be effectively improved, the absorption in the body is improved, and the dissolution rate of the methicillin dispersible tablet is improved. And bioavailability.
  • the Methosoli dispersible tablet of the present invention can achieve dissolution of more than 80% in a short time.
  • the preparation of the poorly soluble drug methicillin dispersible tablet is realized in the form of a dispersible tablet by the solid dispersion technique, the dissolution rate of the drug is improved, and the dissolution rate is improved.
  • Oral bioavailability provides patients with a new clinical drug option.
  • Messocycline dispersible tablets were prepared by means of powder direct compression tablets, which greatly improved production efficiency and reduced production costs.
  • the prepared methicillin dispersible tablet has stable quality, disintegration meets requirements, rapid dissolution, uniform content, good mouthfeel, and good patient compliance.
  • a method of preparing a methicillin preparation may include: (d1) dissolving the methicillin in acetone, and mixing an aqueous solution of hydroxypropyl ⁇ -cyclodextrin with a mesosurcellane solution; Evaporate the solvent to obtain crystals a powder; (d2) ultrafinely pulverizing the crystal powder, and mixing with a skeleton slow-release material, a filler; (d3) granulating the mixture obtained in the step (d2), and drying the obtained granules (d4) The dried granules are mixed with the lubricant and the disintegrant, and the resulting mixture is tableted.
  • it may further comprise: (d5) film-wrapping the film obtained by tableting the step (d4) to obtain a methicillin sustained-release tablet.
  • the Messocycline sustained-release tablet obtained by the above-mentioned method can be prepared quickly and efficiently, and the operation is simple, convenient, quick and convenient, suitable for industrial production, and at the same time, the quality of the obtained Mesopril sustained-release tablet is prepared. Stable, high bioavailability, good medication compliance, and long-lasting effective action.
  • the coating weight gain is from 2% to 3% by mass percent, based on the total mass of the core.
  • the core-coated film coating described in the step (5) the coating powder material is selected from the white stomach-soluble film coating premix Oubadai 81W68907.
  • the preparation method of the coating liquid the coating powder is dispersed with purified water, and is prepared to a solid content of 15%, and stirred for 60 minutes.
  • the process parameters of the coating are: atomization pressure 0.2MP (megapascal), thimble pressure 0.2MP, coating pan speed 15r/s, feed rate 3r/min, inlet air temperature 75°C, inlet frequency 1100Hz, material temperature 35 ⁇ 45 ° C, the coating weight gain 2% ⁇ 3% end.
  • the mesosurcellol sustained release tablet has a hardness of 5-8 N (Newton).
  • the dissolution rate of the methicillin sustained-release tablet is good.
  • the inventors have improved the solubility of mesosomel in water based on the technique of solid dispersion, and at the same time, the mesosurcellane sustained-release tablet was prepared by the mechanism of sustained release of the skeleton.
  • the results of the pharmacokinetic study of the methicillin sustained-release tablet prepared by the above method and the common preparation in the animal show that the mesoxalilide sustained-release tablet of the present invention has a half-life extension of 2 to 5 times in vivo.
  • the drug release curve shows that the drug release is stable and can achieve a stable release for 24 hours.
  • the above method combines the solid dispersion technology with the skeleton sustained-release technology, and on the one hand solves the problem of low bioavailability of mesoshulid oral administration, and on the one hand, the sustained-release tablet reduces the number of medications and improves the medication for patients. Compliance.
  • this method differs from the fact that the Mesosurril raw material is directly formed into a sustained-release tablet, but the solubility of the methicillin is first improved by the solid dispersion technique, and then it is made into a sustained-release tablet, which not only achieves a slowness. The purpose of release also increases the bioavailability of the drug in the body.
  • a method of preparing a methicillin preparation may include: (e1) mixing the methicillin and the solubilizing agent, and subjecting the obtained mixture to micronization treatment; (e2) to the step a filler is added to the mixture obtained in (e1), and the obtained mixture is subjected to micronization treatment to obtain fine powder particles; (e3) the fine powder particles and the suspending agent, the flavoring agent, and the The binder and the solvent are mixed; (e4) The mixture obtained in the step (e3) is sequentially subjected to soft materials, wet granules, dried, and granulated to obtain methicillyl granules.
  • the methicillin can be uniformly dispersed in the raw material mixture, the aggregation of the fine particles of the methicillin can be prevented, and the stable presence in the mixture can be effectively improved, and the dissolution of the methicillin can be effectively improved.
  • methicillin Since methicillin is insoluble in water, if it is in accordance with the general granule preparation process, its particle-soluble agent is poor, and it is dissolved. The degree is also far from the requirements of the pharmacopoeia.
  • the methicillin and the auxiliary materials are mixed, and the micronized treatment is carried out twice, and the preparation of the granules is carried out by wet granulation, and the solubility and dissolution effect of the obtained mesosomel are good at the same time.
  • the taste is good and the quality is stable, which solves the problem of inconvenient patient medication and poor medication compliance.
  • it has also solved the deficiencies in children because of the need for a smaller dose of treatment, while tablets and capsules are not conducive to separate administration.
  • a method of preparing a methicillin preparation may include: (f1) mixing the methicillin with the filler, and subjecting the resulting mixture to micronization to a particle size of 5 -100 ⁇ m in order to obtain the fine powder particles of the mixture, the disintegrant, the binder, the lubricant passed through a 60 mesh to 80 mesh sieve, and used; (f2) the binder and the purification Mixing water to obtain the aqueous binder solution, the mass fraction of the aqueous binder is 5% to 20%; (f3) mixing the fine powder particles of the mixture with the internally added disintegrant to obtain The first mixture; (f4) mixing the first mixture with the aqueous binder solution, and the resulting mixture is made into a soft material, and the resulting soft material is sieved through a 18 mesh sieve to obtain the (f5) drying the wet granules at 55 ° C to 65 ° C for 1 to 4 hours, then sieving the granules through
  • the above-mentioned Mesoshuli capsule can be obtained quickly and efficiently, and the operation is simple, convenient and quick, and is suitable for industrial large-scale production, and can be effectively improved by micronizing the methicillyl. Dissolution and bioavailability of mesosurcellol.
  • the inventors have unexpectedly discovered that by micronizing a mixture of methicillin and a filler, the insoluble methicillin bulk drug can be sufficiently dispersed in the filler, especially when the filler is In the case of lactose and microcrystalline cellulose, the micronized methicillin and the filler have a particle diameter of from 1 to 100 ⁇ m, and the methicillin can be sufficiently dispersed in the hydrophilic lactose. It can significantly improve the dissolution of the Mesoshuli capsule.
  • the wet granulation process is employed, and the disintegrant in the formulation is creatively used internally and externally, and the disintegrant can promote the disintegration of the granules, and the disintegration agent can accelerate the dispersion of the granules.
  • the disintegrating agent only the internal addition method is employed, and the dissolution rate of the Mesorizol capsule obtained by the process of the internal and external addition method of the disintegrating agent is remarkably improved.
  • a method of preparing a methicillin preparation may include: (g1) mixing the methicillin ultrafinely pulverized with the filler, the disintegrant, and the binder, The resulting mixture is made into a soft material, and the soft material is formed into a pellet core by extrusion spheronization; (g2) a porogen, an anti-adhesive agent and a barrier layer solvent are mixed to obtain the a barrier coating liquid; (g3) mixing a high molecular polymer, a plasticizer, and purified water to obtain the sustained release layer coating liquid; (g4) drying the drug loaded core and then placing it in a fluidized In the bed, the separation layer coating liquid is sprayed on the surface of the drug-loaded pellet core by means of a bottom spray coating to form the separation layer on the surface of the drug-loaded pellet core; (g5) the surface is formed with After drying the drug-loaded pellet core of the release layer, the sustained-release layer coating liquid is sprayed on the surface of the drug
  • the Mesorizol sustained-release capsule obtained as described above can be prepared quickly and efficiently, and the operation is simple, convenient and quick, and is suitable for industrial production. Moreover, the methicillin sustained-release capsule prepared according to the present invention is stable in quality.
  • the Meso sululi raw material is prepared by micronizing the raw material, and the Mesoshuli drug-loading pellet core is prepared by extrusion spheronization, and then fluidized.
  • the bed is coated with the release layer and the sustained-release layer on the drug-loaded pill core.
  • the preparation of the poorly soluble drug methicillin sustained-release capsule is realized in the form of sustained-release pellets, and the solubility of methicillin is improved, the absorption of the drug in the body is improved, and the absorption is improved.
  • the dissolution and oral bioavailability of methicillin can achieve a slow release of methicillin, achieve one dose per day, improve patient compliance, and provide a new clinical benefit for patients. Drug selection.
  • the present invention is based on a solid dispersion technique that improves the solubility of mesosomel in water while preparing a Methosoli sustained release capsule using a sustained release coating technique.
  • the sustained-release pellets have uniform particle size, stable drug release, and can be continuously released for more than 12 hours.
  • the methicillin sustained-release capsule prepared by the invention consists of a plurality of pellets with uniform particle size, and the release behavior is more stable, and has higher safety than the sustained-release tablet, and has a more stable blood concentration and lowering. The probability of an adverse reaction in the patient
  • the invention provides a method of treating inflammation, pain or rheumatoid arthritis.
  • the method comprises administering to the patient a mesoxulide formulation as described above. Thereby, the effects of anti-inflammatory, analgesic or analgesic effects can be effectively exerted.
  • Figure 1 shows the results of dissolution measurement of mesosurcellol dispersible tablets according to one embodiment of the present invention
  • Figure 2 shows the results of dissolution measurement of Mesosurril dispersion tablets according to one embodiment of the present invention
  • Figure 3 shows the results of dissolution measurement of Mesosurril dispersion tablets according to one embodiment of the present invention
  • Figure 4 shows the results of dissolution measurement of mesosurcellol dispersible tablets according to one embodiment of the present invention
  • Figure 5 shows the results of dissolution measurement of mesosurcellol dispersible tablets according to one embodiment of the present invention
  • Figure 6 is a graph showing the comparison of the dissolution test results of the prepared mesosurcellol sustained-release tablets according to an embodiment of the present invention and Comparative Example d1;
  • Figure 7 is a graph showing the comparison of the dissolution test results of the prepared methicillin sustained-release tablets according to an embodiment of the present invention and Comparative Example d2;
  • Figure 8 shows the results of dissolution measurement of methicillin sustained-release tablets according to an embodiment of the present invention
  • Figure 9 shows the results of dissolution measurement of methicillin sustained release tablets according to one embodiment of the present invention.
  • Figure 10 shows the results of dissolution measurement of methicillin sustained release tablets according to one embodiment of the present invention.
  • Figure 11 shows the results of dissolution measurement of methicillin sustained release tablets according to one embodiment of the present invention.
  • Figure 12 shows the results of dissolution measurement of methicillin sustained release tablets according to one embodiment of the present invention.
  • Figure 13 shows the results of dissolution measurement of methicillin sustained-release tablets according to an embodiment of the present invention
  • Figure 14 shows the results of dissolution measurement of methicillin sustained-release tablets according to an embodiment of the present invention.
  • Figure 15 shows the results of dissolution measurement of methicillin sustained release tablets according to one embodiment of the present invention.
  • Figure 16 shows the results of pharmacokinetic experiments of methicillin sustained-release tablets and ordinary tablets according to an embodiment of the present invention
  • Figure 17 shows the dissolution test results of Mesosurry sustained-release capsules according to one embodiment of the present invention.
  • Figure 18 shows the dissolution test results of Mesosurry sustained-release capsules according to one embodiment of the present invention.
  • Figure 19 shows the results of a pharmacokinetic test of Mesosolide sustained release capsules in accordance with one embodiment of the present invention.
  • the Mesocycline API in the examples is a class 1.1 chemical original drug, which is made by Renfu Pharmaceutical Group. Where specific techniques or conditions are not indicated in the examples, they are carried out according to the techniques or conditions described in the literature in the art or in accordance with the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are conventional products that can be obtained commercially.
  • the difficulty in the prescription process is to improve the dissolution of the product.
  • the formulation of Mesosolide film-coated tablets having a specification of 100 mg/tablet was studied. Specifically, since the water solubility and fluidity of the methicillin bulk drug are poor, it is considered to add a water-soluble auxiliary material. And the disintegrant promotes dissolution, and nine prescriptions are designed, see Table a1.
  • hypromellose needs to be added with purified water to prepare 4% hypromellose aqueous solution (g/g).
  • Povidone K30 needs purified water to make 8% poly
  • the wet granulation process was used to prepare the methicillin core, and the dissolution rate was determined.
  • the preparation method is as follows:
  • povidone K30 PVPK30
  • step (4) drying: the wet granules of the drug obtained in step (4) are dried at 60 ° C ⁇ 5 ° C for about 2 h;
  • Tableting Calculate the theoretical tablet weight according to the measured drug content of the total mixed particles, adjust the tableting machine to a suitable filling amount, and control the pressure so that the core hardness of the film-coated tablet is within 5-7 kg. The film is available.
  • the dissolution of the above nine prescriptions in the dissolution medium was determined for 45 minutes, wherein the dissolution medium was phosphate buffer solution (sodium hydroxide 2.30 g, potassium dihydrogen phosphate 7.65 g, Water was added to dissolve it to 1000 ml, and the pH was adjusted to 8.8 with phosphoric acid.
  • phosphate buffer solution sodium hydroxide 2.30 g, potassium dihydrogen phosphate 7.65 g
  • Water was added to dissolve it to 1000 ml, and the pH was adjusted to 8.8 with phosphoric acid.
  • the dissolution measurement results are shown in Table a2.
  • the dissolution rate of the designed nine prescriptions in the dissolution medium for 45 minutes showed that the prescriptions were prescription a1, prescription a4, prescription a5, and prescription a7, and the dissolution rates were all above 80%.
  • Mesosurrol is poorly water-soluble, and hypromellose has a retarding effect, it may affect the dissolution during sample retention, and it takes a long time to completely swell in water, which is not conducive to industrial production, so it is not preferred. It acts as a binder.
  • lactose is used as a filler alone, cracking occurs in large-scale industrial production, so the present invention does not use lactose in the selection of diluents.
  • Microcrystalline cellulose can not only act as a filler, but also has the performance of a disintegrant. Microcrystalline cellulose can achieve good dissolution.
  • this study determined that based on prescription a4 and prescription a7, further investigate the optimal dosage of fillers, the concentration of binders, and improve the way of adding disintegrants to further optimize the formulation and formulation process.
  • Example a2 Formulation and process optimization of Mesoxyl film coated tablets of 100 mg size
  • microcrystalline cellulose was used as a diluent.
  • the prescriptions for different dosages of microcrystalline cellulose are shown in Table a3.
  • Table a3 shows the prescription for preparing 1000 tablets of Mesocycline film. According to the formulation shown in Table a3 and the preparation method described in Example a1, granulation tableting was carried out in a batch of 1000 tablets/batch, the theoretical tablet weight was 240 mg, and then the hardness of the prepared mesoSullimine film-coated tablet was measured. , friability, disintegration time and dissolution, screening for fillers. The results are shown in Table a3.
  • PVP-K30 was selected as the binder, and different concentrations of aqueous solutions were prepared to compare the bonding effects, as follows:
  • the core of the Mesoxulide film-coated tablet was prepared, and the methicillin-dried particles were observed during the preparation, and the prepared Mesocyclyl was determined.
  • the hardness, friability, disintegration time and dissolution of the core of the film-coated tablet, the prescription and the measurement results are shown in Table a4, wherein the prescription shown in Table a4 is the core of the preparation of 1000 pieces of Mesosuris film-coated tablets. The amount of prescription.
  • the preparation method of the adhesive is: weigh 4 g of povidone K30 in a beaker, add 96 g of purified water, stir to clarify, and obtain 4% povidone K30 aqueous solution; wherein prescription a15
  • the preparation method of the adhesive is: weigh 8 g of povidone K30 in a beaker, add 92 g of purified water, stir to clarify, and obtain 8% povidone K30 aqueous solution; wherein the preparation of the adhesive in the prescription a16
  • the method is as follows: weigh 12 g of povidone K30 in a beaker, add 88 g of purified water, stir to clarify, and obtain a 12% aqueous solution of povidone K30; wherein in the prescription a17, the preparation method of the binder is: weigh 6 The gram of povidone K30 was added to the beaker, and 94 g of purified water was added thereto, and the mixture was stirred until clarified to obtain an
  • the binder was prepared by weighing 15 g of povidone K30. In a beaker, 85 g of purified water was added, and the mixture was stirred until clarified to obtain a 15% aqueous solution of povidone K30.
  • the binder is selected as PVPK 30 , and its concentration is 6%. ⁇ 12%, the amount of the adhesive PVPK 30 in the prescription is: 6g ⁇ 12g / 1000 tablets.
  • a mesotrix film-coated tablet core was prepared.
  • the disintegrating agent is added in two ways: an internal addition method and an external addition method, and the internal addition method is to add a disintegrant in the step (3), and the addition method refers to the step (7).
  • a disintegrant is added.
  • the hardness, friability, disintegration time and dissolution of the prepared mesoxyl film-coated core were measured, and the results are shown in Table 6.
  • the formulation shown in Table 5 is a prescription amount for preparing 100 tablets of Mesopril film-coated tablets.
  • the dissolution results of prescription a20 and prescription a21 are not much different, indicating that a certain amount of disintegrant can be maintained to maintain good dissolution, and at the same time, cost can be saved.
  • the internal and external addition method, the addition of disintegrant can promote the disintegration of the particles, and the addition of the disintegrant can accelerate the dispersion of the particles and is advantageous for improving the dissolution.
  • the disintegration time and dissolution rate of the prescription a23 can be optimized, so the amount of PVPP and the addition method are determined as follows: 0.7 g is added, and 0.5 g is added. Therefore, the tentative best prescription is prescription a23.
  • the methicillin tablets were prepared according to the formulation shown in Table a7 and the preparation method in Example a1.
  • the disintegrant is added in two ways: an internal addition method and an external addition method.
  • the internal addition means that a disintegrating agent is added in the mixing step
  • the external addition means that the dry particles and the disintegrant are uniformly mixed before the lubricant is added in the total mixing step.
  • the samples are prepared by the wet granulation process according to the prescription in Table a7, and the preparation method is as follows:
  • step (4) drying: the wet granules of the drug obtained in step (4) are dried at 60 ° C ⁇ 5 ° C for about 2 h;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • Tableting Calculate the theoretical tablet weight according to the measured drug content of the total mixed particles, adjust the tableting machine to a suitable filling amount, and control the pressure so that the film core hardness is within 5-7 kg. That is.
  • the prescription a24-prescription a28 shown in Table a7 is a prescription for preparing 1000 tablets of mesosomeril tablets. the amount.
  • the process using the internal and external addition method of the disintegrator uses only the internal addition method with respect to the disintegrant, and the dissolution degree thereof is remarkably improved. Therefore, the amount of the disintegrant is determined and added in such a manner that the amount of the disintegrant added is 1/2 of the amount of the disintegrant, and the amount added is another 1/2 of the amount of the disintegrant. Therefore, the provisional prescription is prescription a28.
  • the preparation process of the present invention was further optimized to further improve the dissolution of the mesosurcellil film core of the present invention.
  • group A and group B mesotherapine film-coated tablet cores
  • the method for preparing the group A mesosomes film-coated tablet cores was as follows, group B meso Preparation method of Shuli tablets and group A mesosome
  • the method for preparing the film-coated core is different in that the mixture of the main drug mesotrophin and the adjuvant filler is not subjected to micronization. details as follows:
  • the preparation method of group A mesoxyl film film core is as follows:
  • step (4) drying: the wet granules of the drug obtained in step (4) are dried at 60 ° C ⁇ 5 ° C for about 2 h;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • Tableting Calculate the theoretical tablet weight according to the measured drug content of the total mixed particles, adjust the tableting machine to a suitable filling amount, and control the pressure so that the film core hardness is within 5-7 kg. That is.
  • the tablet weight and the appropriate sheet thickness are combined, and at the same time, the friability requirement is considered, and the tableting machine is used for tableting.
  • the hardness of the film-coated core was controlled in the interval shown in Table a9, and then the friability, dissolution and disintegration time of the film-coated cores of different hardness were measured, and the results are shown in Table a9.
  • prescription a30 is a 50mg mesoxolic tablet, which is prescribed: mesocycline 50g, microcrystalline cellulose 170g, povidone K30 8g, crospovidone (plus) 6g, cross-linking Povidone (additional) 6 g, magnesium stearate 2.5 g.
  • Prescription a29 is a 100mg Mesoxulil tablet with a prescription of: Mesocycline 100g, microcrystalline cellulose 120g, Povidone K30 8g, crospovidone (Plus) 6g, cross-linked polyglycol Ketone (plus) 6 g, magnesium stearate 2.5 g.
  • the preparation method is as follows:
  • the main drug (Mexosole) and the auxiliary filler are mixed for micronization (particle size is 5 micrometers to 100 micrometers), and the other auxiliary materials are crushed and passed through a 80 mesh sieve for use;
  • step (4) drying: the wet granules of the drug obtained in step (4) are dried at 60 ° C ⁇ 5 ° C for about 2 h;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • the surface of the Mesocycline tablet core (the core described in the present invention, that is, the Meissouoli tablets which are not coated in the above embodiment).
  • the coating material is used to isolate the medicine in the film-coated tablet from the outside, and the film-coated film coated with the film coating on the surface of the Mesocycline drug is obtained, thereby preventing moisture, light, air oxidation and enhancing the stability of drug preservation. It masks the bad smell in the film-coated tablets and reduces the purpose of drug stimulation.
  • the coating material is: white stomach-soluble Opadry 81W68907, produced by Shanghai Kalakang Coating Technology Co., Ltd.
  • the coated powder was added to purified water to prepare a solution having a solid content of 20%, and the mixture was stirred for 45 minutes with a spiral stirring paddle.
  • the prepared coating liquid can be pumped directly from the liquid dispensing container by a peristaltic pump.
  • the inlet air temperature was set at 85 ° C, the average bed temperature was 41 ° C, the coating pan speed was 15 to 23 r/min, and the spray speed was 3 to 4 g/min. After each piece of weight gains to the set value, stop spraying the coating liquid, blow it with cold air, and then take out the film after the film temperature drops to room temperature, put it in the film bag, weigh it, and take it for sampling.
  • Coating weight gain Coating effect magnifying glass
  • Disintegration time s
  • the core has been completely wrapped, but the edges are incomplete 78 3.0%
  • the coated tablets are completely wrapped, the color is uniform, and the edges are complete.
  • the coated tablets are completely wrapped, the color is uniform, and the edges are complete.
  • the coated tablets are completely wrapped, the color is uniform, and the edges are complete. 171
  • the weight gain of the coating is controlled to be 3.0%-3.5% of the weight of the core when the coating is selected, which can meet the appearance requirements of the coated tablet without affecting the disintegration time and dissolution. Degree, can also play a better shading effect.
  • Mesocycline 50g microcrystalline cellulose 170g, povidone K30 8g, crospovidone (additional) 6g, crospovidone (additional) 6g, magnesium stearate 2.5g, a total of 1000 sheet.
  • binder weigh 8 grams of adhesive povidone K30 in a beaker, add 92 grams of purified water, stir until clarified, to obtain 8% povidone K30 binder aqueous solution I, spare;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • Tableting Calculate the theoretical tablet weight according to the measured drug content of the total mixed particles, adjust the tableting machine to a suitable filling amount, and control the pressure so that the film core hardness is within 5-7 kg. That is.
  • Mesocycline 50g microcrystalline cellulose 120g, povidone K30 10g, crospovidone (inward) 2.5g, crospovidone (additional) 2.5g, magnesium stearate 1g, co-made 1000 pieces.
  • Preparation method with binder: Weigh 10 g of adhesive povidone K30 in a beaker, add 90 g of purified water, stir until clear, to obtain 10% povidone K30 binder aqueous solution I; the rest of the preparation The method is the same as in Example 4.
  • Preparation method with binder: weigh 6 grams of adhesive povidone K30 in a beaker, add 94 grams of purified water, stir until clarified, to obtain 6% povidone K30 binder aqueous solution I; the rest of the preparation The method is the same as in Example 4.
  • Preparation method with binder: weigh 12 grams of adhesive povidone K30 in a beaker, add 88 grams of purified water, stir until clarified, to obtain 12% povidone K30 binder aqueous solution I; the rest of the preparation The method is the same as in Example 4.
  • Preparation method with binder: weigh 7 g of adhesive povidone K30 in a beaker, add 93 g of purified water, stir until clear, to obtain 7% povidone K30 binder aqueous solution I; the rest of the preparation
  • the method is the same as in Example 4.
  • Preparation method with binder: Weigh 10 g of adhesive povidone K30 in a beaker, add 90 g of purified water, stir until clear, to obtain 10% povidone K30 binder aqueous solution I; the rest of the preparation The method is the same as in Example 4.
  • Preparation method with binder: weigh 7 g of adhesive povidone K30 in a beaker, add 93 g of purified water, stir until clear, to obtain 7% povidone K30 binder aqueous solution I; the rest of the preparation
  • the method is the same as in Example 4.
  • a 50 mg size Mesoxulide film-coated tablet (batch No. 131205) was exposed to a Petri dish and placed at high temperature (60 ° C), high humidity (RH 92.5%, 25 ° C), and strong light (4500 lx ⁇ 500 lx). On the 5th and 10th days, samples were taken on the 5th and 10th day. The appearance, content, dissolution, related substances, weight loss rate and other items of the preparation were observed and compared with the inspection data of the samples before the inspection. The test results are shown in Table 13.
  • the impurity 1 is a compound of the formula I disclosed in Chinese Patent Application No. CN103553984A, and its structural formula is as follows:
  • the PVC blister + double-sided composite aluminum film bag package has good water vapor permeability and good sealing performance, and can effectively ensure the long-term stability of the product. Therefore, the choice of PVC blister + double-sided composite aluminum film bag packaging is the best inner packaging material for Mesosureli film film.
  • Example h1 Interaction experiment between main drug and auxiliary material
  • liquid chromatography in order to examine whether there is an interaction between the main drug and the selected auxiliary material in the prescription, and whether the crystal form is changed during the preparation process, liquid chromatography is used (according to the embodiment 8 of the Chinese invention patent application CN103553984A)
  • the Methotrex HPLC method was used to study the interaction between the selected excipients and the main drug.
  • the mixture of the main excipient, the main drug and each of the individual excipients, and the mixture of the main drug and all the excipients are placed under the influencing factors for 10 days, and the traits, related substances and contents of the mixture are compared after 0 days and 10 days. The change.
  • the batch number of the API (Missuoshuli): 101217 batch (made by Renfu Pharmaceutical Group Co., Ltd., purity 99.8%), the Mesoshuli API was first passed through a 60 mesh sieve, and each accessory was passed through a 80 mesh sieve.
  • Sample h1 a mixture of the main drug and microcrystalline cellulose (mass ratio 1:5);
  • Sample h2 a mixture of the main drug and lactose (mass ratio 1:5);
  • Sample h3 a mixture of the main drug and povidone K30 (mass ratio 5:1)
  • Sample h4 mixture of main drug and crospovidone (mass ratio 5:2)
  • Sample h5 a mixture of the main drug and magnesium stearate (20:1 by mass)
  • Sample h6 a mixture of the main drug and the mixed auxiliary material (mass ratio 1:5);
  • the samples of h1 ⁇ h6 were placed under high temperature, high humidity and light conditions for 10 days. Compared with 0 days, the traits and content did not change significantly. The impurity 1 did not increase and no new impurities were produced. The results showed that The compatibility between the excipients and the main drug is good, and there is no interaction between the mesosomel and the excipients.
  • Example h2 Formulation study of Mesosurrol film-coated tablets
  • the difficulty in the prescription process is to improve the dissolution of the product.
  • a prescription of a 50 mg/table MesoSullid tablet was studied. Specifically, since the water solubility and fluidity of the Mesocycline bulk drug are poor, it is considered to add a water-soluble adjuvant and The disintegrant promotes dissolution and nine prescriptions are designed, see Table h2.
  • hypromellose needs to be added with purified water to prepare 4% hypromellose aqueous solution (g/g).
  • Povidone K30 needs purified water to make 8% poly An aqueous solution of ketene K30 (g/g).
  • the wet granulation process was used to prepare the methicillin core, and the dissolution rate was determined.
  • the preparation method is as follows:
  • povidone K30 PVPK30
  • step (4) drying: the wet granules of the drug obtained in step (4) are dried at 60 ° C ⁇ 5 ° C for about 2 h;
  • the dissolution of the above nine prescriptions in the dissolution medium was determined for 45 minutes, wherein the dissolution medium was phosphate buffer solution (sodium hydroxide 2.30 g, potassium dihydrogen phosphate 7.65 g, Add water to dissolve 1000 ml, adjust the pH to 8.8 with phosphoric acid, and the dissolution test results are shown in Table h3.
  • phosphate buffer solution sodium hydroxide 2.30 g, potassium dihydrogen phosphate 7.65 g
  • the dissolution of the designed nine prescriptions in the dissolution medium for 45 minutes showed that the preferred prescription was prescription h1, prescription h4, and prescription h8.
  • Mesosurrol is poorly water-soluble, and hypromellose has a retarding effect, it may affect the dissolution during sample retention, and it takes a long time to completely swell in water, which is not conducive to industrial production, so it is not preferred. It acts as a binder.
  • lactose is used as a filler alone, cracking can occur in large-scale industrial production. Therefore, the present invention does not use lactose alone in the selection of diluents.
  • lactose as a filler has good water solubility
  • microcrystalline cellulose can be used not only as a filler but also as a disintegrant
  • a combination of both lactose and microcrystalline cellulose is selected as a diluent (in this context, "Filling agent” and “diluent” can be used interchangeably to achieve good dissolution.
  • this study determined that based on the prescription h1, further investigate the optimal proportion and amount of fillers, the concentration of binders, and improve the way of adding disintegrants to further optimize the formulation and formulation process.
  • Example h3 Formulation and process optimization of Mesoxyl film coated tablets of 50 mg size
  • the adhesive is prepared by weighing 8 g of povidone K30 into a beaker, adding 92 g of purified water, stirring to clarify, and obtaining an aqueous solution of 8% povidone K30.
  • the povidone K30 was selected as the binder, and different concentrations of aqueous solution were prepared to compare the adhesion effect.
  • the effect of the amount of binder on the mesosole tablet was investigated as follows:
  • the methicillin tablets were prepared, and the mesocholi soft materials and granules were observed during the preparation, and the prepared methicillin tablets were determined.
  • the hardness, friability, disintegration time and dissolution of the agent, prescription and measurement results are shown in Table h5.
  • the prescription shown in Table h5 is the amount of the original auxiliary material for preparing 1000 tablets of Mesocycline tablets.
  • the preparation method of the adhesive is: weigh 4 g of povidone K30 in a beaker, add 96 g of purified water, stir to clarify, and obtain 4% povidone K30 aqueous solution; wherein the prescription h16 The preparation method of the adhesive is: weigh 8 g of povidone K30 in a beaker, add 92 g of purified water, stir to clarify, and obtain 8% povidone K30 aqueous solution; wherein the preparation of the adhesive in the prescription h17 The method is as follows: weigh 12 g of povidone K30 in a beaker, add 88 g of purified water, stir to clarify, and obtain 12% povidone K30 aqueous solution; wherein in the prescription h18, the preparation method of the binder is: weigh 6 Keke povidone K30 in a beaker, add 94 grams of purified water, stir until clarified, to obtain 6% povidone K30 aqueous solution; in the
  • the obtained soft material has a moderate degree of dryness and wetness, and is easy to be sieved.
  • the obtained particles are round, uniform, and have good fluidity, and are easy to be tableted. Therefore, it is determined that the amount of the binder is 6 to 12 g / 1000 tablets.
  • the methicillin tablets were prepared according to the formulation shown in Table h6 and the preparation method in Example h2.
  • the disintegrant is added in two ways: an internal addition method and an external addition method.
  • the internal addition method is to add a disintegrant in the mixing step, and the addition method means that the dry particles and the disintegrant are uniformly mixed before the lubricant is added in the total mixing step.
  • the mesoxulide tablets are separately prepared by the wet granulation process according to the prescription in Table h6, and the preparation method is as follows:
  • step (4) drying: the wet granules of the drug obtained in step (4) are dried at 60 ° C ⁇ 5 ° C for about 2 h;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • the hardness, friability, disintegration time, and dissolution of the prepared methicillin tablets were measured, and the results are shown in Table h6.
  • the formula of the prescription h20-prescription h24 shown in Table h6 is the prescription amount for preparing 1000 pieces of mesosomeril tablets.
  • the process using the internal and external addition method of the disintegrator uses only the internal addition method with respect to the disintegrant, and the dissolution degree thereof is remarkably improved, and the dissolution degree thereof can be increased to 85% or more. Therefore, the amount of the disintegrant is determined and added in such a manner that the amount of the disintegrant added is 1/2 of the amount of the disintegrant, and the amount added is another 1/2 of the amount of the disintegrant. Therefore, the provisional prescription is prescription h24.
  • the preparation process of the present invention is further optimized based on the prescription h24 in Example h3 to further improve the dissolution of the mesosomeril tablet of the present invention.
  • group A and group B mesoxulide tablets were prepared separately, and the method for preparing the group A mesosomeli tablets was as follows, and the preparation of the group B mesoxolide tablets was carried out.
  • the method differs from the preparation method of the group A mesosomeli tablet in that the mixture of the main drug mesotrophin and the adjuvant filler is not subjected to micronization treatment. details as follows:
  • the main drug (Mexosole) and the auxiliary filler are mixed for micronization (particle size is 5 micrometers to 100 micrometers), and the other auxiliary materials are crushed and passed through a 80 mesh sieve for use;
  • step (4) drying: the wet granules of the drug obtained in step (4) are dried at 60 ° C ⁇ 5 ° C for about 2 h;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • the tablet weight and the appropriate sheet thickness are combined, and at the same time, the friability requirement is considered, and the tableting machine is used for tableting.
  • the hardness of the tablets was controlled in the interval shown in Table h8, and then the friability, dissolution and disintegration time of the tablets of different hardness were measured, and the measurement results are shown in Table h8.
  • the prescription h24 is a 50 mg meso sulphon tablet, and the prescription is: mesocycline 50 g, lactose 50 g, microcrystalline cellulose 100 g, povidone K30 8 g, crospovidone (inward) 6 g , crospovidone (additional) 6g, magnesium stearate 2.5g.
  • the prescription h25 is a methicillin tablet with a specification of 100 mg, and the prescription is: mesocycline 100 g, lactose 40 g, microcrystalline cellulose 80 g, povidone K30 8 g, crospovidone (inward) 6 g, Dividone (additional) 6g, magnesium stearate 2.5g.
  • the preparation method is as follows:
  • the main drug (Mexosole) and the auxiliary filler are mixed for micronization (particle size is 5 micrometers to 100 micrometers), and the other auxiliary materials are crushed and passed through a 80 mesh sieve for use;
  • step (4) drying: the wet granules of the drug obtained in step (4) are dried at 60 ° C ⁇ 5 ° C for about 2 h;
  • Total mixing adding the prescribed amount of dry granules to the dry granules, and adding the prescription amount of stearic acid. Magnesium, mixed evenly, to obtain total mixed particles;
  • Tableting Calculate the theoretical tablet weight according to the measured drug content of the total mixed particles, adjust the tableting machine to a suitable filling amount, and control the pressure to make the tablet hardness 4-5 kg, 5-6 kg, 6
  • the above-mentioned different hardness of mesosomeril tablets can be obtained by tableting within 7 kg and 7-8 kg.
  • the appropriate coating material on the surface of the Mesosurril tablet core (the core of the film here, that is, the Mesocycline tablet which is not coated in the above embodiment).
  • the core of the film here, that is, the Mesocycline tablet which is not coated in the above embodiment.
  • the medicine in the tablet from the outside, obtain a tablet coated with a film coating on the surface of the Mesosurrol drug, thereby achieving moisture resistance, protection from light, isolation of air oxidation, enhancement of stability of drug preservation, and masking of the tablet. Poor smell and reduce the purpose of drug stimulation.
  • the coating material is: white stomach-soluble Opadry 81W68907, produced by Shanghai Kalakang Coating Technology Co., Ltd.
  • the coated powder was added to purified water to prepare a solution having a solid content of 20%, and the mixture was stirred for 45 minutes with a spiral stirring paddle.
  • the prepared coating liquid can be pumped directly from the liquid dispensing container by a peristaltic pump.
  • the inlet air temperature was set at 85 ° C, the average bed temperature was 41 ° C, the coating pan speed was 15 to 23 r/min, and the spray speed was 3 to 4 g/min. After each piece of weight gains to the set value, stop spraying the coating liquid, blow it with cold air, and then take out the film after the film temperature drops to room temperature, put it in the film bag, weigh it, and take it for sampling.
  • Coating weight gain Coating effect magnifying glass
  • Disintegration time s
  • the weight gain of the coating is controlled to be 3.0%-3.5% of the weight of the core when the coating is selected, which can meet the appearance requirements of the coated tablet without affecting the disintegration time and dissolution. Degree, can also play a better shading effect.
  • binder weigh 8 grams of adhesive povidone K30 in a beaker, add 92 grams of purified water, stir until clarified, to obtain 8% povidone K30 binder aqueous solution I, spare;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • binder weigh 8 grams of adhesive povidone K30 in a beaker, add 92 grams of purified water, stir until clarified, to obtain 8% povidone K30 binder aqueous solution I, spare;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • Packaging The methicillyl tablet is packaged with a polyvinyl chloride blister + double-sided composite aluminum film bag.
  • binder weigh 8 grams of adhesive povidone K30 in a beaker, add 92 grams of purified water, stir until clarified, to obtain 8% povidone K30 binder aqueous solution I, spare;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • Equipped with the binder Weigh 6 g of the adhesive povidone K30 in a beaker, add 94 g of purified water, stir until clear, to obtain a binder aqueous solution I of 6% povidone K30; the rest of the preparation method is the same as the implementation Example 5.
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • Preparation method with binder: weigh 12 grams of adhesive povidone K30 in a beaker, add 88 grams of purified water, stir until clarified, to obtain 12% povidone K30 binder aqueous solution I; the rest of the preparation The method is the same as in the example h5.
  • Preparation method with binder: weigh 7 g of adhesive povidone K30 in a beaker, add 93 g of purified water, stir until clear, to obtain 7% povidone K30 binder aqueous solution I; the rest of the preparation
  • the method is the same as in the example h5.
  • binder weigh 10 grams of binder methylcellulose in a beaker, add 90 grams of purified water, stir until clarified, to obtain 10% hypromellose binder aqueous solution I, spare;
  • Total mixing adding the prescribed amount of dry disintegrating agent to the dry granules, and adding the prescribed amount of magnesium stearate, and mixing uniformly to obtain the total mixed particles;
  • binder weigh 10 grams of binder methylcellulose in a beaker, add 90 grams of purified water, stir until clarified, to obtain 10% hypromellose binder aqueous solution I, spare;
  • Table h11 show that the traits, hardness, friability and weight difference of the 9 batches of samples all meet the requirements, and the dissolution rate is high, and both can reach 90%, meeting the requirements.
  • the influencing factors test results show that the film-coated tablets are placed under high temperature, high humidity and light for 10 days.
  • the content and related substances have no significant changes, and the quality is basically stable, indicating that the prescription is scientifically feasible, the process is reasonable and the reproducibility is good.
  • the surface of the high-humidity 10-day film there was slight moisture absorption, and the dissolution rate decreased, suggesting that moisture should be taken care of when selecting the package. Therefore, the product needs to be stored in a sealed and dry place.
  • the PVC blister + double-sided composite aluminum film bag package has good water vapor permeability and good sealing performance, and can effectively ensure the long-term stability of the product. Therefore, the choice of PVC blister + double-sided composite aluminum film bag packaging is the best inner packaging material for Mesosureli film film.
  • the dosage form is produced using conventional tablet pharmaceutical equipment and prepared by a direct compression process.
  • the specific preparation method is as follows:
  • Step 1 The prescribed amount of mesotrophin is micronized, and the particle size after micronization is 1-30 micrometers. Mix the powder silica gel evenly; after the Aspartame is finely ground through the 80 mesh sieve, mix the methicillin, the microsilica gel and the aspartame;
  • Step 2 the prescribed amount of mannitol and microcrystalline cellulose are micronized, the particle size after micronization is 120-200 microns; the low-substituted hydroxypropyl cellulose is passed through a 80 mesh sieve, and the povidone K30 is passed through a 40 mesh sieve. Weighed according to the prescription amount and sequentially added to the mixed drug in the above step 1 in the above order and mixed;
  • Step 3 Adding a prescribed amount of silica to the mixed drug obtained in the above step 2, sieving and mixing, and performing intermediate content detection, determining the tablet weight and then using direct compression tablet technology to compress the tablet, that is, the Mesoshuli oral cavity Disintegrating tablets.
  • the methicillin orally disintegrating tablet was prepared in the same manner as in Example b1 except that the particle size of the methicillin was 60-100 ⁇ m after micronization, and the mannitol and the microcrystalline cellulose were micronized. The particle size is 10-60 microns.
  • Step 1 The prescribed amount of mesotrophil is micronized, and the particle size after micronization is 30-60 micrometers, and the micro-silica gel is added to be evenly mixed; after the orange essence is finely ground through the 80-mesh sieve, the Mesotrophil is obtained. , micro-powder silica gel and orange flavor are evenly mixed;
  • Step 2 micronizing the prescribed amount of mannitol and microcrystalline cellulose, the particle size after micronization is 60-120 micrometers; the cross-linked povidone is passed through a 80 mesh sieve, and the sodium carboxymethylcellulose is passed through a 40 mesh sieve. , weighed according to the prescription amount and sequentially added to the mixed medicine in the above step 1 in the above order and mixed;
  • Step 3 adding a prescribed amount of magnesium stearate to the mixed drug obtained in the above step 2, sieving and mixing, performing intermediate content detection, determining the tablet weight, and then using direct compression tablet technology to compress the tablet, that is, Mesocyclyl Orally disintegrating tablets.
  • Step 1 The prescribed amount of mesotrophin is micronized, and the particle size after micronization is 30-60 micrometers, and the micro-powder silica gel is uniformly mixed; after the aspartame is finely ground through the 80 mesh sieve, Messo Lime, micronized silica gel and aspartame are evenly mixed;
  • Step 2 the prescribed amount of mannitol and microcrystalline cellulose are micronized, the particle size after micronization is 60-120 microns; the cross-linked povidone is passed through a 80 mesh sieve, and the povidone K30 is passed through a 40 mesh sieve.
  • the prescription amount is separately weighed and sequentially added to the mixed medicine in the above step 1 in the above order, and mixed;
  • Step 3 adding a prescribed amount of magnesium stearate to the mixed drug obtained in the above step 2, sieving and mixing, performing intermediate content detection, determining the tablet weight, and then using direct compression tablet technology to compress the tablet, that is, Mesocyclyl Orally disintegrating tablets.
  • Step 1 The prescribed amount of mesotrophin is micronized, and the particle size after micronization is 1-30 micrometers, and the micro-powder silica gel is uniformly mixed; the aspartame is finely ground through an 80-mesh sieve, and the mesosole is used. , micro-powder silica gel and aspartame are evenly mixed;
  • Step 2 micronizing the prescribed amount of mannitol and microcrystalline cellulose, the particle size after micronization is 60-120 micrometers; sodium carboxymethyl starch is passed through a mesh of 80 mesh, and hypromellose is passed through a 40 mesh sieve. Weighed according to the prescription amount and sequentially added to the mixed drug in the above step 1 in the above order and mixed;
  • Step 3 adding a prescription amount of polyethylene glycol to the mixed drug obtained in the above step 2, sieving and mixing, performing intermediate content detection, determining the tablet weight, and then using direct compression technology to compress the tablet, that is, Mesocyclyl Orally disintegrating tablets.
  • Mesosole 100g, mannitol 40g, microcrystalline cellulose 60g, povidone K30 40g, crospovidone 12g, aspartame 10g, magnesium stearate 6g, 0.4 g of micronized silica gel was prepared into 1000 tablets of Mesocycline orally disintegrating tablets.
  • Step 1 The prescribed amount of mesotrophil is micronized, and the particle size after micronization is 30-60 micrometers, and the micro-powder silica gel is uniformly mixed; the aspartame is finely ground through an 80-mesh sieve, and the mesosole is used. , micro-powder silica gel and aspartame are evenly mixed;
  • Step 2 micronizing the prescribed amount of mannitol and microcrystalline cellulose, the particle size after micronization is 10-60 micrometers; the cross-linked povidone is passed through a 80 mesh sieve, and the povidone K30 is passed through a 40 mesh sieve.
  • the prescription amount is separately weighed and sequentially added to the mixed medicine in the above step 1 in the above order, and mixed;
  • Step 3 adding a prescribed amount of magnesium stearate to the mixed drug obtained in the above step 2, sieving and mixing, performing intermediate content detection, determining the tablet weight, and then using direct compression tablet technology to compress the tablet, that is, Mesocyclyl Orally disintegrating tablets.
  • Step 1 The prescribed amount of mesotrophin is micronized, the particle size after micronization is 30-60 micrometers, and the micro-silica gel is added to be evenly mixed; the orange flavor is finely ground through an 80-mesh sieve, and the methicillyl, Micronized silica gel and orange flavor are evenly mixed;
  • Step 2 the prescribed amount of mannitol and microcrystalline cellulose are micronized, the particle size after micronization is 30-60 microns; the cross-linked povidone is passed through a 80 mesh sieve, and the povidone K30 is passed through a 40 mesh sieve.
  • the prescription amount is separately weighed and sequentially added to the mixed medicine in the above step 1 in the above order, and mixed;
  • Step 3 adding a prescribed amount of magnesium stearate to the mixed drug obtained in the above step 2, sieving and mixing, performing intermediate content detection, determining the tablet weight, and then using direct compression tablet technology to compress the tablet, that is, Mesocyclyl Orally disintegrating tablets.
  • Step 1 The prescribed amount of mesotrophin is micronized, the particle size after micronization is 30-60 micrometers, and the micro-silica gel is added to be evenly mixed; the orange flavor is finely ground through an 80-mesh sieve, and the methicillyl, Micronized silica gel and orange flavor are evenly mixed;
  • Step 2 micronizing the prescribed amount of mannitol and microcrystalline cellulose, the particle size after micronization is 100-150 microns; passing croscarmellose sodium through 80 mesh sieve, hydroxypropyl cellulose over 40 Mesh sieve, weighed according to the prescription amount and sequentially added to the mixed drug in the above step 1 in the above order and mixed;
  • Step 3 Adding a prescribed amount of silica to the mixed drug obtained in the above step 2, sieving and mixing, and performing intermediate content detection, determining the tablet weight and then using direct compression tablet technology to compress the tablet, that is, the Mesoshuli oral cavity Disintegrating tablets.
  • Example b1 - Example b12 The hardness, disintegration time limit, friability and dissolution of the methicillin orally disintegrating tablets prepared in Example b1 - Example b12 were determined by the following test methods and test instruments, as follows:
  • Dissolution method large cup paddle method
  • Dissolution medium pH 8.8 phosphate buffer, volume 1000ml;
  • the final sampling time is 30 minutes.
  • the dissolution measurement method is as follows:
  • samples were taken at 5, 15, 25, 35, 45, 60 minutes, filtered, and the appropriate amount of the filtrate was accurately aspirated, and diluted with the dissolution medium to about 20 ⁇ g of Messoper per 1 ml. Lee.
  • Example b12 The dissolution of the methicillin orally disintegrating tablet sample prepared in Example b1 - Example b12 was determined according to the above method.
  • Example b1 - Example b12 the methicillium orally disintegrating tablet prepared in Example b1 - Example b12 was exposed to a Petri dish at high temperature (60 ° C), high humidity (RH 92.5%, 25 °C), glare (4500lx ⁇ 500lx) for 10 days, and 0, 5, and 10 days, using the liquid chromatography method disclosed in Example 8 of Chinese Patent Application 201310476323.3 to determine the oral disintegration of mesosomel The total impurity content of the sheet.
  • Example b1 - Example b12 The results of the disintegration time limit, friability, tablet hardness and dissolution of the methicillin orally disintegrating tablets prepared in Example b1 - Example b12 are shown in Table b1, and the influencing factors for the 10-day measurement are shown in Table b2.
  • the Mesorizol orally disintegrating tablet of the present invention has a disintegration time limit of 15 s to 45 s, a hardness of 5-8 kg, a friability of less than 0.5%, and a phosphate acidity at pH 8.8 for 10 minutes.
  • the amount of dissolution in the salt buffer solution is greater than 85%.
  • the above data indicates that the Mesoshuli orally disintegrating tablet obtained by applying the prescription and preparation process of the present invention has a very stable quality after 10 days of influencing factors.
  • the comparative example b1 Compared with the preparation process of the present invention, the comparative example b1 has the following differences: (1) the methicillin raw material, and the mannitol, the microcrystalline cellulose are not micronized, and (2) the microsilica gel is not added. (3) Preparation of methicillin orally disintegrating tablets by wet granulation.
  • the preparation process is as follows:
  • Equipped with a binder Take a prescription amount of povidone K30, add purified water to make a 10% by mass solution, and set aside.
  • auxiliary material is passed through an 80 mesh sieve, and the Messocycline is passed through a 60 mesh sieve.
  • the raw and auxiliary materials are weighed according to the prescription amount, and the raw and auxiliary materials are uniformly mixed and used.
  • Drying and sizing Spread the wet granules on the pan, place in an oven, dry at 60 ⁇ 5°C, flip once every half hour, take out after about 2h, and sieve the whole granules with 18 mesh to obtain dry granules. weight.
  • Total mixing According to the weight of dry granules, add magnesium stearate and mix well.
  • Tableting Calculate the theoretical tablet weight according to the measured drug content of the total mixed particles, adjust the tableting machine to a suitable filling amount, control the pressure so that the hardness of the film is within 5-8 kg, and the tablet is Messo Orally disintegrating tablets.
  • Disintegration measurement method 2 ml of hot water at 37 ° C was added to a 10 ml test tube, and the tablets to be tested were gently put into the test piece, and the time was started. The complete disintegration time of the tablets was observed, and the measurement was terminated at 1 min to observe whether the tablets completely collapsed. solution.
  • Test results According to the requirements of quality control of Chinese oral disintegrating tablets, the tablets obtained by comparing the experimental prescriptions and preparation methods of the examples can not be used within the hardness of 4-8 kg (take 4kg, 5kg, 6kg, 7kg and 8kg). Completely disintegrated within 1 min. When the hardness is 1kg and 2kg, the disintegration time is 50s and 55s, respectively, and the friability is also high, 1.1% and 1.5% respectively.
  • the methicillin orally disintegrating tablet (Example b1 - Example b12) prepared according to the direct compression technical solution of the present invention has a disintegration time of 15 s to 45 s in the range of hardness of 5-8 kg, and is friable. The degree is less than 0.5%, and the dissolution is good and the quality is stable.
  • mesosomes 25 parts by weight of mesosomes, 5 parts by weight of aspartame, 60 parts by weight of microcrystalline cellulose, 5 parts by weight of hydroxypropylmethylcellulose, 2 parts by weight of sodium carboxymethyl starch, and 0.5 parts by weight of magnesium stearate
  • liquid A Dissolving the above-mentioned prescription amount of mesosomel in 25 ml of acetone to obtain liquid A, and dissolving the prescribed amount of microcrystalline cellulose and hydroxypropylmethylcellulose in 100 ml of purified water to obtain liquid B;
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • the dissolution rate of the Mesopril dispersion tablets prepared according to the Chinese Pharmacopoeia 2010 edition two appendix XD method was determined by the Chinese Pharmacopoeia 2010 edition two appendix XC second method device. Specifically, the water is 9000 ml as a release medium, and the rotation speed is 100 rpm, and samples are taken at 5, 10, 15, 30, 45, and 60 minutes to determine the dissolution rate of the methicillin dispersible tablet. The measurement results are shown in Fig. 1.
  • mesosomes 25 parts by weight of mesosomes, 10 parts by weight of sucrose, 30 parts by weight of lactose, 50 parts by weight of microcrystalline cellulose, 5 parts by weight of povidone, 3 parts by weight of crospovidone, 0.5 parts by weight of micronized silica gel
  • liquid A Dissolving the above-mentioned prescription amount of mesosomel in 25 ml of ethanol to obtain liquid A, and dissolving the prescribed amount of lactose, microcrystalline cellulose and povidone in 100 ml of purified water to obtain liquid B;
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • mesosomes 50 parts by weight of mesosomes, 10 parts by weight of aspartame, 100 parts by weight of microcrystalline cellulose, 10 parts by weight of hydroxypropylmethylcellulose, 5 parts by weight of sodium carboxymethyl starch, and 1 part by weight of magnesium stearate
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • Dissolution test The experimental method was the same as that of Example c1, and the dissolution test results of the Mesocycline dispersible tablet are shown in Fig. 2.
  • mesosomes 50 parts by weight of mesosomes, 10 parts by weight of stevioside, 80 parts by weight of mannitol, 8 parts by weight of hydroxypropylcellulose, 6 parts by weight of croscarmellose sodium, and 1 part by weight of magnesium stearate
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • mesosomes 50 parts by weight of mesosomes, 10 parts by weight of aspartame, 100 parts by weight of starch, 8 parts by weight of dextrin, 6 parts by weight of low-substituted hydroxypropylcellulose, and 1 part by weight of sodium fumarate
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • mesosomes 50 parts by weight of mesosomes, 20 parts by weight of sucrose, 110 parts by weight of lactose, 10 parts by weight of hydroxypropylmethylcellulose, 6 parts by weight of sodium carboxymethyl starch, and 1 part by weight of sodium lauryl sulfate
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • Dissolution test The experimental method was the same as that of Example c1, and the dissolution test results of the Mesosuris dispersible tablet are shown in Fig. 3.
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • mesosomes 100 parts by weight of mesosomes, 20 parts by weight of aspartame, 70 parts by weight of lactose, 80 parts by weight of microcrystalline cellulose, 15 parts by weight of hydroxypropylmethylcellulose, 5 parts by weight of sodium carboxymethyl starch, and stearic acid 2 parts by weight of magnesium sulfate
  • liquid A Dissolving the above-mentioned prescription amount of mesosomel in 100 ml of ethanol to obtain liquid A, and dissolving the prescribed amount of lactose, microcrystalline cellulose, and hydroxypropylmethylcellulose in 150 ml of purified water to obtain liquid B;
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • Dissolution test The experimental method was the same as that of Example c1, and the dissolution test results of the Mesopril dispersion tablets are shown in Fig. 4.
  • mesosomes 100 parts by weight of mesosomes, 20 parts by weight of aspartame, 130 parts by weight of microcrystalline cellulose, 15 parts by weight of hydroxypropylmethylcellulose, 10 parts by weight of sodium carboxymethyl starch, and 2 parts by weight of silica gel
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • methicillin 100 parts by weight of methicillin, 20 parts by weight of sucrose, 30 parts by weight of lactose, 120 parts by weight of microcrystalline cellulose, 15 parts by weight of hydroxypropylmethylcellulose, 15 parts by weight of sodium carboxymethyl starch, and magnesium stearate 2 Parts by weight
  • liquid A Dissolving the above-mentioned prescription amount of mesosomel in 100 ml of acetone to obtain liquid A, and dissolving the prescribed amount of lactose, microcrystalline cellulose, and hydroxypropylmethylcellulose in 150 ml of purified water to obtain liquid B;
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • mesosomes 100 parts by weight of mesosomes, 20 parts by weight of aspartame, 67.5 parts by weight of lactose, 80 parts by weight of microcrystalline cellulose, 15 parts by weight of hydroxypropylmethylcellulose, 12 parts by weight of crospovidone, and stearic acid 2 parts by weight of magnesium sulfate
  • liquid A Dissolving the above-mentioned prescription amount of mesosomel in 100 ml of acetone to obtain liquid A, and dissolving the prescribed amount of lactose, microcrystalline cellulose, and hydroxypropylmethylcellulose in 150 ml of purified water to obtain liquid B;
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • liquid A Dissolving the above-mentioned prescription amount of methicillin in 125 ml of acetone to obtain liquid A, and dissolving the prescribed amount of lactose, microcrystalline cellulose, and hydroxypropylmethylcellulose in 150 ml of purified water to obtain liquid B;
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • Dissolution test The experimental method was the same as that of Example c1, and the dissolution test results of the Mesopril dispersion tablets are shown in Fig. 5.
  • suspension solution is first homogenized by a homogenizer, and then spray-dried to collect the powder;
  • the invention adopts the technology of solid dispersion, prepares the methicillin sustained-release tablets by the wet granulation process, and then coats the pressed plain tablets, and the preparation method is as follows:
  • the mixed powder of 3 was added to the wet granulator, mixed for 15 minutes, and the mixed powder was granulated in pure water for 90 s under the conditions of stirring speed 3 r/s and cutting speed 10 r/s, and the obtained granules were 60. Dry at °C for 90 minutes;
  • the prescribed amount of magnesium stearate and sodium carboxymethyl starch are added, and the mixture is uniformly mixed, and the tablet hardness is controlled to be 5-8 N;
  • the pressed plain film is coated with a film.
  • the preparation method of the coating liquid the coating powder is dispersed with purified water, and is prepared to a solid content of 15%, and stirred for 60 minutes.
  • the process parameters of the coating are: atomization pressure 0.2MP (megapascal), thimble pressure 0.2MP, coating pan speed 15r/s, feed rate 3r/min, inlet air temperature 75°C, inlet frequency 1100Hz, material temperature 35 ⁇ 45 ° C, the coating weight gain 2% ⁇ 3% end.
  • the dissolution rate of the methicillin sustained-release tablets prepared according to the Chinese Pharmacopoeia 2010 edition two appendix XD method was determined by the Chinese Pharmacopoeia 2010 edition two appendix XC second method device.
  • the dissolution rate of methicillin sustained-release tablets was measured by taking 1000 ml of a buffer salt of pH 6.8 as a solvent at a rotation speed of 50 rpm at 1, 4, 8, 12, 16, 20, and 24 hours. The results are shown in Fig. 6.
  • the comparative example does not employ a solid dispersion technique, which is prepared by a wet granulation process, and then the pressed plain tablet is coated with a film to prepare a methicillin sustained-release tablet.
  • the preparation method is as follows:
  • the pressed plain film is coated with a film.
  • the preparation method of the coating liquid the coating powder is dispersed with purified water, and is prepared to a solid content of 15%, and stirred for 60 minutes.
  • the process parameters of the coating are: atomization pressure 0.2MP (megapascal), thimble pressure 0.2MP, coating pan speed 15r/s, feed rate 3r/min, inlet air temperature 75°C, inlet frequency 1100Hz, material temperature 35 ⁇ 45 ° C, the coating weight gain 2% ⁇ 3% end.
  • Dissolution test The measurement method was the same as that of Example d1, and the measurement results are shown in Fig. 6.
  • the solid dispersion technique was used to prepare the methicillin sustained-release tablet, and the comparative example d1 was not prepared by the technique of the solid dispersion to obtain the methicillin sustained-release tablet.
  • the Mesocycline sustained-release tablets obtained by the embodiment d1 of the present invention and the comparative example d1 were respectively compared, and the dissolution test results of the two were compared, and the results showed that the technique of preparing the solid dispersion can significantly improve the Mesoshu In view of the overall dissolution in the sustained release tablets, it is preferred to use the technical method of the solid dispersion as a preparation method of the methicillin sustained release tablet.
  • Microcrystalline cellulose 25g Hydroxypropylmethylcellulose K4M 100g Carboxymethyl starch sodium 7.5g Magnesium stearate 2.5g
  • solubilizing agent hydroxypropyl ⁇ -cyclodextrin was not used in the formulation of Comparative Example d2, but poloxamer 188 was used.
  • Comparative Example d2 also employs the technique of solid dispersion, and the methicillin sustained-release tablet is prepared by a wet granulation process, and then the pressed plain tablet is coated with a film, and the preparation method is the same as that of the example d1.
  • Dissolution test The measurement method was the same as that of Example d1, and the measurement results are shown in Fig. 7.
  • the mesosurcellane sustained-release tablets obtained by the embodiment d1 of the present invention and the comparative example d2 were respectively compared, and the dissolution test results of the two were compared, and the results showed that the use of the solubilizing agent hydroxypropyl ⁇ -cyclodextrin was obvious. Improve the dissolution of methicillin in sustained release tablets. Whether or not to adopt hydroxypropyl ⁇ -cyclodextrin inclusion will directly affect the final concentration of drug release. Therefore, the use of hydroxypropyl ⁇ -cyclodextrin inclusion in the formulation can effectively improve the dissolution of methicillin.
  • the preparation method was the same as in Example d1.
  • Dissolution test The measurement method was the same as in Example d1, and the dissolution test results are shown in Fig. 8.
  • the preparation method was the same as in Example d1.
  • Dissolution test The measurement method was the same as that of Example d1, and the measurement results are shown in Fig. 9.
  • the preparation method was the same as in Example d1.
  • Dissolution test The measurement method was the same as that of Example d1, and the measurement results are shown in Fig. 10.
  • the preparation method was the same as in Example d1.
  • Dissolution test The measurement method was the same as that of Example d1, and the measurement results are shown in Fig. 11.
  • the preparation method was the same as in Example d1.
  • Dissolution test The measurement method was the same as in Example d1, and the measurement results are shown in Fig. 12.
  • the preparation method was the same as in Example d1.
  • Dissolution test The measurement method was the same as that of Example d1, and the measurement results are shown in Fig. 13.
  • the preparation method was the same as in Example d1.
  • Dissolution test The measurement method was the same as that of Example d1, and the measurement results are shown in Fig. 14.
  • Hydroxypropylmethylcellulose K4M 100g Carboxymethyl starch sodium 7.5g Magnesium stearate 2.5g
  • the preparation method was the same as in Example d1.
  • the preparation method was the same as in Example d1.
  • the preparation method was the same as in Example d1.
  • the preparation method was the same as in Example d1.
  • the preparation method was the same as in Example d1.
  • the preparation method was the same as in Example d1.
  • Dissolution test The measurement method was the same as that of Example d1, and the measurement results are shown in Fig. 15.
  • Example d15 Drug stability test of the methicillin sustained-release tablet of the present invention
  • Example d1 100 mg of Mesosurry sustained-release tablets prepared in Example d1 were exposed to a Petri dish at high temperature (60 ° C), high humidity (RH 92.5%, 25 ° C ), glare (4500lx ⁇ 500lx) for 10 days, sampling on the 0th, 5th, 10th day, observe the appearance, content, dissolution, related substances, weight loss rate and other items, and the inspection data before the inspection For comparison, the results of the 10-day influencing factors are shown in the following table. D1 is shown.
  • the Mesoxullo sustained-release tablet of the present invention showed no significant change in the main indexes, indicating that the quality of the Mesorizol sustained-release tablet of the present invention is stable and reliable. of. PVC blister and double-sided composite aluminum film bag packaging can meet the needs of the product.
  • Example d16 Screening study on the prescription of the methicillin sustained-release tablets of the present invention
  • the prescription screening was judged on the basis of the release profile of sustained-release tablets. From the above six prescriptions, the dissolution, peak time and release rate measurement results can be concluded whether the use of hydroxypropyl ⁇ -cyclodextrin inclusion will directly affect To the final concentration of drug release, the use of hydroxypropyl beta cyclodextrin inclusion can effectively improve the solubility of mesotherap. In addition, the amount of hydroxypropylmethylcellulose will directly affect the release rate of the sustained-release tablets in the medium, so the specific release behavior can be obtained by adjusting the amount of hydroxypropylmethylcellulose as needed, Mesocycline and hydroxy The weight ratio of propylmethylcellulose meets the prescription requirements at 1:1.
  • Microcrystalline cellulose acts as a filler and plays a minor role in the regulation of specific release behavior. Overall, the composition of prescription d6 is superior, which can meet the demand for Mesocycline sustained-release tablets. And the weight ratio of the main drug mesoxolide to the backbone sustained-release material hydroxypropylmethylcellulose is optimal at 1:1, and the methicillin cyclodextrin is used to encapsulate methicillin. In the case of treatment, the dissolution is preferred.
  • the methicillin sustained-release tablet prepared in the example d1 was used as a research object, and the methicillin sustained-release tablet and the mesosomel tablet (prepared by the prescription and process of the embodiment a9 of the present invention) were compared in the Beagle dog.
  • the pharmacokinetic behavior of the body, the pharmacokinetics of Mesoxulil sustained-release tablets and Mesosurril tablets are shown in Figure 16.
  • the AUC 0- oxime of Mesocycline sustained-release tablets is larger than that of Mesosuroli tablets, and the half-life is prolonged significantly, achieving the purpose of designing the sustained-release tablets initially, providing a smooth and effective effect.
  • the blood drug concentration avoids or reduces the appearance of blood drug peaks and valleys, which is beneficial to improve the safety of drug use, reduce the number of medications, and improve patient compliance.
  • Example e1 Formulation screening and preparation process optimization of mesoshuli granules
  • mesoxi granules 50 mg was used to optimize the formulation and preparation process of the methicillin granules, as follows:
  • the prescription of methicillin granules is as specified in Table e1, and then prepared according to the prescription shown in Table e1 and the preparation method described below.
  • Mesopril granules were then observed and tested for the traits, mouthfeel and dissolution of the prepared methicillin granules according to a conventional method, wherein the mouthfeel was orally tried by a volunteer.
  • the dissolution test was carried out in a pH 8.8 phosphate buffer solution by dissolving sodium hydroxide and potassium dihydrogen phosphate in water according to the method specified in the Chinese Pharmacopoeia 2010 edition, and adjusting with phosphoric acid. Obtained from pH to 8.8.
  • Prescription e1 Prescription e2
  • Prescription e3 Prescription e4
  • Prescription e5 Prescription e6
  • Mesoshuli 50 50 50 50 50 50 50 50 50 50 50 Hydroxypropyl ⁇ -cyclodextrin / / 250 250 300 250 Mannitol 500 500 400 400 500 500 Microcrystalline cellulose 100 80 60 35 20 35 aspartame / 5 10 15 20 25 Povidone 40 60 80 100 100 100 100 75% ethanol solution 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
  • the inventor creatively improved and optimized the pretreatment of the raw materials, mixed the methicillin, the solubilizing agent and the filler auxiliary, and successively carried out the micronization treatment twice, and then used the wet granulation to prepare the granules.
  • the specific preparation process is as follows:
  • Microcrystalline cellulose, aspartame, and povidone are passed through an 80 mesh sieve for use;
  • step 4 Mix the raw materials in step 2 and step 3 above uniformly, add soft material made of 75% ethanol solution, sieve the soft material through 16 mesh to make wet granules, dry at 40 °C, sift through 16 mesh sieve, and measure granules.
  • the main drug content determine the loading, determine the weight difference, and package it into granules.
  • the inventors mixed methicillin, hydroxypropyl ⁇ -cyclodextrin and mannitol for micronization treatment, and further screened the prescription e7-prescription e11, and the prescription e7-prescription e11 is shown in the table.
  • E3 the dissolution test results of the methicillin granules prepared according to the prescription e7-prescription e11 are shown in Table e4.
  • the measured particle size is 1-10 ⁇ m;
  • the measured particle size is 10-30 ⁇ m;
  • the measured particle size is 30-60 ⁇ m;
  • the measured particle size is 60-80 ⁇ m;
  • the particle diameter measured was 80-100 ⁇ m.
  • the dissolution effect of the Mesosulide granules prepared according to the prescription e7-prescription e11 is superior to that of the Mesoshuli granules obtained by the general pretreatment, and the dissolution rate meets the requirements of the Pharmacopoeia.
  • methicillin, hydroxypropyl ⁇ -cyclodextrin and mannitol are mixed micronized at 30-60 ⁇ m, and methicillin: hydroxypropyl ⁇ -cyclodextrin: mannitol weight ratio At 1:5:8, the dissolution is best.
  • the inventors conducted experiments on the 30-day influencing factors of the main drug in the prescription to investigate the drug compatibility of the excipients and the main drug in the prescription and the stability of the drug, as follows:
  • the methicillin granules prepared according to the prescription e4 were exposed to a culture dish and placed at a high temperature (60 ° C), high humidity (relative humidity 92.5%), and under light conditions for 30 days, and at 0 days and 5 days, Samples were taken at 10 days and 30 days to observe the appearance of methicillin granules, and the related substances and contents in methicillin granules were determined by high performance liquid chromatography. The experimental results are shown in Table e5.
  • Test conditions Exterior relative substance(%) Content 0 days yellow 0.26 99.7 5 days of illumination yellow 0.28 99.8 10 days of illumination yellow 0.29 98.9 30 days of illumination yellow 0.31 99.5 60 ° C for 5 days yellow 0.30 99.4 10 days at 60 ° C yellow 0.36 99.3 60 ° C for 30 days yellow 0.39 98.7 Relative humidity 92.5% 5 days yellow 0.27 99.6 Relative humidity 92.5% 10 days yellow 0.30 99.1 Relative humidity 92.5% 30 days yellow 0.36 98.5
  • the related substance refers to an intermediate, a by-product or the like which is produced during the synthesis or a product which is degraded during storage and transportation.
  • the labeled amount refers to the theoretical amount of the main drug.
  • the content refers to the weight percentage of the main drug in the labeled amount.
  • the inventors studied the prescriptions and preparation processes of different specifications such as 25 mg, 75 mg, 100 mg, and 125 mg, and obtained the same technical effects as the above-mentioned specification and process of 50 mg.
  • the preparation process is as follows:
  • Microcrystalline cellulose, aspartame, and povidone are passed through an 80 mesh sieve for use;
  • step 4 Mix the raw materials in step 2 and step 3 above uniformly, add soft material made of 75% ethanol solution, sieve the soft material through 16 mesh to make wet granules, dry at 40 °C, sift through 16 mesh sieve, and measure granules.
  • the main drug content determine the loading, determine the weight difference, and package it into granules.
  • the preparation process is as follows:
  • Microcrystalline cellulose, aspartame, and povidone are passed through an 80 mesh sieve for use;
  • step 4 Mix the raw materials in step 2 and step 3 above uniformly, add soft material made of 75% ethanol solution, sieve the soft material through 16 mesh to make wet granules, dry at 40 °C, sift through 16 mesh sieve, and measure granules.
  • the main drug content determine the loading, determine the weight difference, and package it into granules.
  • the preparation process is as follows:
  • Microcrystalline cellulose, aspartame, and povidone are passed through an 80 mesh sieve for use;
  • step 4 Mix the raw materials in step 2 and step 3 above uniformly, add soft material made of 75% ethanol solution, sieve the soft material through 16 mesh to make wet granules, dry at 40 °C, sift through 16 mesh sieve, and measure granules.
  • the main drug content determine the loading, determine the weight difference, and package it into granules.
  • the inventors performed the stability test of the methicillyl granules obtained in Example e3 to Example e16 for 6 months in the same manner as in Example e2, and the results showed that the drug obtained in each place had good stability.
  • the obtained mesoxyl granules are of stable quality.
  • hypromellose needs to be added with purified water to prepare 4% hypromellose aqueous solution (g/g).
  • Povidone K30 needs purified water to make 8% poly

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Abstract

微晶纤维素在制备美索舒利制剂中的用途，及其制备方法。

Description

微晶纤维素在制备美索舒利制剂中的用途、用于美索舒利的辅料、美索舒利制剂及其制备方法 技术领域
本发明涉及制药领域，具体地，涉及微晶纤维素在制备美索舒利制剂中的用途、用于美索舒利的辅料、美索舒利制剂及其制备方法。
背景技术
美索舒利是由军事医学科学院与人福医药集团合作开发的1.1类化学新药。美索舒利是一种非甾体抗炎药(简称NSAID)，主要作用机制为抑制环氧合酶(COX-2)活性，从而抑制花生四烯酸最终生成前列环素(PGⅡ)、前列腺素(PGE1，PGE2)和血栓素A2(TXA2)，即减少前列腺素、血栓素等炎性介质的合成，因而具有很好的解热、镇痛、抗炎、消肿等作用。美索舒利原料不溶于水，目前仍没有适合的美索舒利制剂见于报道。因而，开发疗效好、副作用小、溶出度高、生物利用度高、且质量稳定的美索舒利制剂，具有非常重要的意义。
然而，目前对用于制备美索舒利制剂的辅料及美索舒利制剂及其制备方法的研究，仍有待加强。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提出一种疗效好、副作用小、溶出度高、生物利用度高、且质量稳定的美索舒利制剂。
在本发明的一个方面，本发明提供了微晶纤维素在制备美索舒利制剂中的用途。根据本发明的实施例，所述美索舒利制剂质量稳定、美索舒利的溶出度高、生物利用度高。
根据本发明的实施例，所述美索舒利制剂为选自胶囊剂、颗粒剂或片剂的口服固体制剂形式。由此，能够满足不同患者的不同需要，患者用药依从性好。发明人发现，当选择微晶纤维素作为美索舒利制剂的填充剂时，不仅药物可压性好，崩解符合要求，溶出度高，且可提高片剂的硬度和片面的光洁度。
根据本发明的实施例，所述片剂为选自薄膜衣片、口腔崩解片、分散片、缓释片中的至少一种。由此，服用方便，患者依从性好。
根据本发明的实施例，所述胶囊剂为胶囊、缓释胶囊中的至少一种。由此，服用方便，患者依从性好。
在本发明的另一方面，本发明提供了一种用于美索舒利的辅料。根据本发明的实施例， 所述辅料包括：微晶纤维素作为填充剂。由此，根据本发明实施例的辅料能够有效用于制备美索舒利制剂，且所述美索舒利制剂质量稳定、美索舒利的溶出度高、生物利用度高。
根据本发明的实施例，所述填充剂进一步包括选自乳糖、糊精、蔗糖、淀粉和甘露醇中的至少一种，其中，所述淀粉为选自玉米淀粉、可压性淀粉和预胶化淀粉中的至少一种。由此，能够改善药物的可压性，减少主要成分的剂量偏差，促进美索舒利制剂的崩解和溶出。
根据本发明的实施例，所述辅料进一步包括：选自崩解剂、粘合剂、润滑剂、助悬剂、矫味剂、增溶剂、骨架缓释材料、溶剂和助流剂中的至少一种。
根据本发明的实施例，所述崩解剂为选自交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素和交联羧甲基纤维素钠中的至少一种。由此，美索舒利制剂能够快速崩解，有利于美索舒利的溶出。
根据本发明的实施例，所述粘合剂为选自聚维酮K30、羟丙甲基纤维素、甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、淀粉浆、糊精中的至少一种。由此，粘合作用良好。
根据本发明的实施例，所述润滑剂为选自硬脂酸镁、微粉硅胶、硬脂酰富马酸钠、十二烷基硫酸钠、二氧化硅、聚乙二醇中的至少一种。由此，润滑效果较好。
根据本发明的实施例，所述助悬剂为选自聚维酮、羟丙甲基纤维素、羧甲基纤维素钠、微晶纤维素中的至少一种。
根据本发明的实施例，所述矫味剂为选自阿斯巴甜、香橙香精、蔗糖、甜菊苷、阿司帕坦中的至少一种。由此，美索舒利制剂的口感较好，患者用药依从性好。
根据本发明的实施例，所述增溶剂为选自羟丙基β-环糊精、泊洛沙姆188中的至少一种。由此，能够有效改善美索舒利的溶解性。
根据本发明的实施例，所述骨架缓释是材料为选自羟丙甲基纤维素K4M、羟丙甲基纤维素K15M、羟丙甲基纤维素K100M，羟丙甲基纤维素E50、羟丙甲基纤维素E4M中的至少一种。由此，能够使得美索舒利缓慢释放，达到24小时缓释的效果。
根据本发明的实施例，所述溶剂为体积分数为75％的乙醇溶液。
根据本发明的实施例，所述助流剂为微粉硅胶。由此，有利于提高流动性。
在本发明的再一方面，本发明提供了一种美索舒利制剂。根据本发明的实施例，该美索舒利制剂包括：美索舒利；以及前面所述的辅料。发明人发现，本发明的美索舒利制剂溶出度高、崩解时间段、副作用小、质量稳定，能够有效发挥抗炎、镇痛、解热的功效，且制备工艺简单、成本低。
根据本发明的实施例，所述美索舒利制剂为选自胶囊剂、颗粒剂或片剂的口服固体制剂形式。由此，能够满足不同患者的不同需要，患者用药依从性好。
根据本发明的实施例，所述片剂为选自薄膜衣片、口腔崩解片、分散片、缓释片中的至少一种。由此，服用方便，患者依从性好。
根据本发明的实施例，所述胶囊为胶囊、缓释胶囊中的至少一种。由此，服用方便，患者依从性好。
根据本发明的实施例，美索舒利薄膜衣片包括：所述美索舒利25-150重量份；所述填充剂50-200重量份；所述粘合剂6-12重量份；所述崩解剂5-20重量份；以及所述润滑剂0.8-4重量份。发明人发现，本发明的美索舒利薄膜衣片溶出度高、崩解时间段、副作用小、质量稳定，能够有效发挥抗炎、镇痛、解热的功效，且制备工艺简单、成本低。另外，发明人意外地发现，包含上述比例原辅料的美索舒利薄膜衣片具有优于其他比例的药物性能。
发明人经过大量实验发现，当选择微晶纤维素为薄膜衣片的填充剂时，不仅药物可压性好，崩解速度快，溶出度高，且可提高薄膜衣片的硬度和片面的光洁度。
发明人经过大量的实验发现，单独以乳糖为填充剂时，工业大生产会出现裂片现象，所以本发明在稀释剂(在本发明中“稀释剂”和“填充剂”可以互换使用)的辅料选择上不单独选用乳糖。而微晶纤维素不仅能作为填充剂，而且具备崩解剂的性能，选取微晶纤维素可达到良好的溶出效果。而且发明人发现，当选择微晶纤维素或微晶纤维素和乳糖的组合为填充剂时，不仅药物可压性好，崩解速度快，溶出度高，且可提高薄膜衣片的硬度和片面的光洁度。另外，根据本发明的实施例，当采用聚维酮K30作为粘合剂、以及采用交联聚维酮为崩解剂时，美索舒利薄膜衣片的崩解速度较快，溶出度较高。
根据本发明的实施例，美索舒利口腔崩解片包括：所述美索舒利25-125重量份；所述甘露醇20-60重量份；所述微晶纤维素30-70重量份；所述粘合剂5-40重量份；所述崩解剂2-30重量份；所述矫味剂5-20重量份；所述润滑剂0.5-10重量份；以及所述助流剂0.1-0.5重量份。由此，本发明的美索舒利口腔崩解片崩解时间快，溶出度好、且质量稳定。且该口腔崩解片口服后在口腔中迅速崩解分散成细微颗粒或粉末，尤其适用于吞咽困难的病人及老年患者，并且该口腔崩解片在到达胃肠道之前已经以细微颗粒或粉末形式存在，药物溶出加快，在胃肠道面积分布大，吸收点多，对于难溶性药物如美索舒利，可提高其生物利用度。
发明人意外的发现，采用甘露醇与微晶纤维素混合作为填充剂，所得的美索舒利口腔崩解片服用方便、疗效明显、口感好，且有利于美索舒利口腔崩解片快速崩解。而且，由于本发明的美索舒利口腔崩解片采用了微晶纤维素作为辅助的填充剂，使得甘露醇的用量得以降低，从而降低了整个处方的成本，并克服了由于甘露醇用量过大而导致的所得口崩片脆碎度较高，不适宜运输储存和使用的缺点。同时适宜于压片工艺的应用，进一步降低了成本。
另外，通过向美索舒利口腔崩解片中加入助流剂微粉硅胶能够有效防止美索舒利和辅料可能导致的物料粘附，加入很小比例的微粉硅胶，也可有效消除静电，同时还可以增加美索舒利药物的亲水性。同时，本发明的美索舒利口腔崩解片不仅崩解时间快，溶出度好、质量稳定，且不存在碎脆度较高、易出现小块状物掉落及裂片现象，利于工业化生产，适合长期存放运输和使用以及广泛的推广和应用。
根据本发明的实施例，美索舒利分散片包括：所述美索舒利25-125重量份；所述矫味剂5-20重量份；所述填充剂60-150重量份；所述粘合剂5-30重量份；所述崩解剂2-20重量份；以及所述润滑剂0.5-3重量份。发明人发现，本发明的美索舒利分散片质量稳定、崩解符合要求、溶出迅速、美索舒利浓度在体内迅速达到稳态、含量均匀、口服生物利用度高、患者用药依从性好。
发明人经过大量实验，利用固体分散体技术以分散片的形式，实现了难溶性药物美索舒利分散片的制备，改善了药物的溶解速度，提高了口服生物利用度，为患者提供了一个新的临床用药选择。且包括上述比例原辅料的美索舒利分散片具有优于其他比例的药物性能。
根据本发明的实施例，美索舒利缓释片包括：所述美索舒利25～125重量份；所述骨架缓释材料80～127.5重量份；所述填充剂5～75重量份；所述润滑剂1.5～2.5重量份；所述增溶剂15～20重量份；以及所述崩解剂3～9重量份。发明人发现，本发明的美索舒利缓释片，能够实现24小时缓释，且质量稳定、生物利用度高、用药依从性好。
需要说明的是，发明人利用超细粉碎、固体分散体、环糊精包合等技术，采用缓释骨架片的形式，实现了难溶性药物美索舒利缓释片的制备，并且提高了美索舒利在水中的溶解度，改善了药物在体内的吸收，提高了口服生物利用度，为患者提供了一个新的临床用药选择。而且，本发明的美索舒利缓释片一方面解决了美索舒利口服生物利用度低的问题，一方面做成缓释片减少了服药次数，提高了患者用药的顺应性。本发明不同于将美索舒利原料直接做成缓释片，而是通过固体分散体技术先改善了美索舒利的溶解性，再将其制成缓释片，不但达到了缓慢释放的目的，还提高了药物在体内的生物利用度。
根据本发明的实施例，美索舒利颗粒剂包括：所述美索舒利25-125重量份；所述增溶剂25-500重量份；所述填充剂125-600重量份；所述助悬剂15-75重量份；所述矫味剂5-40重量份；所述粘合剂25-200重量份；以及所述溶剂10-200重量份。发明人发现，本发明的美索舒利颗粒剂能够有效用于解热、镇痛、抗炎、消肿，且质量稳定、溶出好、口感好、用药依从性好，而且还解决了小儿由于只需较小剂量治疗，而片剂和胶囊剂不利于分开给药等不足之处，特别是对于老、幼和有吞咽功能障碍的患者服用非常方便。
发明人通过大量实验发现，在美索舒利颗粒剂中，当美索舒利与助悬剂的重量比为1： 0.6-0.8时，美索舒利处于良好的混悬状态，不会沉淀；另外当美索舒利与矫味剂的重量比为1：0.2-0.4时，其口感最好。最优选所述美索舒利、助悬剂、矫味剂的重量比为1：0.7：0.3。以上很好的解决了儿童和老年患者对该药的用药依从性问题。
进一步的，发明人通过实验，意外的发现，将美索舒利、增溶剂羟丙基β-环糊精混合后，进行微粉化处理1次，再加入填充剂到上述微粉化处理的颗粒中，继续微粉化至粒径为1-100微米的颗粒，且美索舒利：羟丙基β-环糊精：填充剂的重量配比在1：1-10：5-16，此时，在颗粒剂中美索舒利的溶出效果好。特别是选择填充剂含有甘露醇时，美索舒利的溶出效果更佳。其原因可能是：微粉化的美索舒利与羟丙基β-环糊精混合，在湿法制粒过程中在乙醇水溶液的湿润下，羟丙基β-环糊精起到了包合作用，包合物具有良好的可润湿性，因此药物得到了增溶，同时，甘露醇本身有甜味，无吸湿性，干燥快，化学稳定性好，制粒性好，且是水溶性辅料，微粉化的药物粒子周围吸附着大量甘露醇的粒子，这样就可以防止美索舒利的细小药物粒子的相互聚集，使其稳定地存在于混合物中。当甘露醇溶于水时，美索舒利细小的药物粒子便直接暴露于溶出介质中，直接导致药物溶解(和溶出)的速度大大加快。因此，羟丙基β-环糊精与甘露醇的组合应用，对美索舒利药物的溶解(和溶出)起到了良好的协同作用，大大增强的美索舒利药物的溶解度和溶出度。
另外，发明人发现：当美索舒利、羟丙基β-环糊精和填充剂混合微粉的粒径在30-60微米，且美索舒利：羟丙基β-环糊精：填充剂的重量配比在1：5：8时，其溶出的效果最好。
根据本发明的实施例，本发明所得到的美索舒利颗粒剂，其处方中各辅料与主药的药物相容性良好，辅料对主药稳定性无影响。本发明所得颗粒剂经加速6个月稳定性试验，质量稳定。
根据本发明的实施例，所述美索舒利胶囊包括：所述美索舒利25-150重量份；所述填充剂50-200重量份；所述粘合剂5-20重量份；所述崩解剂5-20重量份；以及所述润滑剂0.8-4重量份。发明人发现，本发明的美索舒利胶囊能够有效发挥抗炎、镇痛、解热的功效，且溶出度高、生物利用度高、副作用小。
根据本发明的实施例，在美索舒利胶囊中，优选乳糖和微晶纤维素的组合作为填充剂。由此，能够促进美索舒利的溶出，特别是选择乳糖和微晶纤维素的组合时，能够有效提高美索舒利的溶解度，进而提高美索舒利的溶出度和生物利用度。特别的，当乳糖和微晶纤维素的质量比为(0.5～5)：1时，能够有效提高美索舒利的溶解度，进而提高美索舒利的溶出度和生物利用度。
根据本发明的实施例，所述美索舒利缓释胶囊包括：缓释微丸和空心胶囊，所述缓释微丸包括载药丸芯和包衣层，所述包衣层包括隔离层和缓释层，其中，所述载药丸芯包括： 所述美索舒利50～100重量份；所述崩解剂10～20重量份；所述填充剂100～145重量份；以及所述粘合剂30～50重量份。本发明的美索舒利缓释胶囊能够实现缓慢释放，并能够大大提高难溶性药物美索舒利的口服生物利用度，且能够有效减少用药剂量和用药次数，毒副作用较低，患者的用药依从性较好。另外，本发明的美索舒利缓释胶囊服用方便，只需每日给药1～2次，且药物缓慢释放，能够有效避免血药浓度起伏过大而出现有效血药浓度的忽高忽低，且毒副作用小。
发明人经过大量的实验，利用超细粉碎技术等，采用缓释微丸的形式，实现了难溶性药物美索舒利缓释胶囊的制备，并且提高了美索舒利的溶解度，改善了药物在体内的吸收，提高了美索舒利药物的溶出度和口服生物利用度，并能够实现美索舒利药物的缓慢释放，实现每日1次给药，提高了患者的用药依从性，并且本发明所述美索舒利缓释胶囊的质量稳定，为患者提供了一个新的临床用药选择。
而且，根据本发明实施例的缓释微丸粒径均匀，药物释放平稳，能够持续释药12小时以上。根据本发明实施例的的美索舒利缓释胶囊由很多粒径大小均匀的微丸组成，其释放行为将更加稳定，具有较好的安全性、平稳的血药浓度，降低了患者出现不良反应的几率。
根据本发明的实施例，所述隔离层包括：致孔剂、抗粘剂、以及隔离包衣层溶剂；所述缓释层包含高分子聚合物、增塑剂、以及纯化水。
根据本发明的实施例，所述致孔剂聚维酮K30。
根据本发明的实施例，所述抗粘剂为滑石粉。
根据本发明的实施例，所述隔离层溶剂为无水乙醇。
根据本发明的实施例，所述高分子聚合物为选自聚丙烯酸树脂、乙基纤维素中的至少一种。
根据本发明的实施例，所述乙基纤维素为乙基纤维素水分散体，
根据本发明的实施例，所述增塑剂为选自丙二醇、聚乙二醇4000、苯甲酸二甲酯、柠檬酸三乙酯的至少一种。
在本发明的又一方面，本发明提供了一种制备前面所述的美索舒利制剂的方法。根据本发明的实施例，该方法包括：将美索舒利进行微粉化处理，并将所得到的美索舒利微粉化颗粒与前面所述的辅料混合，以便获得药物混合物；将所述药物混合物制成胶囊剂、颗粒剂或片剂。发明人发现，利用发明的该方法能够快速有效的制备获得前面所述的美索舒利制剂，且操作简单，方便快捷，适合工业化大生产。其中，通过将美索舒利进行微粉化处理，能够使得美索舒利充分的分散在辅料中，进而能够大大提高美索舒利的溶出度。
根据本发明的实施例，所述美索舒利微粉颗粒的粒径为1-100微米。由此，由该粒度的美索舒利微粉颗粒制备的美索舒利制剂的溶出度明显优于其他粒度。
根据本发明的实施例，制备美索舒利制剂的方法可以包括：(a1)将美索舒利和填充剂混合，并将所得到的混合物进行微粉化处理，以便获得粒径为5微米至100微米的混合物微粉颗粒，将崩解剂、粘合剂和润滑剂分别粉碎后过80目筛，备用；(a2)将所述粘合剂与纯化水混合，配制得质量分数为6％～12％的粘合剂水溶液aⅠ，备用；(a3)将所述混合物微粉颗粒与內加的崩解剂混合，得混合物aⅡ；(a4)将所述粘合剂水溶液aⅠ加入所述混合物aⅡ中，并将所得到的混合物制成软材，将所得软材过18目不锈钢筛制粒，以便获得湿颗粒；(a5)于55℃～65℃下，将所述湿颗粒干燥1～4h，然后过18目不锈钢筛整粒，以便获得干颗粒；(a6)将所述干颗粒与外加的崩解剂混合，再将所得到的混合物与硬脂酸镁混合，以便获得所述药物混合物；(a7)测定所述药物混合物的含药量，并计算理论片重，然后将所述药物混合物进行压片，以便获得所述美索舒利片芯；(a8)将包衣粉末加入纯化水中，配制成固含量为20％的包衣溶液，然后利用所述包衣溶液对所述美索舒利片芯进行包衣处理，以便获得所述美索舒利薄膜衣片。发明人通过将美索舒利进行微粉化处理，能够使得难溶性的美索舒利充分的分散辅料中，采用这种方法制成的美索舒利薄膜衣片，其溶出度可以显著得到改善。
本发明创造性的将崩解剂分内加崩解剂和外加崩解剂这两种形式，分两次添加，外加崩解剂可以促进颗粒的崩解，内加崩解剂则能加快颗粒的分散，可以大大提高美索舒利薄膜衣片的溶出度。从本发明实施例中所述的结果可以看出，采用崩解剂内外加法的工艺，相对于崩解剂只采用内加法的工艺，其溶出度明显提高。故确定崩解剂的用量及添加方式为：崩解剂的内加量为崩解剂处方量的1/2，外加量为崩解剂处方量的另1/2。
根据本发明的实施例，压片时将片重控制在理论片重±5％范围内，硬度控制在5～7kg。由此，获得的美索舒利薄膜衣片外观、片重等符合要求，且崩解速度快，溶出度高。
根据本发明的实施例，包衣处理的参数可以为：平均进风温度为85℃，平均片床温度为41℃，雾化压力为2.5bar，平均包衣锅转速为15～23rpm，平均物料流速3～4g/min。由此，美索舒利薄膜衣片的片面光洁，外观符合要求。
由本发明所制备得到的美索舒利薄膜衣片，其性状、硬度、脆碎度、片重差异均符合要求，且溶出度较高，且均能达到90％，符合要求。
根据本发明的实施例，制备美索舒利制剂的方法可以包括：(b1)将所述美索舒利进行微粉化，以便获得美索舒利微粉；(b2)将所述美索舒利微粉与助流剂和矫味剂混合；(b3)将所述填充剂进行微粉化，以便获得粒径为20-100微米的填充剂微粉；(b4)将所述步骤(b3)中所得到的混合物与所述崩解剂和所述粘合剂混合；(b5)将所述步骤(b4)中所得到的混合物与所述润滑剂混合，以便获得药物混合物；(b6)通过直接压片法将所述药物混合物制成美索舒利口腔崩解片。
发明人经过长期实践发现，制备美索舒利口腔崩解片时，先将美索舒利和填充剂进行微粉化处理后，其所构成的比表面积大，使所得美索舒利口腔崩解片能够快速崩解。尤其是当采用微晶纤维素与甘露醇的组合作为填充剂，且先将美索舒利、微晶纤维素、甘露醇混合进行微粉化处理后，制备获得的美索舒利口腔崩解片崩解速度较快，且溶出度较好。
采用本发明的处方及制备工艺，最终可确保美索舒利口腔崩解片有很好的口感和崩解，有利于口腔崩解片能够快速崩解，溶出度好、且制剂的质量稳定，有利于其工业化生产。而且，采用该方法制得的美索舒利口腔崩解片，其崩解时限为15s-45s，硬度5-8kg，脆碎度小于0.5％，10分钟在pH8.8磷酸盐缓冲溶液中溶出量大于85％，且质量稳定。其中，所述pH8.8的磷酸盐缓冲液是通过将氢氧化钠和磷酸二氢钾加水溶解，并用磷酸调pH至8.8而获得的。
根据本发明的实施例，制备美索舒利制剂的方法可以包括：(c1)将所述美索舒利溶于有机溶剂，以便获得有机相溶液；(c2)将所述填充剂和所述粘合剂溶于纯化水，以便获得水相溶液；(c3)将所述有机相溶液与所述水相溶液混合，以便获得混合的美索舒利混悬溶液；(c4)将所述混合的美索舒利混悬溶液进行均质后，进行喷雾干燥，以便获得喷雾干燥粉末；(c5)将所述喷雾干燥粉末与所述润滑剂、所述崩解剂和所述矫味剂混合，以便获得药物混合物；(c6)对所述药物混合物取样，并进行含量测定，测定结果合格后，将所述药物混合物直接粉末压片，以便获得美索舒利分散片。
根据本发明的实施例，将美索舒利溶于有机溶剂中，形成有机相，再缓慢加入溶解有填充剂和粘合剂的水相溶液中，得到美索舒利混悬溶液，再将所述混悬溶液进行均质，得到的混悬溶液颗粒粉碎的更加细小及更加均匀，经喷雾干燥后，将所得喷雾干燥粉末与润滑剂、崩解剂和矫味剂混合，得药物混合物，进行含量测定后，将所述药物混合物直接粉末压片，以便获得美索舒利分散片。利用本发明所述的制备美索舒利制剂的制备工艺和技术，可以有效提高美索舒利的溶解度，有助于提高其在体内的吸收，进而提高了美索舒利分散片的溶出度及生物利用度。本发明所述美索舒利分散片能够在短时间内达到80％以上的溶出。
根据本发明的实施例，在本发明所述的方法中，利用固体分散体技术以分散片的形式，实现了难溶性药物美索舒利分散片的制备，改善了药物的溶解速度，提高了口服生物利用度，为患者提供了一个新的临床用药选择。同时，采用粉末直压片的方式制备了美索舒利分散片，大大提高了生产效率，降低了生产成本。制备获得的美索舒利分散片质量稳定、崩解符合要求、溶出迅速、含量均匀、口感良好、患者用药依从性好。
根据本发明的实施例，制备美索舒利制剂的方法可以包括：(d1)将所述美索舒利溶于丙酮，并将羟丙基β环糊精水溶液与美索舒利丙酮溶液相混合，挥干溶剂，以便获得结晶 粉末；(d2)将所述结晶粉末进行超细粉碎，并与骨架缓释材料、填充剂混合；(d3)将步骤(d2)中得到的混合物进行制粒，并将制得的颗粒进行干燥；(d4)将干燥后的颗粒与所述润滑剂和所述崩解剂混合，并将所得到的混合物进行压片。根据本发明的实施例，可以进一步包括：(d5)将所述步骤(d4)压片得到的片芯包薄膜衣，以便获得美索舒利缓释片。利用本发明的该方法，能够快速有效地制备获得前面所述的美索舒利缓释片，且操作简单、方便快捷，适合的工业化生产，同时，制备获得的美索舒利缓释片质量稳定、生物利用度高、用药依从性好，且有效作用时间较长。
根据本发明的实施例，基于所述片芯的总质量，按照质量百分比计，包衣增重为2％-3％。
根据本发明的实施例，步骤(5)中所述的片芯包薄膜衣，包衣粉材料选用白色胃溶型薄膜包衣预混剂欧巴代81W68907。包衣液的配制方法：将包衣粉用纯化水分散，配制到15％固含量，搅拌60分钟即可。包衣的工艺参数为：雾化压力0.2MP(兆帕)，顶针压力0.2MP，包衣锅转速15r/s，进液速度3r/min，进风温度75℃，进风频率1100Hz，物料温度35～45℃，包衣增重2％～3％结束。
根据本发明的实施例，所述美索舒利缓释片的硬度为5-8N(牛顿)。由此，美索舒利缓释片的溶出度较好。
根据本发明的实施例，发明人基于固体分散体的技术改善了美索舒利在水中的溶解度，同时利用骨架缓释的机理制备了美索舒利缓释片。用上述方法制备的美索舒利缓释片与普通制剂在动物体内药代动力学研究中的结果表明，本发明的美索舒利缓释片其体内半衰期延长了2～5倍，其体内释药曲线显示药物释放平稳，能够实现24小时的稳定释放。进一步的，上述方法将固体分散技术与骨架缓释技术相结合，一方面解决了美索舒利口服生物利用度低的问题，一方面做成缓释片减少了服药次数，提高了患者用药的顺应性。而且，该方法不同于将美索舒利原料直接做成缓释片，而是通过固体分散体技术先改善了美索舒利的溶解性，再将其制成缓释片，不但达到了缓慢释放的目的，还提高了药物在体内的生物利用度。
根据本发明的实施例，制备美索舒利制剂的方法可以包括：(e1)将所述美索舒利和所述增溶剂混合，并将所得到的混合物进行微粉化处理；(e2)向步骤(e1)中得到的混合物中加入填充剂，并将所得到的混合物进行微粉化处理，以便获得微粉颗粒；(e3)将所述微粉颗粒和所述助悬剂、所述矫味剂、所述粘合剂以及所述溶剂混合；(e4)将步骤(e3)中所得到的混合物依次经制软材、制湿颗粒、干燥、整粒，以便获得美索舒利颗粒剂。通过微粉化处理，可以使得美索舒利在原料混合物中分散均匀，防止美索舒利细小颗粒聚集，使其稳定的存在于混合物中，且能够有效提高美索舒利的溶出度。
由于美索舒利不溶于水，如果按照一般的颗粒剂制备工艺，其颗粒溶解性剂差，溶出 度也远达不到药典规定要求。本发明的上述方法将美索舒利、以及辅料混合，并进行两次微粉化处理，再利用湿法制粒进行颗粒剂的制备，所得到的美索舒利的溶解度和溶出效果均好，同时口感好，质量稳定，很好的解决了患者服药不便、用药依从性差的问题。而且还解决了小儿由于只需较小剂量治疗，而片剂和胶囊剂不利于分开给药等不足之处。
根据本发明的实施例，制备美索舒利制剂的方法可以包括：(f1)将所述美索舒利与所述填充剂混合，并将所得到的混合物进行微粉化处理至粒径为5-100微米，以便获得所述混合物微粉颗粒，将所述崩解剂、所述粘合剂、所述润滑剂过60目～80目筛，备用；(f2)将所述粘合剂与纯化水混合，以便获得所述粘合剂水溶液，所述粘合剂水溶液的质量分数为5％～20％；(f3)将所述混合物微粉颗粒与所述内加的崩解剂混合，以便获得所述第一混合物；(f4)将所述第一混合物与所述粘合剂水溶液混合，并将所得到的混合物进行制软材，将所得软材过18目筛制粒，以便获得所述湿颗粒；(f5)于55℃～65℃下，将所述湿颗粒进行干燥1～4小时，然后过18目筛整粒，以便获得所述干颗粒；(f6)将所述干颗粒与所述外加的崩解剂混合，以便获得第二混合物；(f7)将所述第二混合物与硬脂酸镁混合，以便获得所述药物混合物；(f8)将所述药物混合物进行含量检测，并将含量检测合格的所述药物混合物进行胶囊灌装，以便获得所述美索舒利胶囊。利用本发明的该方法，能够快速有效的制备获得前面所述的美索舒利胶囊，且操作简单、方便快捷，适合工业化大生产，而且通过将美索舒利进行微粉化处理，能够有效提高美索舒利的溶出度和生物利用度。
发明人经过大量实验，意外地发现：通过将美索舒利和填充剂的混合物进行微粉化，能够将难溶的美索舒利原料药能够充分的分散在填充剂中，特别是当填充剂为乳糖和微晶纤维素时，经过微粉化处理的美索舒利与填充剂的粒径为1-100微米，所述美索舒利能充分的分散在亲水性的乳糖中，由此，能够显著提高美索舒利胶囊的溶出度。另外，采用湿法制粒工艺，并创造性的将处方中的崩解剂采用内外加法，外加崩解剂可以促进颗粒的崩解，内加崩解剂则能加快颗粒的分散。相对于崩解剂只采用内加法的工艺，本发明采用崩解剂内外加法的工艺所得的美索舒利胶囊的溶出度明显提高。
根据本发明的实施例，制备美索舒利制剂的方法可以包括：(g1)将所述美索舒利超细粉碎后与所述填充剂、所述崩解剂和所述粘合剂混合，将所得到的混合物制成软材，并将所述软材通过挤出滚圆的方法制成所述载药丸芯；(g2)将致孔剂、抗粘剂和隔离层溶剂混合，以便获得所述隔离层包衣液；(g3)将高分子聚合物、增塑剂和纯化水混合，以便获得所述缓释层包衣液；(g4)将所述载药丸芯干燥后，置于流化床中，采用底喷包衣的方式，将所述隔离层包衣液喷于所述载药丸芯表面，以便在所述载药丸芯的表面形成所述隔离层；(g5)将表面形成有隔离层的载药丸芯干燥后，将所述缓释层包衣液喷于所述表面形成有隔离层的载药丸芯的表面，以便获得所述缓释微丸；(g6)于30～40℃，优选35℃下，将所 述缓释微丸熟化6～10小时，优选6小时；(g7)将经过熟化的缓释微丸填充于空心胶囊中，以便获得所述美索舒利缓释胶囊。利用本发明的该方法，能够快速有效地制备获得前面所述的美索舒利缓释胶囊，且操作简单、方便快捷，适合工业化生产。且根据本发明所制备得到的美索舒利缓释胶囊质量稳定。
根据本发明的实施例，本发明美索舒利缓释胶囊的制备方法中，美索舒利原料采用微粉化处理原料，经挤出滚圆技术制备美索舒利载药丸芯，然后采用流化床对载药丸芯进行隔离层和缓释层的包衣，这个过程控制简单，易于工业化大生产的实现，并且本发明所得到的美索舒利缓释胶囊质量稳定可控。
根据本发明的实施例，采用缓释微丸的形式，实现了难溶性药物美索舒利缓释胶囊的制备，并且提高了美索舒利的溶解度，改善了药物在体内的吸收，提高了美索舒利药物的溶出度和口服生物利用度，并能够实现美索舒利药物的缓慢释放，实现每日1次给药，提高了患者的用药依从性，为患者提供了一个新的临床用药选择。
根据本发明的实施例，本发明基于固体分散体的技术改善了美索舒利在水中的溶解度，同时利用缓释包衣技术制备了美索舒利缓释胶囊。其中的缓释微丸粒径均匀，药物释放平稳，能够持续释药12小时以上。用本发明制备的美索舒利缓释胶囊由很多粒径大小均匀的微丸组成，其释放行为将更加稳定，比缓释片具有更高的安全性，具有更加平稳的血药浓度，降低了患者出现不良反应的几率
在本发明的再一方面，本发明提供了一种治疗炎症、疼痛或类风湿性关节炎的方法。根据本发明的实施例，该方法包括：对患者给药前面所述的美索舒利制剂。由此，能够有效发挥抗炎、镇痛或止痛的功效。
附图说明
图1显示了根据本发明的一个实施例，美索舒利分散片的溶出度测定结果；
图2显示了根据本发明的一个实施例，美索舒利分散片的溶出度测定结果；
图3显示了根据本发明的一个实施例，美索舒利分散片的溶出度测定结果；
图4显示了根据本发明的一个实施例，美索舒利分散片的溶出度测定结果；
图5显示了根据本发明的一个实施例，美索舒利分散片的溶出度测定结果；
图6显示了根据本发明的一个实施例、以及对比实施例d1，制备所得美索舒利缓释片的溶出度测定对比结果图；
图7显示了根据本发明的一个实施例、以及对比实施例d2，制备所得美索舒利缓释片的溶出度测定对比结果图；
图8显示了根据本发明的一个实施例，美索舒利缓释片的溶出度测定结果；
图9显示了根据本发明的一个实施例，美索舒利缓释片的溶出度测定结果；
图10显示了根据本发明的一个实施例，美索舒利缓释片的溶出度测定结果；
图11显示了根据本发明的一个实施例，美索舒利缓释片的溶出度测定结果；
图12显示了根据本发明的一个实施例，美索舒利缓释片的溶出度测定结果；
图13显示了根据本发明的一个实施例，美索舒利缓释片的溶出度测定结果；
图14显示了根据本发明的一个实施例，美索舒利缓释片的溶出度测定结果；
图15显示了根据本发明的一个实施例，美索舒利缓释片的溶出度测定结果；
图16显示了根据本发明的一个实施例，美索舒利缓释片与普通片的药代动力学实验结果；
图17显示了根据本发明的一个实施例，美索舒利缓释胶囊的溶出度测试结果；
图18显示了根据本发明的一个实施例，美索舒利缓释胶囊的溶出度测试结果；以及
图19显示了根据本发明的一个实施例，美索舒利缓释胶囊的药代动力学测试结果。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中的美索舒利原料药为1.1类化学原创药物，为人福医药集团自制。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
以下美索舒利薄膜衣片的实施例a1-a12，为按照1000片处方量投料，以下实施例只是进行说明，并不限制发明范围。
实施例a1：美索舒利薄膜衣片处方研究
由于主药美索舒利几乎不溶于水，且主药量也较大，因此，处方工艺的难点在于提高本品的溶出度。在本实施例中，对规格为100mg/片的美索舒利薄膜衣片的处方进行了研究，具体而言，由于美索舒利原料药水溶性及流动性均差，考虑加入水溶性辅料及崩解剂促进溶出，设计了9个处方，见表a1。
表a1 不同的处方设计
Figure PCTCN2014085783-appb-000001
Figure PCTCN2014085783-appb-000002
注：在粘合剂的配制上，羟丙甲纤维素需加纯化水配制成4％的羟丙甲纤维素水溶液(g/g)，聚维酮K30需加纯化水配制成8％的聚维酮K30水溶液(g/g)，“-”表示不含相应组分。
按表a1中的处方，采用湿法制粒工艺，先制备得到美索舒利片芯，测定溶出度，
制备方法具体如下：
(1)原辅料前处理：将主药(美索舒利)、各辅料分别粉碎后，主药过60目筛，辅料过80目筛，备用；
(2)配粘合剂：
当处方中的粘合剂选择聚维酮K30(PVPK30)时，称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液Ⅰ，备用；
当处方中的粘合剂选择羟丙甲纤维素时，称取4克羟丙甲纤维素于烧杯中，加纯化水96克，搅拌至澄清，得4％羟丙甲纤维素水溶液Ⅰ，备用；
(3)混合：称取处方量的主药、填充剂混合均匀后，再加入崩解剂交联聚维酮(PVPP)混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使薄膜衣片的片芯硬度在5～7kg以内，压片即得。
溶出度测定：
按中国药典2010版溶出度项下的测定方法，测定上述9个处方在溶出介质中45分钟的溶出度，其中溶出介质为磷酸盐缓冲液(氢氧化钠2.30g，磷酸二氢钾7.65g，加水使溶解为1000ml，用磷酸调pH至8.8)，溶出度测定结果见表a2。
表a2 各薄膜衣片片芯处方的溶出度对比
处方 a1 a2 a3 a4 a5 a6 a7 a8 a9
溶出度(％) 80.6 78.8 74.9 82.3 80.5 72.0 82.5 78.6 77.9
从溶出结果看，所设计的9个处方在溶出介质中45分钟的溶出度显示，较优的处方为处方a1、处方a4、处方a5、处方a7，其溶出度均达到了80％以上。由于美索舒利水溶性差，而羟丙甲纤维素有阻溶作用，可能会在样品留样期间影响溶出度，加之其在水中完全溶胀所需时间较长，不利于工业化生产，因此不优选其作为粘合剂。但由于前期实验研究表明：单独以乳糖为填充剂时，工业大生产会出现裂片现象，所以本发明在稀释剂的辅料选择上不选用乳糖。而微晶纤维素不仅能作为填充剂，而且具备崩解剂的性能，选取微晶纤维素可达到良好的溶出效果。
故本研究确定以处方a4和处方a7为基础，进一步考察筛选填充剂的最佳用量、粘合剂的浓度，以及改进崩解剂的添加方式，对处方和制剂工艺进行进一步优化。
实施例a2：100mg规格的美索舒利薄膜衣片处方及工艺优化
本研究根据中国药典2010版对薄膜衣片的剂型要求，参照CDE颁布的《化学药物制剂研究基本技术指导原则》，结合薄膜衣片的特点，以性状、硬度、脆碎度、崩解时间、溶出度等为考察指标，对本品处方所使用辅料的种类和用量进行了进一步的筛选。
(1)填充剂的筛选
调整微晶纤维素的比例和用量，考察稀释剂(在本文中，“填充剂”和“稀释剂”可以互换使用)不同用量对压片成形性和溶出度的影响，具体处方和结果如下：
本研究采用微晶纤维素作为稀释剂，微晶纤维素不同用量的处方见表a3，表a3所示为制备1000片美索舒利薄膜衣片的处方量。按照表a3所示处方及实施例a1中所述的制备方法，以1000片/批的批量进行制粒压片，理论片重为240mg，然后测定制备获得的美索舒利薄膜衣片的硬度、脆碎度、崩解时间和溶出度，筛选填充剂。结果见表a3。
表a3 填充剂的筛选处方及测定结果
Figure PCTCN2014085783-appb-000003
Figure PCTCN2014085783-appb-000004
由表a3的结果可以看出，微晶纤维素按上述4个处方的用量，溶出度均能达到80％以上，其中以处方a12的崩解和溶出度最好。
(2)粘合剂的筛选
选取PVP-K30作为粘合剂，并配制不同浓度的水溶液对其粘合效果进行了比较研究，具体如下：
按照表a4所示的处方以及实施例a1中的制备方法，制备获得美索舒利薄膜衣片的片芯，制备过程中观察美索舒利干颗粒情况，并测定制备获得的美索舒利薄膜衣片的片芯的硬度、脆碎度、崩解时间和溶出度，处方和测定结果见表a4，其中，表a4所示处方为制备1000片美索舒利薄膜衣片的片芯的处方量。
其中，在处方a14中，粘合剂的配制方法为：称取4克聚维酮K30于烧杯中，加纯化水96克，搅拌至澄清，得4％聚维酮K30水溶液；其中处方a15中，粘合剂的配制方法为：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液；其中处方a16中，粘合剂的配制方法为：称取12克聚维酮K30于烧杯中，加纯化水88克，搅拌至澄清，得12％聚维酮K30水溶液；其中处方a17中，粘合剂的配制方法为：称取6克聚维酮K30于烧杯中，加纯化水94克，搅拌至澄清，得6％聚维酮K30水溶液；其中处方a18中，粘合剂的配制方法为：称取15克聚维酮K30于烧杯中，加纯化水85克，搅拌至澄清，得15％聚维酮K30水溶液。
表a4 粘合剂的筛选
Figure PCTCN2014085783-appb-000005
从表a4的结果可以看出，当粘合剂浓度为4％时，软材干，较松散，不易起粘，由于得 到的干颗粒小且松散，细粉较多，流动性差，容易造成片重差异不合格，可压性差，造成硬度偏低，脆碎度高，无法满足包衣需求；当粘合剂用量达到15％时，所制得软材较硬，不易过筛，粘筛网较严重，且多为条状，而且延长了崩解时间；而当粘合剂的浓度为6％～12％时，所制得的软材干湿程度适中，易过筛且得到的颗粒圆整，均匀，流动性好，易于进行压片，得到薄膜衣片的片芯硬度、脆碎度、崩解时间等考察指标合格，因此，选择粘合剂为PVPK30，，其浓度为6％～12％，在处方中粘合剂PVPK30的用量为：6g～12g/1000片。
(3)崩解剂的筛选
在本实施例中，考察了崩解剂的用量以及崩解剂的添加方式对美索舒利薄膜衣片片芯的影响，具体如下：
按照表a5所示的配方以及实施例a1中的制备方法，制备获得美索舒利薄膜衣片片芯。需要说明的是，在本实施例中，崩解剂的添加方式为两种：内加法和外加法，内加法为在步骤(3)中加入崩解剂，外加法是指在步骤(7)中加入崩解剂。然后测定制备获得的美索舒利薄膜衣片片芯的硬度、脆碎度、崩解时间和溶出度，测定结果见表6。其中，表5所示的配方为制备100片美索舒利薄膜衣片片芯的处方量。
表a5 崩解剂的处方筛选
Figure PCTCN2014085783-appb-000006
表a6 崩解剂的处方筛选实验结果
处方 a19 a20 a21 a22 a23
硬度(kg) 6.1 5.2 6.4 6.8 5.9
崩解时间(s) 64 45 50 39 27
脆碎度(％) 0.13 0.18 0.20 0.17 0.12
溶出度(％) 91.0 93.6 93.4 92.3 96.0
从表a6的结果可以看出，处方a20和处方a21溶出度结果差异不大，说明减少一定量的崩解剂仍可以保持较好的溶出，同时还可以节约成本。采用内外加法，外加崩解剂可以促进颗粒的崩解，内加崩解剂则能加快颗粒的分散，有利于提高溶出度。从上述结果可以看出，处方a23的崩解时间和溶出度都能达到最优，故确定PVPP的用量及添加方式为：内加0.7g，外加0.5g。因此，暂定最佳处方为处方a23。
在本实施例中，考察了崩解剂的用量以及崩解剂的添加方式对美索舒利薄膜衣片片芯的影响，具体如下：
按照表a7所示的配方以及实施例a1中的制备方法，制备获得美索舒利片。
需要说明的是，在本实施例中，崩解剂的添加方式为两种：内加法和外加法。
内加法是指在混合步骤中加入崩解剂，外加法是指总混步骤中，在加入润滑剂之前，先将干颗粒和崩解剂混合均匀。
当崩解剂进行内外加法时，按表a7中的处方，采用湿法制粒工艺，分别制备样品，制备方法如下：
(1)原辅料前处理：将主药(美索舒利)、各辅料分别粉碎后，主药过60目筛，辅料过80目筛，备用；
(2)配粘合剂：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液Ⅰ，备用；
(3)混合：称取处方量的主药、处方量的填充剂混合均匀后，再加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使薄膜衣片片芯硬度在5～7kg以内，压片即得。
然后测定制备获得的美索舒利薄膜衣片片芯的硬度、脆碎度、崩解时间和溶出度，测定结果见表a7。其中，表a7所示处方a24-处方a28的配方为制备1000片美索舒利片的处方 量。
表a7 崩解剂的处方筛选
Figure PCTCN2014085783-appb-000007
从表a7的结果可以看出，处方a24、处方a25和处方a26溶出度结果差异不大，说明减少一定量的崩解剂仍可以保持较好的溶出，同时还可以节约成本。处方a27和处方a28的崩解剂均采用内外加法，溶出度明显提高。外加崩解剂可以促进颗粒的崩解，内加崩解剂则能加快颗粒的分散，有利于提高溶出度。从上述结果可以看出，采用崩解剂内外加法的工艺，相对于崩解剂只采用内加法的工艺，其溶出度明显提高。故确定崩解剂的用量及添加方式为：崩解剂的内加量为崩解剂处方量的1/2，外加量为崩解剂处方量的另1/2。因此，暂定处方为处方a28。
实施例a3：美索舒利薄膜衣片制备工艺进一步优化实验
1、对美索舒利原料药粒径考察
按照如下步骤考察美索舒利原料药的粒径对美索舒利片的影响，具体如下：
以实施例2中的处方a28为基础，对本发明的制备工艺进一步优化，以便进一步提高本发明所述美索舒利薄膜衣片片芯的溶出度。
具体地，按照处方a28，分别制备两组(A组和B组)美索舒利薄膜衣片片芯，制备A组美索舒利薄膜衣片片芯的方法如下所述，B组美索舒利片剂的制备方法与A组美索舒利 薄膜衣片片芯的制备方法区别在于，主药美索舒利和辅料填充剂的混合物未进行微粉化处理。具体如下：
A组美索舒利薄膜衣片片芯的制备方法如下：
(1)原辅料前处理：将主药(美索舒利)和填充剂微晶纤维素混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使薄膜衣片片芯硬度在5～7kg以内，压片即得。
然后测定制备获得的美索舒利薄膜衣片片芯的溶出度，测定结果见表a8。
表a8
Figure PCTCN2014085783-appb-000008
由表a8的结果可知，相对于未经微粉化的美索舒利，先将美索舒利和填充剂微晶纤维素混合进行微粉化，再制得的美索舒利薄膜衣片片芯的溶出度可以显著得到改善。
2、压片工艺考察
根据生产条件，结合片重及适宜片厚，同时要考虑满足脆碎度要求，采用压片机进行压片。将薄膜衣片片芯的硬度大小控制在表a9所示区间，然后测定不同硬度的薄膜衣片片芯的脆碎度、溶出度和崩解时间，测定结果见表a9。
表a9 考察硬度对实验结果的影响
Figure PCTCN2014085783-appb-000009
Figure PCTCN2014085783-appb-000010
从表a9的结果可知：当薄膜衣片片芯的硬度在4～7kg之间的范围时，崩解时间和溶出度受其影响不大；而当硬度在7～8kg时，溶出度降低；而当硬度在4～5kg时，脆碎度大；考虑到薄膜衣片片芯还需要包衣，对脆碎度的要求较高，因此，将薄膜衣片片芯的硬度控制在5～7kg为较理想的范围。
其中，处方a30是规格为50mg的美索舒利片，其处方为：美索舒利50g，微晶纤维素170g，聚维酮K30 8g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.5g。
处方a29是规格为100mg的美索舒利片，其处方为：美索舒利100g，微晶纤维素120g，聚维酮K30 8g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.5g。
制备方法如下：
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，分别控制压力使薄膜衣片片芯硬度在4～5kg、5～6kg、6～7kg、7～8kg以内进行压片即得上述不同硬度的美索舒利片。
3、包衣工艺研究
为了保证薄膜衣片质量和方便服用，常在美索舒利片芯(本发明中所述的片芯，即是指上述实施例中未进行包衣的美索舒利片)表层包裹适宜的衣层材料，使薄膜衣片中的药物与外界隔离，得到在美索舒利药物表面覆盖有薄膜衣的薄膜衣片，从而达到防潮、避光、隔绝空气氧化、增强药物保存的稳定性，掩盖薄膜衣片中的不良嗅味和减少药物刺激的目的。
(1)包衣材料为：白色胃溶型欧巴代81W68907，上海卡乐康包衣技术有限公司生产。
(2)包衣液配制
将包衣粉末加入到纯化水中，配制成固含量20％的溶液，用螺旋式的搅拌桨搅拌45分钟即可。制好的包衣液可以通过蠕动泵，直接从配液容器中泵出使用。
(3)包衣条件
设定进风温度85℃，平均片床温度为41℃，包衣锅转速15～23r/min，喷浆速度3～4g/min。每片增重至设定值后，停止喷包衣液，吹冷风干燥，待片温降至室温后出片，用薄膜袋装好，称重，取样检查。
(4)包衣粉用量的筛选
取上述制备的130804批美索舒利薄膜衣片片芯样品，按片芯重量的5％，称取包衣粉，加纯化水制成固含量为20％的溶液，考察不同包衣增重的包衣效果，考察结果见表a10。
表a10 包衣粉用量的筛选
包衣增重 包衣效果(放大镜观察) 崩解时间(s)
1.8％ 片芯已基本包裹完全，但边缘不完整 78
3.0％ 包衣片完全包裹，颜色均匀，边缘完整 105
3.5％ 包衣片完全包裹，颜色均匀，边缘完整 113
4.0％ 包衣片完全包裹，颜色均匀，边缘完整 171
表a10的结果表明，包衣粉用量为片芯重量的3.0％以上时，包衣片外观已能满足要求，且随着包衣粉用量增加，崩解时间相应延长，当包衣粉用量为4.0％时，崩解时间存在加速延长的可能。对上述三种外观满足要求的包衣片进行基本性能评价如下表a11所示：
表a11 包衣片基本性能评价
Figure PCTCN2014085783-appb-000011
结合表a10和表a11的结果综合考虑，选择包衣时将包衣增重控制在片芯重量的3.0％-3.5％，既能满足包衣片的外观要求，又不影响崩解时间和溶出度，还能起到较好的遮光效果。
实施例a4：美索舒利薄膜衣片的制备
处方：
美索舒利50g，微晶纤维素170g，聚维酮K30 8g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.5g，共制成1000片。
制备方法：
(1)原辅料前处理：将主药(美索舒利)和填充剂微晶纤维素混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克粘合剂聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使薄膜衣片片芯硬度在5～7kg以内，压片即得。
(9)包衣：将包衣粉末白色胃溶型欧巴代81W68907加入到纯化水中，配制成固含量为20％的包衣溶液，用螺旋式的搅拌桨搅拌45分钟即可。采用普通改造糖衣锅对片芯进行包衣，得美索舒利薄膜衣片。其中，包衣过程的主要参数如下：平均进风温度为85℃，平均片床温度为41℃，雾化压力为2.5bar，平均包衣锅转速为15～23rpm，平均物料流速3～4g/min，增重3％～3.5％，得所述美索舒利薄膜衣片。
(10)包装：采用聚氯乙烯泡罩+双面复合铝膜袋对所述美索舒利薄膜衣片进行包装。
实施例a5：美索舒利薄膜衣片的制备
处方：
美索舒利50g，微晶纤维素150g，聚维酮K30 8g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.4g，共制成1000片。
制备方法：同实施例5。
实施例a6：美索舒利薄膜衣片的制备
处方：
美索舒利50g，微晶纤维素120g，聚维酮K30 10g，交联聚维酮(内加)2.5g，交联聚维酮(外加)2.5g，硬脂酸镁1g，共制成1000片。
制备方法：配粘合剂：称取10克粘合剂聚维酮K30于烧杯中，加纯化水90克，搅拌至澄清，得10％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例4。
实施例a7：美索舒利薄膜衣片的制备
处方：
美索舒利25g，微晶纤维素200g，聚维酮K30 6g，交联聚维酮(内加)8g，交联聚维酮(外加)8g，硬脂酸镁0.8g，共制成1000片。
制备方法：配粘合剂：称取6克粘合剂聚维酮K30于烧杯中，加纯化水94克，搅拌至澄清，得6％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例4。
实施例a8：美索舒利薄膜衣片的制备
处方：
美索舒利75g，微晶纤维素150g，聚维酮K30 12g，交联聚维酮(内加)10g，交联聚维酮(外加)10g，硬脂酸镁4g，共制成1000片。
制备方法：配粘合剂：称取12克粘合剂聚维酮K30于烧杯中，加纯化水88克，搅拌至澄清，得12％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例4。
实施例a9：美索舒利薄膜衣片的制备
处方：
美索舒利100g，微晶纤维素120g，聚维酮K30 7g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.5g，共制成1000片。
制备方法：配粘合剂：称取7克粘合剂聚维酮K30于烧杯中，加纯化水93克，搅拌至澄清，得7％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例4。
实施例a10：美索舒利薄膜衣片的制备
处方：
美索舒利100g，微晶纤维素120g，聚维酮K30 10g，交联聚维酮(内加)7g，交联聚维酮(外加)7g，硬脂酸镁3g，共制成1000片。
制备方法：配粘合剂：称取10克粘合剂聚维酮K30于烧杯中，加纯化水90克，搅拌至澄清，得10％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例4。
实施例a11：美索舒利薄膜衣片的制备
处方：
美索舒利125g，微晶纤维素90g，聚维酮K30 7g，交联聚维酮(内加)5g，交联聚维酮(外加)5g，硬脂酸镁2g，共制成1000片。
制备方法：配粘合剂：称取7克粘合剂聚维酮K30于烧杯中，加纯化水93克，搅拌至澄清，得7％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例4。
实施例a12：质量评价
1、性能评价
对本发明实施例a4-实施例a11所述的共8个样品，进行性状、硬度、脆碎度、片重差异、溶出度的检查，以便于对本发明所制备得到的美索舒利进行性能评价，结果见表a12。
表a12 美索舒利片性能评价
Figure PCTCN2014085783-appb-000012
表a12结果显示，8批样品的性状、硬度、脆碎度、片重差异均符合要求，且溶出度较高，且均能达到90％，符合要求。
2、10天影响因素实验：
接下来，对上述实施例a4制备获得美索舒利薄膜衣片进行影响因素实验，具体如下：
将50mg规格的美索舒利薄膜衣片(批号131205)袒露于培养皿中，在高温(60℃)、高湿(RH92.5％，25℃)、强光(4500lx±500lx)条件下放置10天，于第5、10天取样，观察制剂外观、含量、溶出度、有关物质、失重率等项目，并与考察前样品的检查数据进行比较，检测结果见表13。
其中，杂质1为中国发明专利申请CN103553984A所公开的式Ⅰ所示化合物，其结构式如下：
Figure PCTCN2014085783-appb-000013
表a13 美索舒利薄膜衣片(50mg/片)(批号131205)影响因素试验考察结果
Figure PCTCN2014085783-appb-000014
3、内包材的选择：
接下来，对上述50mg规格的美索舒利薄膜衣片，生产了3批，批号分别为131206、131207、131208、分别进行了四种包装的对比研究，四种拟选包装依次为：聚氯乙烯(PVC)泡罩、PVC泡罩+双面复合铝膜袋、双面复合铝膜袋及塑料瓶。然后，将分别采用四种包装的薄膜衣片在温度为40℃±2℃、相对湿度为75％±5％条件下放置6个月，进行了加速6个月的对比考察，分别于第0、1、2、3、6月取样，进行了稳定性试验各考察指标的检测， 加速6个月的实验数据见表a14。
表a14 美索舒利薄膜衣片(50mg/片，PVC泡罩+双面复合铝膜袋)加速6个月实验结果
Figure PCTCN2014085783-appb-000015
Figure PCTCN2014085783-appb-000016
加速6个月后，四种包装的含量、有关物质溶出度都无显著变化。PVC泡罩包装和塑料瓶包装的片子片重有明显增加，提示这两种包装的片子都有不同程度的吸潮，可能是因为塑料瓶和PVC泡罩包装的气密性差，受湿度影响较大。双面复合铝膜袋包装的虽然各个指标变化不大，但由于开封后不易保存，所以不采用。PVC泡罩+双面复合膜铝袋包装的片子，外观性状、含量、有关物质及溶出度都比较稳定。可见PVC泡罩+双面复合铝膜袋包装耐水蒸气渗透性、密封性能良好，能有效保证本品的长期稳定性。因此，选择PVC泡罩+双面复合铝膜袋包装为美索舒利薄膜衣片的最优内包材。
以下美索舒利薄膜衣片的实施例h1-h14，为按照1000片处方量投料，以下实施例只是进行说明，并不限制发明范围。
实施例h1：主药与辅料相互作用实验
在本实施例中，为了考察主药与处方中所选辅料之间是否有相互作用，以及制剂过程中晶型是否有改变，采用液相色谱法(按照中国发明专利申请CN103553984A实施例8公开的美索舒利HPLC检测方法)对所选的辅料与主药之间的相互作用进行了研究。
具体的，将单独辅料、主药与每一种单独辅料的混合物，主药与所有辅料的混合物分别在影响因素条件下放置10天，比较0天及10天后，混合物的性状、有关物质及含量的变化。
1、供试品的制备
原料药(美索舒利)的批号：101217批(人福医药集团股份公司自制，纯度99.8％)，先将美索舒利原料药过60目筛，各辅料均过80目筛。
h1号样品：主药与微晶纤维素(质量比1:5)混合物；
称取0.1g美索舒利原料药与0.5g微晶纤维素，过60目筛混合3次，编号h①
h2号样品：主药与乳糖(质量比1:5)混合物；
称取0.1g美索舒利原料药与0.5g乳糖，过60目筛混合3次，编号h②
h3号样品：主药与聚维酮K30(质量比5:1)的混合物
称取0.5g美索舒利原料药与0.1g聚维酮K30，过60目筛混合3次，编号h③
h4号样品：主药与交联聚维酮(质量比5:2)混合物
称取0.5g美索舒利原料药与0.2g交联聚维酮，过60目筛混合3次，编号h④
h5号样品：主药与硬脂酸镁(质量比20:1)的混合物
称取2g美索舒利原料药与0.1g硬脂酸镁，过60目筛混合3次，编号h⑤
h6号样品：主药与混合辅料(质量比1:5)混合物；
称取称取0.1g美索舒利原料药与0.5g混合物(其中乳糖0.23g+微晶纤维素0.23g+交联聚维酮0.04g)，过60目筛混合3次，编号h⑥
2、试验方法
将上述h1-h6号样品分别置于高温、高湿及光照条件下10天，比较0天及10天后，混合物的性状、有关物质及含量的变化，试验结果见表h1。
表h1 主药与辅料相容性实验结果
Figure PCTCN2014085783-appb-000017
Figure PCTCN2014085783-appb-000018
3、结论
h1～h6号样品在高温、高湿及光照条件下放置10天后的测定结果，与0天相比较，性状、含量未有明显变化，杂质1没有增加趋势，且没有产生新的杂质，结果表明，各辅料与主药之间相容性良好，美索舒利与各辅料之间没有相互作用。
实施例h2：美索舒利薄膜衣片的处方研究
由于主药美索舒利几乎不溶于水，且主药量也较大，因此，处方工艺的难点在于提高本品的溶出度。在本实施例中，对规格为50mg/片的美索舒利片剂的处方进行了研究，具体而言，由于美索舒利原料药水溶性及流动性均差，考虑加入水溶性辅料及崩解剂促进溶出，设计了9个处方，见表h2。
表h2 不同的处方设计
Figure PCTCN2014085783-appb-000019
注：在粘合剂的配制上，羟丙甲纤维素需加纯化水配制成4％的羟丙甲纤维素水溶液(g/g)，聚维酮K30需加纯化水配制成8％的聚维酮K30水溶液(g/g)。
按表h1中的处方，采用湿法制粒工艺，先制备得到美索舒利片芯，测定溶出度，
制备方法具体如下：
(1)原辅料前处理：将主药(美索舒利)、各辅料分别粉碎后，主药过60目筛，辅料过80目筛，备用；
(2)配粘合剂：
当处方中的粘合剂选择聚维酮K30(PVPK30)时，称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液Ⅰ，备用；
当处方中的粘合剂选择羟丙甲纤维素时，称取4克羟丙甲纤维素于烧杯中，加纯化水96克，搅拌至澄清，得4％羟丙甲纤维素水溶液Ⅰ，备用；
(3)混合：称取处方量的主药、填充剂混合均匀后，再加入崩解剂交联聚维酮(PVPP)混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
溶出度测定：
按中国药典2010版溶出度项下的测定方法，测定上述9个处方在溶出介质中45分钟的溶出度，其中溶出介质为磷酸盐缓冲液(氢氧化钠2.30g，磷酸二氢钾7.65g，加水使溶解为1000ml，用磷酸调pH至8.8)，溶出度测定结果见表h3。
表h3 各片剂处方的溶出度对比
处方 1 2 3 4 5 6 7 8 9
溶出度(％) 81.3 71.6 70.9 80.2 72.3 71.1 72.8 80.6 71.9
从溶出结果看，所设计的9个处方在溶出介质中45分钟的溶出度显示，较优的处方为处方h1、处方h4、处方h8。由于美索舒利水溶性差，而羟丙甲纤维素有阻溶作用，可能会在样品留样期间影响溶出度，加之其在水中完全溶胀所需时间较长，不利于工业化生产，因此不优选其作为粘合剂。但由于前期实验研究表明：单独以乳糖为填充剂时，工业大生产会出现裂片现象，所以本发明在稀释剂的辅料选择上不单独选用乳糖。但是由于作为填充剂的乳糖水溶性好，而微晶纤维素不仅能作为填充剂，而且具备崩解剂的性能，选取乳糖和微晶纤维素二者的组合同时作为稀释剂(在本文中，“填充剂”和“稀释剂”可以互换使用)，可达到好的溶出效果。
故本研究确定以处方h1为基础，进一步考察筛选填充剂的最佳比例和用量、粘合剂的浓度，以及改进崩解剂的添加方式，对处方和制剂工艺进行进一步优化。
实施例h3：50mg规格的美索舒利薄膜衣片处方及工艺优化
本研究根据中国药典2010版对片剂的剂型要求，参照CDE颁布的《化学药物制剂研究基本技术指导原则》，结合片剂的特点，以性状、硬度、脆碎度、崩解时间、溶出度等为考察指标，对本品处方所使用辅料的种类和用量进行进一步的筛选。
(1)稀释剂的筛选
在实施例h2中处方h1的基础上，调整乳糖和微晶纤维素的比例和用量，考察稀释剂不同比例及用量对压片成形性和溶出度的影响，具体如下：
按照表h4所示处方及实施例h2中所述的制备方法，以1000片/批的批量进行制粒、压片，然后测定制备获得的美索舒利片剂的硬度、脆碎度、崩解时间和溶出度，筛选填充剂。结果见表h4。
其中处方h10-处方h14中，粘合剂的配制方法为：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液。
表h4 填充剂的筛选处方及测定结果
Figure PCTCN2014085783-appb-000020
Figure PCTCN2014085783-appb-000021
由表h4的结果可以看出，上述h5个处方中，处方h12中由于乳糖所占比例较大、微晶纤维素所占比例较小，导致崩解性能稍差，溶出度稍低，而处方h10、h11、h13、h14的崩解和溶出度均较好，其溶出度均能达到80％以上，故选择乳糖和微晶纤维素的质量比为(0.25～3)：1，其中处方h10所得的溶出度最好、且崩解时间适中，故优选乳糖和微晶纤维素的最佳质量比为0.5：1。
(2)粘合剂用量的选择
选取聚维酮K30作为粘合剂，并配制不同浓度的水溶液对其粘合效果进行了比较研究，考察粘合剂的用量对美索舒利片剂的影响，具体如下：
按照表h5所示的处方以及实施例h2中的制备方法，制备获得美索舒利片剂，制备过程中观察美索舒利软材和颗粒的情况，并测定制备获得的美索舒利片剂的硬度、脆碎度、崩解时间和溶出度，处方及测定结果见表h5，
其中，表h5所示处方为制备1000片美索舒利片剂的原辅料用量。
其中，在处方h15中，粘合剂的配制方法为：称取4克聚维酮K30于烧杯中，加纯化水96克，搅拌至澄清，得4％聚维酮K30水溶液；其中处方h16中，粘合剂的配制方法为：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液；其中处方h17中，粘合剂的配制方法为：称取12克聚维酮K30于烧杯中，加纯化水88克，搅拌至澄清，得12％聚维酮K30水溶液；其中处方h18中，粘合剂的配制方法为：称取6克聚维酮K30于烧杯中，加纯化水94克，搅拌至澄清，得6％聚维酮K30水溶液；其中处方h19中，粘合剂的配制方法为：称取15克聚维酮K30于烧杯中，加纯化水85克，搅拌至澄清，得15％聚维酮K30水溶液。
表h5 粘合剂用量的处方筛选
Figure PCTCN2014085783-appb-000022
Figure PCTCN2014085783-appb-000023
从表h5的结果可以看出，在处方h15中，当粘合剂浓度为4％时，软材干，易过筛，颗粒小，细粉多，会导致片剂韧性不足，且压片时得到的片剂含量均匀性不合格；在处方h18中当粘合剂用量达到15％时，所制得软材较湿，较难过筛，颗粒有条状、紧实，而且延长了崩解时间；粘合剂用量的提高对溶出、颗粒流动性没有太大改善作用。而在处方h16、处方h17中，当粘合剂的浓度为6g(6％)、8g(8％)、或10g(10％)时，所制得的软材干湿程度适中，易过筛且得到的颗粒圆整，均匀，流动性好，易于进行压片。故确定粘合剂的用量为6～12g/1000片。
(3)崩解剂用量的筛选
在本实施例中，考察了崩解剂的用量以及崩解剂的添加方式对美索舒利片剂的影响，具体如下：
按照表h6所示的配方以及实施例h2中的制备方法，制备获得美索舒利片。
需要说明的是，在本实施例中，崩解剂的添加方式为两种：内加法和外加法。
内加法是在混合步骤中加入崩解剂，外加法是指总混步骤中，在加入润滑剂之前，先将干颗粒和崩解剂混合均匀。
当崩解剂进行内外加法时，按表h6中的处方，采用湿法制粒工艺，分别制备美索舒利片剂，制备方法如下：
(1)原辅料前处理：将主药(美索舒利)、各辅料分别粉碎后，主药过60目筛，辅料过80目筛，备用；
(2)配粘合剂：称取10克聚维酮K30于烧杯中，加纯化水90克，搅拌至澄清，得10％聚维酮K30水溶液Ⅰ，备用；
(3)混合：称取处方量的主药、处方量的填充剂混合均匀后，再加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
然后测定制备获得的美索舒利片剂的硬度、脆碎度、崩解时间和溶出度，测定结果见表h6。其中，表h6所示处方h20-处方h24的配方为制备1000片美索舒利片的处方量。
表h6 崩解剂的处方筛选
Figure PCTCN2014085783-appb-000024
注：“-”表示不含有相应组分
从表h6的结果可以看出，处方h20、处方h21和处方h22溶出度结果差异不大，说明减少一定量的崩解剂仍可以保持较好的溶出，同时还可以节约成本。处方h23和处方h24的崩解剂均采用内外加法，溶出度明显提高。外加崩解剂可以促进颗粒的崩解，内加崩解剂则能加快颗粒的分散，有利于提高溶出度。从上述结果可以看出，采用崩解剂内外加法的工艺，相对于崩解剂只采用内加法的工艺，其溶出度明显提高，其溶出度可提高到85％以上。故确定崩解剂的用量及添加方式为：崩解剂的内加量为崩解剂处方量的1/2，外加量为崩解剂处方量的另1/2。因此，暂定处方为处方h24。
实施例h4：制备工艺进一步优化实验
1、对美索舒利原料药粒径考察
按照如下步骤考察美索舒利原料药的粒径对美索舒利片的影响，具体如下：
以实施例h3中的处方h24为基础，对本发明的制备工艺进一步优化，以便进一步提高本发明所述美索舒利片的溶出度。
具体地，按照处方h24，分别制备两组(A组和B组)美索舒利片剂，制备A组美索舒利片剂的方法如下所述，B组美索舒利片剂的制备方法与A组美索舒利片剂的制备方法区别在于，主药美索舒利和辅料填充剂的混合物未进行微粉化处理。具体如下：
A组美索舒利片剂的制备方法如下：
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
然后测定制备获得的两组美索舒利片剂的溶出度，测定结果见表h7。
表h7
Figure PCTCN2014085783-appb-000025
由表h7的结果可知，相对于未经微粉化的美索舒利，先将美索舒利和填充剂乳糖、以及微晶纤维素混合进行微粉化，再制得的美索舒利片剂的溶出度可以显著得到改善。
2、压片工艺考察
根据生产条件，结合片重及适宜片厚，同时要考虑满足脆碎度要求，采用压片机进行压片。将片剂的硬度大小控制在表h8所示区间，然后测定不同硬度的片剂的脆碎度、溶出度和崩解时间，测定结果见表h8。
表h8 考察硬度对实验结果的影响
Figure PCTCN2014085783-appb-000026
从表h8的结果可知：当片剂的硬度在4～7kg之间的范围时，崩解时间和溶出度受其影响不大；而当硬度在7～8kg时，溶出度降低；而当硬度在4～5kg时，脆碎度大；考虑到片剂还需要包衣，对脆碎度的要求较高，因此，将片剂的硬度控制在5～7kg为较理想的范围。
其中，处方h24是规格为50mg的美索舒利片，其处方为：美索舒利50g，乳糖50g，微晶纤维素100g，聚维酮K30 8g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.5g。
处方h25是规格为100mg的美索舒利片，其处方为：美索舒利100g，乳糖40g，微晶纤维素80g，聚维酮K30 8g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.5g。
制备方法如下：
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸 镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，分别控制压力使片剂硬度在4～5kg、5～6kg、6～7kg、7～8kg以内进行压片即得上述不同硬度的美索舒利片。
3、包衣工艺研究
为了保证片剂质量和方便服用，常在美索舒利片芯(此处的片芯，即是指上述实施例中未进行包衣的美索舒利片剂)表层包裹适宜的衣层材料，使片剂中的药物与外界隔离，得到在美索舒利药物表面覆盖有薄膜衣的片剂，从而达到防潮、避光、隔绝空气氧化、增强药物保存的稳定性，掩盖片剂中的不良嗅味和减少药物刺激的目的。
(1)包衣材料为：白色胃溶型欧巴代81W68907，上海卡乐康包衣技术有限公司生产。
(2)包衣液配制
将包衣粉末加入到纯化水中，配制成固含量20％的溶液，用螺旋式的搅拌桨搅拌45分钟即可。制好的包衣液可以通过蠕动泵，直接从配液容器中泵出使用。
(3)包衣条件
设定进风温度85℃，平均片床温度为41℃，包衣锅转速15～23r/min，喷浆速度3～4g/min。每片增重至设定值后，停止喷包衣液，吹冷风干燥，待片温降至室温后出片，用薄膜袋装好，称重，取样检查。
(4)包衣粉用量的筛选
取按照处方h25的处方及工艺，特别是压片时，控制压力使片剂硬度在5～7kg以内进行压片得到的美索舒利片样品，按片芯重量的5％，称取包衣粉，加纯化水制成固含量为20％的溶液，考察不同包衣增重的包衣效果，考察结果见表h9。
表h9 包衣粉用量的筛选
包衣增重 包衣效果(放大镜观察) 崩解时间(s)
1.8％ 片芯已基本包裹完全，但边缘不完整 80
3.0％ 包衣片完全包裹，颜色均匀，边缘完整 101
3.5％ 包衣片完全包裹，颜色均匀，边缘完整 112
4.0％ 包衣片完全包裹，颜色均匀，边缘完整 166
表h9的结果表明，包衣粉用量为片芯重量的3.0％以上时，包衣片外观已能满足要求，且随着包衣粉用量增加，崩解时间相应延长，当包衣粉用量为4.0％时，崩解时间存在加速延长的可能。对上述三种外观满足要求的包衣片进行基本性能评价如下表h10所示：
表h10 包衣片基本性能评价
Figure PCTCN2014085783-appb-000027
结合表h9和表h10的结果综合考虑，选择包衣时将包衣增重控制在片芯重量的3.0％-3.5％，既能满足包衣片的外观要求，又不影响崩解时间和溶出度，还能起到较好的遮光效果。
实施例h5：美索舒利薄膜衣片的制备
处方：
美索舒利50g，乳糖50g，微晶纤维素100g，聚维酮K30 8g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.5g，共制成1000片。
制备方法：
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂乳糖、微晶纤维素混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克粘合剂聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
(9)包衣：将包衣粉末白色胃溶型欧巴代81W68907加入到纯化水中，配制成固含量为20％的包衣溶液，用螺旋式的搅拌桨搅拌45分钟即可。采用普通改造糖衣锅对片芯进行包衣，得美索舒利薄膜衣片。其中，包衣过程的主要参数如下：平均进风温度为85℃，平均片床温 度为41℃，雾化压力为2.5bar，平均包衣锅转速为15～23rpm，平均物料流速3～4g/min，增重3％～3.5％，得所述美索舒利片剂。
(10)包装：采用聚氯乙烯泡罩+双面复合铝膜袋对所述美索舒利片剂进行包装。
实施例h6：美索舒利薄膜衣片的制备
处方：
美索舒利50g，乳糖113g，微晶纤维素57g，聚维酮K30 8g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.4g，共制成1000片。
制备方法：
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂乳糖、微晶纤维素混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克粘合剂聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于55℃下干燥4h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
(9)包衣：将包衣粉末白色胃溶型欧巴代81W68907加入到纯化水中，配制成固含量为20％的包衣溶液，用螺旋式的搅拌桨搅拌45分钟即可。采用普通改造糖衣锅对片芯进行包衣，得美索舒利薄膜衣片。其中，包衣过程的主要参数如下：平均进风温度为85℃，平均片床温度为41℃，雾化压力为2.5bar，平均包衣锅转速为15～23rpm，平均物料流速3～4g/min，增重3％～3.5％，得所述美索舒利片剂。
(10)包装：采用聚氯乙烯泡罩+双面复合铝膜袋对所述美索舒利片剂进行包装
实施例h7：美索舒利薄膜衣片的制备
处方：
美索舒利50g，乳糖135g，微晶纤维素45g，聚维酮K30 8g，交联聚维酮(内加)8g，交联聚维酮(外加)8g，硬脂酸镁2g，共制成1000片。
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂乳糖、微晶纤维素混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克粘合剂聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于65℃下干燥1h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
(9)包衣：将包衣粉末白色胃溶型欧巴代81W68907加入到纯化水中，配制成固含量为20％的包衣溶液，用螺旋式的搅拌桨搅拌45分钟即可。采用普通改造糖衣锅对片芯进行包衣，得美索舒利薄膜衣片。其中，包衣过程的主要参数如下：平均进风温度为85℃，平均片床温度为41℃，雾化压力为2.5bar，平均包衣锅转速为15～23rpm，平均物料流速3～4g/min，增重3％～3.5％，得所述美索舒利片剂。
(10)包装：采用聚氯乙烯泡罩+双面复合铝膜袋对所述美索舒利片剂进行包装。
实施例h8：美索舒利薄膜衣片的制备
处方：
美索舒利25g，乳糖30g，微晶纤维素120g，聚维酮K30 6g，交联聚维酮(内加)3g，交联聚维酮(外加)3g，硬脂酸镁2g，共制成1000片。
制备方法：
配粘合剂：称取6克粘合剂聚维酮K30于烧杯中，加纯化水94克，搅拌至澄清，得6％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例5。
实施例h9：美索舒利薄膜衣片的制备
处方：
美索舒利25g，玉米淀粉200g，羟丙甲纤维素6g，交联羧甲基纤维素钠(内加)2.5g，交联羧甲基纤维素钠(外加)2.5g，硬脂酸镁0.8g，共制成1000片。
制备方法：
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂玉米淀粉混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取6克粘合剂羟丙甲纤维素于烧杯中，加纯化水94克，搅拌至澄清，得6％羟丙甲纤维素的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
(9)包衣：将包衣粉末白色胃溶型欧巴代81W68907加入到纯化水中，配制成固含量为20％的包衣溶液，用螺旋式的搅拌桨搅拌45分钟即可。采用普通改造糖衣锅对片芯进行包衣，得美索舒利薄膜衣片。其中，包衣过程的主要参数如下：平均进风温度为85℃，平均片床温度为41℃，雾化压力为2.5bar，平均包衣锅转速为15～23rpm，平均物料流速3～4g/min，增重3％～3.5％，得所述美索舒利片剂。
(10)包装：采用聚氯乙烯泡罩+双面复合铝膜袋对所述美索舒利片剂进行包装。
实施例h10：美索舒利薄膜衣片的制备
处方：
美索舒利100g，乳糖40g，微晶纤维素80g，聚维酮K30 12g，交联聚维酮(内加)7g，交联聚维酮(外加)7g，硬脂酸镁3g，共制成1000片。
制备方法：配粘合剂：称取12克粘合剂聚维酮K30于烧杯中，加纯化水88克，搅拌至澄清，得12％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例h5。
实施例h11：美索舒利薄膜衣片的制备
处方：
美索舒利100g，乳糖80g，微晶纤维素40g，聚维酮K30 7g，交联聚维酮(内加)6g，交联聚维酮(外加)6g，硬脂酸镁2.5g，共制成1000片。
制备方法：配粘合剂：称取7克粘合剂聚维酮K30于烧杯中，加纯化水93克，搅拌至澄清，得7％聚维酮K30的粘合剂水溶液Ⅰ；其余的制备方法同实施例h5。
实施例h12：美索舒利薄膜衣片的制备
处方：
美索舒利125g，甘露醇50g，甲基纤维素10g，交联聚维酮(内加)7g，交联聚维酮(外加)7g，硬脂酸镁4g，共制成1000片。
制备方法：
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂甘露醇混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取10克粘合剂甲基纤维素于烧杯中，加纯化水90克，搅拌至澄清，得10％羟丙甲纤维素的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
(9)包衣：将包衣粉末白色胃溶型欧巴代81W68907加入到纯化水中，配制成固含量为20％的包衣溶液，用螺旋式的搅拌桨搅拌45分钟即可。采用普通改造糖衣锅对片芯进行包衣，得美索舒利薄膜衣片。其中，包衣过程的主要参数如下：平均进风温度为85℃，平均片床温度为41℃，雾化压力为2.5bar，平均包衣锅转速为15～23rpm，平均物料流速3～4g/min，增重3％～3.5％，得所述美索舒利片剂。
(10)包装：采用聚氯乙烯泡罩+双面复合铝膜袋对所述美索舒利片剂进行包装。
实施例h13：美索舒利薄膜衣片的制备
处方：
美索舒利125g，乳糖60g，微晶纤维素60g，聚维酮K30 10g，羧甲基淀粉钠(内加)10g，羧甲基淀粉钠(外加)10g，硬脂酸镁3g，共制成1000片。
制备方法：。
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂甘露醇混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取10克粘合剂甲基纤维素于烧杯中，加纯化水90克，搅拌至澄清，得10％羟丙甲纤维素的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂羧甲基淀粉钠混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂羧甲基淀粉钠，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片剂硬度在5～7kg以内，压片即得。
(9)包衣：将包衣粉末白色胃溶型欧巴代81W68907加入到纯化水中，配制成固含量为20％的包衣溶液，用螺旋式的搅拌桨搅拌45分钟即可。采用普通改造糖衣锅对片芯进行包衣，得美索舒利薄膜衣片。其中，包衣过程的主要参数如下：平均进风温度为85℃，平均片床温度为41℃，雾化压力为2.5bar，平均包衣锅转速为15～23rpm，平均物料流速3～4g/min，增重3％～3.5％，得所述美索舒利片剂。
(10)包装：采用聚氯乙烯泡罩+双面复合铝膜袋对所述美索舒利片剂进行包装。
实施例h14：质量评价
1、性能评价
对本发明实施例h5-实施例h13所述的共9个样品，进行性状、硬度、脆碎度、片重差异、溶出度的检查，以便于对本发明所制备得到的美索舒利进行性能评价，结果见表h11
表h11 美索舒利片性能评价
Figure PCTCN2014085783-appb-000028
表h11结果显示，9批样品的性状、硬度、脆碎度、片重差异均符合要求，且溶出度较高，且均能达到90％，符合要求。
2、10天影响因素实验：
接下来，对上述实施例h11制备获得美索舒利片(薄膜衣片)进行影响因素实验，具体如下：
将100mg规格的美索舒利薄膜衣片(批号131101)袒露于培养皿中，在高温(60℃)、高湿(RH92.5％，25℃)、强光(4500lx±500lx)条件下放置10天，于第5、10天取样，观察制剂外观、含量、溶出度、有关物质、失重率等项目，并与考察前样品的检查数据进行比较，检测结果见表h12。
表h12 美索舒利薄膜衣片(100mg/片)(批号131101)影响因素试验结果
Figure PCTCN2014085783-appb-000029
Figure PCTCN2014085783-appb-000030
影响因素试验结果表明：薄膜衣片在高温、高湿、光照下放置10天，含量、有关物质无显著性变化，质量基本稳定，表明，处方科学可行，工艺合理、重现性好。但高湿10天薄膜衣片表面有轻微吸潮，溶出度有所下降，提示选择包装时要注意防潮。因此，产品需要密封干燥处贮存。
3、内包材的选择：
接下来，对上述100mg规格的美索舒利薄膜衣片，生产了3批，批号分别为131201、131202、131203、分别进行了四种包装的对比研究，四种拟选包装依次为：聚氯乙烯(PVC)泡罩、PVC泡罩+双面复合铝膜袋、双面复合铝膜袋及塑料瓶。然后，将分别采用四种包装的薄膜衣片在温度为40℃±2℃、相对湿度为75％±5％条件下放置6个月，进行了加速6个月的对比考察，分别于第1、2、3、6月取样，进行了稳定性试验各考察指标的检测，加速6个月的实验数据见表h13。
表h13 美索舒利薄膜衣片(100mg/片，PVC泡罩+双面复合铝膜袋)加速6个月的实验结果
Figure PCTCN2014085783-appb-000031
Figure PCTCN2014085783-appb-000032
加速6个月后，四种包装的含量、有关物质溶出度都无显著变化。PVC泡罩包装和塑料瓶包装的片子片重有明显增加，提示这两种包装的片子都有不同程度的吸潮，可能是因为塑料瓶和PVC泡罩包装的气密性差，受湿度影响较大。双面复合铝膜袋包装的虽然各个指标变化不大，但由于开封后不易保存，所以不采用。PVC泡罩+双面复合膜铝袋包装的片子，外观性状、含量、有关物质及溶出度都比较稳定。可见PVC泡罩+双面复合铝膜袋包装耐水蒸气渗透性、密封性能良好，能有效保证本品的长期稳定性。因此，选择PVC泡罩+双面复合铝膜袋包装为美索舒利薄膜衣片的最优内包材。
以下美索舒利口腔崩解片的实施例b1-b13，为按照1000片处方量投料，以下实施例只是进行说明，并不限制发明范围。
实施例b1：
处方：美索舒利25克、甘露醇20克、微晶纤维素30克、聚维酮K30 5克、低取代羟丙纤维素2克、阿斯巴甜5克、二氧化硅0.5克，微粉硅胶0.1克，共制成1000片美索舒利口腔崩解片。
制法：该剂型使用常规的片剂制药设备生产并用直接压片法工艺制备，具体制备方法如下：
步骤1、将处方量的美索舒利进行微粉化，微粉化后的粒径为1-30微米，加入微 粉硅胶混合均匀；将阿斯巴甜研细过80目筛后，将美索舒利、微粉硅胶和阿斯巴甜混合均匀；
步骤2、将处方量的甘露醇和微晶纤维素进行微粉化，微粉化后的粒径为120-200微米；将低取代羟丙纤维素过80目筛，聚维酮K30过40目筛，按处方量分别称取并按上述顺序依次加入上述步骤1中的混合药物中混匀；
步骤3、向上述步骤2中所得混合药物中加入处方量的二氧化硅，过筛混匀，进行中间体含量检测，确定片重后采用直接压片技术压片，即得美索舒利口腔崩解片。
实施例b2：
处方：美索舒利25克、甘露醇20克、微晶纤维素40克、聚维酮K30 10克、低取代羟丙纤维素2克、阿斯巴甜5克、二氧化硅0.5克，微粉硅胶0.1克，共制成1000片美索舒利口腔崩解片。
制法：
采用与实施例b1相同的方法制备美索舒利口腔崩解片，区别在于：将美索舒利进行微粉化后的粒径为60-100微米，甘露醇和微晶纤维素进行微粉化后的粒径为10-60微米。
实施例b3：
处方：美索舒利50克、甘露醇40克、微晶纤维素60克、羧甲基纤维素钠15克、交联聚维酮10克、香橙香精10克、硬脂酸镁2克，微粉硅胶0.2克，共制成1000片美索舒利口腔崩解片。
制法：
步骤1、将处方量的美索舒利进行微粉化，微粉化后的粒径为30-60微米，加入微粉硅胶混合均匀；将香橙香精研细过80目筛后，将美索舒利、微粉硅胶和香橙香精混合均匀；
步骤2、将处方量的甘露醇和微晶纤维素进行微粉化，微粉化后的粒径为60-120微米；将交联聚维酮过80目筛，羧甲基纤维素钠过40目筛，按处方量分别称取并按上述顺序依次加入上述步骤1中的混合药物中混匀；
步骤3、向上述步骤2中所得混合药物中加入处方量的硬脂酸镁，过筛混匀，进行中间体含量检测，确定片重后采用直接压片技术压片，即得美索舒利口腔崩解片。
实施例b4：
处方：美索舒利50克、甘露醇40克、微晶纤维素60克、聚维酮K30 15克、交联聚维酮12克、阿斯巴甜10克、硬脂酸镁2克，微粉硅胶0.2克，共制成1000片美索舒利口腔崩解片。
制法：
步骤1、将处方量的美索舒利进行微粉化，微粉化后的粒径为30-60微米，加入微粉硅胶混合均匀；将阿斯巴甜研细过80目筛后，将美索舒利、微粉硅胶和阿斯巴甜混合均匀；
步骤2、将处方量的甘露醇和微晶纤维素进行微粉化，微粉化后的粒径为60-120微米；将交联聚维酮过80目筛，聚维酮K30过40目筛，按处方量分别称取并按上述顺序依次加入上述步骤1中的混合药物中混匀；
步骤3、向上述步骤2中所得混合药物中加入处方量的硬脂酸镁，过筛混匀，进行中间体含量检测，确定片重后采用直接压片技术压片，即得美索舒利口腔崩解片。
实施例b5：
处方：美索舒利50克、甘露醇40克、微晶纤维素60克、羧甲基纤维素钠15克、交联聚维酮12克、香橙香精10克、聚乙二醇2克，微粉硅胶0.2克，共制成1000片美索舒利口腔崩解片。
制法：同实施例b3。
实施例b6：
处方：美索舒利75克、甘露醇30克、微晶纤维素60克、羟丙甲纤维素5克、羧甲基淀粉钠15克、阿斯巴甜15克、聚乙二醇5克，微粉硅胶0.3克，共制成1000片美索舒利口腔崩解片。
制法：
步骤1、将处方量的美索舒利进行微粉化，微粉化后的粒径为1-30微米，加入微粉硅胶混合均匀；将阿斯巴甜研细过80目筛，将美索舒利、微粉硅胶和阿斯巴甜混合均匀；
步骤2、将处方量的甘露醇和微晶纤维素进行微粉化，微粉化后的粒径为60-120微米；将羧甲基淀粉钠过80目筛，羟丙甲纤维素过40目筛，按处方量分别称取并按上述顺序依次加入上述步骤1中的混合药物中混匀；
步骤3、向上述步骤2中所得混合药物中加入处方量的聚乙二醇，过筛混匀，进行中间体含量检测，确定片重后采用直接压片技术压片，即得美索舒利口腔崩解片。
实施例b7：
处方：美索舒利75克、甘露醇30克、微晶纤维素60克、羟丙甲纤维素25克、羧甲基淀粉钠15克、阿斯巴甜15克、聚乙二醇5克，微粉硅胶0.3克，共制成1000片美索舒利口腔崩解片。
制法：同实施例b6。
实施例b8：
处方：美索舒利100克、甘露醇40克、微晶纤维素60克、聚维酮K30 40克、交联聚维酮12克、阿斯巴甜10克、硬脂酸镁6克，微粉硅胶0.4克，共制成1000片美索舒利口腔崩解片。
制法：
步骤1、将处方量的美索舒利进行微粉化，微粉化后的粒径为30-60微米，加入微粉硅胶混合均匀；将阿斯巴甜研细过80目筛，将美索舒利、微粉硅胶和阿斯巴甜混合均匀；
步骤2、将处方量的甘露醇和微晶纤维素进行微粉化，微粉化后的粒径为10-60微米；将交联聚维酮过80目筛，聚维酮K30过40目筛，按处方量分别称取并按上述顺序依次加入上述步骤1中的混合药物中混匀；
步骤3、向上述步骤2中所得混合药物中加入处方量的硬脂酸镁，过筛混匀，进行中间体含量检测，确定片重后采用直接压片技术压片，即得美索舒利口腔崩解片。
实施例b9：
处方：美索舒利100克、甘露醇35克、微晶纤维素70克、聚维酮K30 30克、交联聚维酮12克、阿斯巴甜10克、硬脂酸镁6克，微粉硅胶0.4克，共制成1000片美索舒利口腔崩解片。
制法：同实施例b8。
实施例b10：
处方：美索舒利100克、甘露醇60克、微晶纤维素60克、聚维酮K30 40克、交联聚维酮10克、香橙香精15克、硬脂酸镁6克，微粉硅胶0.4克，共制成1000片美索舒利口腔崩解片。
制法：
步骤1、将处方量的美索舒利进行微粉化，微粉化后的粒径为30-60微米，加入微粉硅胶混合均匀；将香橙香精研细过80目筛，将美索舒利、微粉硅胶和香橙香精混合均匀；
步骤2、将处方量的甘露醇和微晶纤维素进行微粉化，微粉化后的粒径为30-60微米；将交联聚维酮过80目筛，聚维酮K30过40目筛，按处方量分别称取并按上述顺序依次加入上述步骤1中的混合药物中混匀；
步骤3、向上述步骤2中所得混合药物中加入处方量的硬脂酸镁，过筛混匀，进行中间体含量检测，确定片重后采用直接压片技术压片，即得美索舒利口腔崩解片。
实施例b11：
处方：美索舒利125克、甘露醇30克、微晶纤维素45克、羟丙基纤维素30克、交联羧甲基纤维素钠30克、香橙香精20克、二氧化硅10克，微粉硅胶0.5克，共制成1000片美索舒利口腔崩解片。
制法：
步骤1、将处方量的美索舒利进行微粉化，微粉化后的粒径为30-60微米，加入微粉硅胶混合均匀；将香橙香精研细过80目筛，将美索舒利、微粉硅胶和香橙香精混合均匀；
步骤2、将处方量的甘露醇和微晶纤维素进行微粉化，微粉化后的粒径为100-150微米；将交联羧甲基纤维素钠过80目筛，羟丙基纤维素过40目筛，按处方量分别称取并按上述顺序依次加入上述步骤1中的混合药物中混匀；
步骤3、向上述步骤2中所得混合药物中加入处方量的二氧化硅，过筛混匀，进行中间体含量检测，确定片重后采用直接压片技术压片，即得美索舒利口腔崩解片。
实施例b12：
处方：美索舒利125克、甘露醇60克、微晶纤维素60克、羟丙基纤维素20克、交联羧甲基纤维素钠30克、香橙香精20克、二氧化硅10克，微粉硅胶0.5克，共制成1000片美索舒利口腔崩解片。
制法：同实施例b11。
实施例b13：
采用下面的试验方法及测试仪器，对实施例b1-实施例b12中制备获得的美索舒利口腔崩解片的硬度、崩解时限、脆碎度和溶出度进行测定，具体如下：
A、硬度测定：
取美索舒利口腔崩解片10片(n＝10)，分别用YD-1片剂硬度测试仪(天津市新天光分析仪器技术有限公司)测定片剂硬度。
B、崩解时限测定，采用静态崩解法。
取美索舒利口腔崩解片1片，置于10ml试管(试管内径为13mm)中，试管内盛有2ml水，水温为37℃，片剂应在1分钟内崩解、分散在水中。倒出过筛，每次用水2ml、分两次冲洗试管和筛网，能全部通过孔径小于710μm的筛网。按上述方法检查6片(n＝6)，应符合规定。
C、脆碎度测定，按照中国药典2010年版附录X G的片剂脆碎度检查法进行试验。
D、溶出度测定：采用RCZ-8A智能溶出仪，溶出测定的条件如下
溶出方法：大杯桨法；
温度：37℃±0.5℃；
转速：75转/分；
溶出介质：pH8.8磷酸盐缓冲液，体积1000ml；
最终取样时间点为30分钟。
溶出度测定方法具体如下：
(1)对照品溶液制备
称取美索舒利对照品25.0mg至250ml量瓶中，加甲醇约8ml完全溶解后，再加入溶出介质稀释并定容，摇匀。精密移取5.0ml至25ml的容量瓶中，用溶出介质定容，得到每1ml中约含20μg的美索舒利对照品溶液。
(2)供试品溶液制备
按“溶出度检查方法”项下的方法，分别于5、15、25、35、45、60分钟取样，滤过，精密吸取续滤液适量，用溶出介质稀释到每1ml约含20μg美索舒利。
(3)溶出度测定
依上法测定实施例b1-实施例b12中制备获得的美索舒利口腔崩解片样品的溶出度。
E、10天影响因素测定，将实施例b1-实施例b12中制备获得的美索舒利口腔崩解片袒露于培养皿中，在高温(60℃)、高湿(RH92.5％，25℃)、强光(4500lx±500lx)条件下放置10天，并于0天、5天及10天时，采用中国发明专利申请201310476323.3实施例8公开的液相色谱法测定美索舒利口腔崩解片的总杂质含量。
实施例b1-实施例b12中制备获得的美索舒利口腔崩解片的崩解时限、脆碎度、药片硬度、溶出度测定结果见表b1，10天影响因素测定见表b2。
表b1：崩解时限、脆碎度、药片硬度、溶出度数值
Figure PCTCN2014085783-appb-000033
Figure PCTCN2014085783-appb-000034
由上述测得的各项数据可知：本发明的美索舒利口腔崩解片，其崩解时限为15s-45s，硬度5-8kg，脆碎度小于0.5％，10分钟在pH8.8磷酸盐缓冲溶液中溶出量大于85％。
表b2：10天影响因素实验结果
Figure PCTCN2014085783-appb-000035
Figure PCTCN2014085783-appb-000036
以上数据说明：应用本发明的处方和制备工艺得到的美索舒利口腔崩解片，其经过10天影响因素实验后，质量仍非常稳定。
对比实施例b1：
与本发明的制备工艺相比，该对比实施例b1中具有以下区别：(1)美索舒利原料、以及甘露醇、微晶纤维素未经微粉化处理，(2)未加入微粉硅胶，(3)采用湿法制粒制备美索舒利口腔崩解片。
处方：美索舒利50克、甘露醇40克、微晶纤维素60克、聚维酮K30 15克、交联聚维酮12克、阿斯巴甜10克、硬脂酸镁2克，共制成1000片美索舒利口腔崩解片。
制备工艺如下：
1)配粘合剂：取处方量的聚维酮K30，加入纯化水制成质量分数10％的溶液，备用。
2)混合：将各辅料分别过80目筛，美索舒利过60目筛，按处方量称取原辅料，将原辅料混合均匀后，备用。
3)制软材及制粒：取过筛混匀后的原辅料，加入10％的聚维酮K30水溶液，制软材，制粒，过18目筛得湿颗粒。
4)干燥及整粒：将湿颗粒平摊于盘，放置烘箱中，于60±5℃下干燥，每半个小时翻动一次，约2h后取出，18目筛整粒，得干颗粒，称重。
5)总混：根据干颗粒重量，加入硬脂酸镁，混合均匀。
6)压片：根据总混颗粒所测得含药量，计算理论片重，将压片机调整到适宜的填充量，控制压力使片子硬度在5～8kg以内，压片即得美索舒利口腔崩解片。
崩解测定方法：在10ml试管中加入37℃的热水2ml，轻轻投入待测片剂，同时开始计时，观察记录片剂完全崩解时间，在1min时终止测定，观察片剂是否完全崩解。
试验结果：按照中国口腔崩解片质量控制要点要求，对比实施例实验处方及制备方法所得的片剂在硬度在4～8kg以内(取4kg、5kg、6kg、7kg和8kg)时，均不能在1min内完全崩解。而硬度为1kg和2kg时，崩解时限分别为50s、55s，脆碎度也均偏高，分别为1.1％、1.5％。
而根据本发明的直接压片技术方案所制得的美索舒利口崩片(实施例b1-实施例b12)在硬度为5-8kg范围内时，其崩解时限为15s-45s，脆碎度小于0.5％，且溶出好，质量稳定。
以下美索舒利分散片的实施例c1-c14按照1000片处方量投料，以下实施例只是进 行说明，并不限制发明范围。
实施例c1
处方：
美索舒利25重量份、阿司帕坦5重量份、微晶纤维素60重量份、羟丙甲基纤维素5重量份、羧甲基淀粉钠2重量份、硬脂酸镁0.5重量份
制备方法：
(1)将上述处方量美索舒利溶于25ml丙酮中得到A液，将处方量的微晶纤维素、羟丙甲基纤维素溶于100ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、阿司帕坦、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
溶出度实验：
以中国药典2010年版二部附录XC第二法装置，照中国药典2010年版二部附录XD第一法测定制备获得的美索舒利分散片的溶出度。具体的，以水9000ml为释放介质，转速100转，在5、10、15、30、45、60分钟取样，测定美索舒利分散片的溶出度，测定结果见图1。
实施例c2
处方：
美索舒利25重量份、蔗糖10重量份、乳糖30重量份、微晶纤维素50重量份、聚维酮5重量份、交联聚维酮3重量份、微粉硅胶0.5重量份
制备方法：
(1)将上述处方量美索舒利溶于25ml乙醇中得到A液，将处方量的乳糖、微晶纤维素、聚维酮溶于100ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的微粉硅胶、蔗糖、交联聚维酮混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
实施例c3
处方：
美索舒利50重量份、阿司帕坦10重量份、微晶纤维素100重量份、羟丙甲基纤维素10重量份、羧甲基淀粉钠5重量份、硬脂酸镁1重量份
制备方法：
(1)将上述处方量美索舒利溶于50ml乙醇中得到A液，将处方量的微晶纤维素、羟丙甲基纤维素溶于120ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、阿司帕坦、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
溶出度实验：实验方法同实施例c1，美索舒利分散片的溶出度测定结果见图2。
实施例c4
处方：
美索舒利50重量份、甜菊苷10重量份、甘露醇80重量份、羟丙基纤维素8重量份、交联羧甲基纤维素钠6重量份、硬脂酸镁1重量份
制备方法：
(1)将上述处方量美索舒利溶于50ml丙酮中得到A液，将处方量的甘露醇、羟丙基纤维素溶于120ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、甜菊苷、交联羧甲基纤维素钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
实施例c5
处方：
美索舒利50重量份、阿司帕坦10重量份、淀粉100重量份、糊精8重量份、低取代羟丙基纤维素6重量份、富马酸钠1重量份
制备方法：
(1)将上述处方量美索舒利溶于50ml丙酮中得到A液，将处方量的淀粉、糊精溶于120ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的富马酸钠、阿司帕坦、低取代羟丙基纤维素混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
实施例c6
处方：
美索舒利50重量份、蔗糖20重量份、乳糖110重量份、羟丙甲基纤维素10重量份、羧甲基淀粉钠6重量份、十二烷基硫酸钠1重量份
制备方法：
(1)将上述处方量美索舒利溶于50ml乙醇中得到A液，将处方量的乳糖、羟丙甲基纤维素溶于120ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的十二烷基硫酸钠、蔗糖、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
实施例c7
处方：
美索舒利75重量份、甜菊苷15重量份、微晶纤维素120重量份、羟丙甲基纤维素12重量份、羧甲基淀粉钠8重量份、硬脂酸镁1.5重量份
制备方法：
(1)将上述处方量美索舒利溶于75ml丙酮中得到A液，将处方量的微晶纤维素、羟丙甲基纤维素溶于150ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、甜菊苷、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
溶出度实验：实验方法同实施例c1，美索舒利分散片的溶出度测定结果见图3。
实施例c8
处方：
美索舒利75重量份、阿司帕坦15重量份、微晶纤维素135重量份、聚维酮12重量份、羧甲基淀粉钠8重量份、硬脂酸镁1.5重量份
制备方法：
(1)将上述处方量美索舒利溶于75ml丙酮中得到A液，将处方量的微晶纤维素、聚维酮溶于150ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、阿司帕坦、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
实施例c9
处方：
美索舒利100重量份、阿司帕坦20重量份、乳糖70重量份、微晶纤维素80重量份、羟丙甲基纤维素15重量份、羧甲基淀粉钠5重量份、硬脂酸镁2重量份
制备方法：
(1)将上述处方量美索舒利溶于100ml乙醇中得到A液，将处方量的乳糖、微晶纤维素、羟丙甲基纤维素溶于150ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、阿司帕坦、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
溶出度实验：实验方法同实施例c1，美索舒利分散片的溶出度测定结果见图4。
实施例c10
处方：
美索舒利100重量份、阿司帕坦20重量份、微晶纤维素130重量份、羟丙甲基纤维素15重量份、羧甲基淀粉钠10重量份、微粉硅胶2重量份
制备方法：
(1)将上述处方量美索舒利溶于100ml丙酮中得到A液，将处方量的微晶纤维素、羟丙甲基纤维素溶于150ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的微粉硅胶、阿司帕坦、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
实施例c11
处方：
美索舒利100重量份、蔗糖20重量份、乳糖30重量份、微晶纤维素120重量份、羟丙甲基纤维素15重量份、羧甲基淀粉钠15重量份、硬脂酸镁2重量份
制备方法：
(1)将上述处方量美索舒利溶于100ml丙酮中得到A液，将处方量的乳糖、微晶纤维素、羟丙甲基纤维素溶于150ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、蔗糖、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
实施例c12
处方：
美索舒利100重量份、阿司帕坦20重量份、乳糖67.5重量份、微晶纤维素80重量份、羟丙甲基纤维素15重量份、交联聚维酮12重量份、硬脂酸镁2重量份
制备方法：
(1)将上述处方量美索舒利溶于100ml丙酮中得到A液，将处方量的乳糖、微晶纤维素、羟丙甲基纤维素溶于150ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、阿司帕坦、交联聚维酮混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
实施例c13
处方：
美索舒利125重量份、阿司帕坦20重量份、乳糖70重量份、微晶纤维素55重量份、羟丙甲基纤维素25重量份、羧甲基淀粉钠5重量份、硬脂酸镁3重量份
制备方法：
(1)将上述处方量美索舒利溶于125ml丙酮中得到A液，将处方量的乳糖、微晶纤维素、羟丙甲基纤维素溶于150ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、阿司帕坦、羧甲基淀粉钠混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
溶出度实验：实验方法同实施例c1，美索舒利分散片的溶出度测定结果见图5。
实施例c14
处方：
美索舒利125重量份、阿司帕坦20重量份、微晶纤维素150重量份、糊精30重量份、交联聚维酮20重量份、硬脂酸镁3重量份
制备方法：
(1)将上述处方量美索舒利溶于125ml丙酮中得到A液，将处方量的微晶纤维素、糊精溶于150ml纯化水中得到B液；
(2)一边搅拌一边将A液缓慢加入B液中，得混合的美索舒利混悬溶液；
(3)将混悬溶液先用均质机进行均质，再进行喷雾干燥，收集粉末；
(4)将粉末与处方量的硬脂酸镁、阿司帕坦、交联聚维酮混合均匀，得混合粉末，取混合粉末的样品，并进行含量测定，含量合格后，进行压片；
(5)将(4)中得到的混合粉末直接加入旋转压片机中，粉末直接压片、片硬度控制在5～7N，即得美索舒利分散片。
以下美索舒利缓释片的实施例d1-d17按照1000片处方量投料，以下实施例只是进行说明，并不限制发明范围。
实施例d1:
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 15g
微晶纤维素 25g
羟丙甲基纤维素K4M 100g
羧甲基淀粉钠 7.5g
硬脂酸镁 2.5g
本发明采用固体分散体的技术，通过湿法制粒工艺，再将压好的素片包薄膜衣，制备得到美索舒利缓释片，制备方法如下：
①将上述处方量美索舒利溶于50ml丙酮中得到A液，将处方量的羟丙基β环糊精溶于40ml纯化水中得到B液；
②一边搅拌一边将A液缓慢加入B液中，将溶液挥干后收集粉末；
③将粉末超细粉碎后与处方量的微晶纤维素和羟丙甲基纤维素K4M混合均匀；
④将③中的混合粉末加入湿法制粒机中，混合15分钟，将混合后的粉末于搅拌速度3r/s、切割速度10r/s条件下进行纯水制粒90s，制得的颗粒于60℃下干燥90分钟；
⑤干燥后的颗粒加入处方量的硬脂酸镁和羧甲基淀粉钠，混合均匀后压片，片硬度控制在5～8N；
⑥将压好的素片包薄膜衣。包衣液的配制方法：将包衣粉用纯化水分散，配制到15％固含量，搅拌60分钟即可。包衣的工艺参数为：雾化压力0.2MP(兆帕)，顶针压力0.2MP，包衣锅转速15r/s，进液速度3r/min，进风温度75℃，进风频率1100Hz，物料温度35～45℃，包衣增重2％～3％结束。
溶出度实验：
以中国药典2010年版二部附录XC第二法装置，照中国药典2010年版二部附录XD第一法测定制备获得的美索舒利缓释片的溶出度。以pH6.8的缓冲盐1000ml为溶剂，转速50转，在1、4、8、12、16、20、24小时取样，测定美索舒利缓释片的溶出度，结果见图6。
对比实施例d1
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 15g
微晶纤维素 25g
羟丙甲基纤维素K4M 100g
羧甲基淀粉钠 7.5g
硬脂酸镁 2.5g
对比实施例未采用固体分散体的技术，其通过湿法制粒工艺，再将压好的素片包薄膜衣，制备得到美索舒利缓释片，制备方法如下：
①将上述处方量美索舒利原料超细粉碎后与微晶纤维素及羟丙甲基纤维素K4M混合均匀；
②将上述混合均匀的粉末加入湿法制粒机中，混合15分钟，然后，于搅拌速度3r/s、切割速度10r/s下，纯水制粒90s，制得的颗粒于60℃下干燥90分钟；
③干燥后的颗粒加入处方量的羧甲基淀粉钠和硬脂酸镁，混合均匀后压片，片硬度控制在5～8N；
④将压好的素片包薄膜衣。包衣液的配制方法：将包衣粉用纯化水分散，配制到15％固含量，搅拌60分钟即可。包衣的工艺参数为：雾化压力0.2MP(兆帕)，顶针压力0.2MP，包衣锅转速15r/s，进液速度3r/min，进风温度75℃，进风频率1100Hz，物料温度35～45℃，包衣增重2％～3％结束。
溶出度实验：测定方法同实施例d1，测定结果见图6。
本发明实施例d1采用了固体分散体的技术来制备得到美索舒利缓释片，而对比实施例d1未采用固体分散体的技术制备得到美索舒利缓释片。通过本发明的实施例d1与对比实施例d1分别所得美索舒利缓释片，将二者的溶出度测定结果进行对比，结果表明，通过制备固体分散体的技术，可以明显提高美索舒利在缓释片中的整体溶出度，因此优选采用固体分散体的技术方法作为美索舒利缓释片的制备方法。
对比实施例d2
处方：
处方 处方量
美索舒利 100g
泊洛沙姆188 15g
微晶纤维素 25g
羟丙甲基纤维素K4M 100g
羧甲基淀粉钠 7.5g
硬脂酸镁 2.5g
与本发明所述实施例d1相比，对比实施例d2的处方中未采用增溶剂羟丙基β环糊精，而是采用泊洛沙姆188。
对比实施例d2也采用固体分散体的技术，通过湿法制粒工艺，再将压好的素片包薄膜衣，制备得到美索舒利缓释片，制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定结果见图7。
通过本发明的实施例d1与对比实施例d2分别所得美索舒利缓释片，将二者的溶出度测定结果进行对比，结果表明，通过采用增溶剂羟丙基β环糊精，可以明显提高美索舒利在缓释片中的溶出度。是否采取羟丙基β环糊精包合，将直接影响到药物释放的终浓度，因此处方中采取羟丙基β环糊精包合可以有效的提高美索舒利的溶出度。
实施例d2
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 20g
微晶纤维素 38.5g
羟丙甲基纤维素K4M 80g
羧甲基淀粉钠 9g
硬脂酸镁 1.5g
制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定溶出度结果见图8。
实施例d3
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 17.5g
微晶纤维素 5g
羟丙甲基纤维素K4M 120g
羧甲基淀粉钠 7.5g
硬脂酸镁 2g
制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定结果见图9。
实施例d4
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 15g
微晶纤维素 25g
羟丙甲基纤维素K15M 100g
羧甲基淀粉钠 7.5g
硬脂酸镁 2.5g
制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定结果见图10。
实施例d5
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 18g
微晶纤维素 25g
羟丙甲基纤维素K100M 100g
羧甲基淀粉钠 7.5g
硬脂酸镁 2g
制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定结果见图11。
实施例d6
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 15g
微晶纤维素 25g
羟丙甲基纤维素E50 100g
羧甲基淀粉钠 7.5g
硬脂酸镁 2.5g
制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定结果见图12。
实施例d7
处方：
处方 处方量
美索舒利 25g
羟丙基β环糊精 15g
微晶纤维素 75g
羟丙甲基纤维素K4M 127.5g
羧甲基淀粉钠 5g
硬脂酸镁 2.5g
制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定结果见图13。
实施例d8
处方：
处方 处方量
美索舒利 50g
羟丙基β环糊精 15g
微晶纤维素 65g
羟丙甲基纤维素K4M 110g
羧甲基淀粉钠 7.5g
硬脂酸镁 2g
制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定结果见图14。
实施例d9
处方：
处方 处方量
美索舒利 75g
羟丙基β环糊精 15g
微晶纤维素 50g
羟丙甲基纤维素K4M 100g
羧甲基淀粉钠 7.5g
硬脂酸镁 2.5g
制备方法同实施例d1。
实施例d10
处方：
处方 处方量
美索舒利 125g
羟丙基β环糊精 20g
微晶纤维素 7.5g
羟丙甲基纤维素K4M 90g
羧甲基淀粉钠 5g
硬脂酸镁 2.5g
制备方法同实施例d1。
实施例d11:
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 16g
乳糖 25g
羟丙甲基纤维素K15M 100g
交联聚维酮 7.5g
微粉硅胶 2.5g
制备方法同实施例d1。
实施例d12:
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 15g
甘露醇 25g
羟丙甲基纤维素K100M 100g
低取代羟丙基纤维素 7.5g
十二烷基硫酸钠 1.5g
制备方法同实施例d1。
实施例d13:
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 15g
淀粉 25g
羟丙甲基纤维素E50 100g
交联羧甲基纤维素钠 7.5g
富马酸钠 2.5g
制备方法同实施例d1。
实施例d14:
处方：
处方 处方量
美索舒利 100g
羟丙基β环糊精 15g
微晶纤维素 25g
羟丙甲基纤维素E4M 100g
羧甲基淀粉钠 7.5g
硬脂酸镁 2g
制备方法同实施例d1。
溶出度实验：测定方法同实施例d1，测定结果见图15。
通过图6-图15的结果可以看出，骨架缓释材料的选择不同对药物释放的影响非常大，通过溶出行为的比较，优选了羟丙甲基纤维素K4M为骨架缓释材料。溶出度溶出度
实施例d15：本发明所述美索舒利缓释片的药物稳定性试验
1、10天影响因素实验：将实施例d1中制备获得的100mg规格的美索舒利缓释片袒露于培养皿中，分别在高温(60℃)、高湿(RH92.5％，25℃)、强光(4500lx±500lx)条件下放置10天，于第0、5、10天取样，观察制剂外观、含量、溶出度、有关物质、失重率等项目，并与考察前样品的检查数据进行比较，10天影响因素实验结果如下表 d1所示。
表d1
Figure PCTCN2014085783-appb-000037
上表d1的10天影响因素试验结果表明，美索舒利缓释片在高温和光照条件下是稳定的，而高湿条件下，缓释片有吸潮的现象，溶出度有所降低，因此在成品包装时应该考虑防潮问题，在密封干燥条件下储存。
2、稳定性试验：加速6个月试验：
发明人对美索舒利缓释片进行了包装材料的研究，选包装材料为PVC泡罩+双面复合铝膜袋。将包装好的美索舒利缓释片在温度为40℃±2℃、相对湿度为75％±5％试验条件下放置6个月，进行了加速6个月的考察，分别于第1、2、3、6月取样，进行了稳定性试验各考察指标的检测，详细结果见下表d2。
表d2：
Figure PCTCN2014085783-appb-000038
由表d2的加速6个月的稳定性实验数据显示，本发明的美索舒利缓释片在主要指标上并没有明显变化，表明本发明的美索舒利缓释片产品质量是稳定可靠的。PVC泡罩加双面复合铝膜袋的包装形式，是能够满足产品需求的。
实施例d16：对本发明所述美索舒利缓释片的处方筛选研究
以美索舒利100mg片为例进行处方筛选研究，美索舒利缓释片处方筛选表，见表d3，筛选结果见表d4。
表d3：
Figure PCTCN2014085783-appb-000039
表d4：
Figure PCTCN2014085783-appb-000040
处方筛选以缓释片溶出释放曲线为依据进行评判，从以上6个处方的溶出度、达峰时间、释放速率测定结果可以得出，是否采取羟丙基β环糊精包合，将直接影响到药物释放的终浓度，因此采取羟丙基β环糊精包合可以有效的提高美索舒利的溶解度。另外羟丙甲基纤维素的用量将直接影响到缓释片在介质中的释放速率，因此根据需要可以通过调节羟丙甲基纤维素的用量来得到特定的释放行为，美索舒利与羟丙甲基纤维素的重量配比在1:1符合处方需求。微晶纤维素作为填充剂，在具体的释放行为调节上起的作用较小。总体来说，处方d6的组成是比较优的，能够满足对美索舒利缓释片的需求。且主药美索舒利与骨架缓释材料羟丙甲基纤维素的重量配比在1:1的时候释放行为最理想，在用羟丙基β环糊精对美索舒利进行包合处理的情况下，溶出较优。
实施例d17
以实施例d1中制备获得的美索舒利缓释片为研究对象，对比了美索舒利缓释片与美索舒利片(通过本发明实施例a9的处方和工艺制备)在Beagle犬体内的药代动力学行为，美索舒利缓释片与美索舒利片的药代动力学实验结果见图16。
由图16的结果可以看出，美索舒利缓释片的AUC0-∞比美索舒利普通片要大，且半衰期明显延长，达到了最初设计缓释片的目的，提供了平稳有效的血药浓度，避免或减小了血药峰谷现象的出现，有利于提高药物使用的安全性，减少服药次数，提高患者的顺应性。
以下美索舒利颗粒剂的e1-e16，为按照1000袋处方量投料，以下实施例只是进行说明，并不限制发明范围。
实施例e1：美索舒利颗粒剂的处方筛选及制备工艺优化
本实施例中，以50mg美索舒利颗粒剂为例(即规格：50mg)，对美索舒利颗粒剂的处方和制备工艺进行优化，具体如下：
初步从颗粒的口感、混悬性、以及颗粒的溶出度等方面考虑，涉及美索舒利颗粒剂的处方，具体处方见表e1，然后按照表e1所示的处方和下述的制备方法制备美索舒利颗粒剂，然后按照常规方法观察并检测制备获得的美索舒利颗粒剂的性状、口感和溶出度，其中，口感通过志愿者口服尝试。溶出度测定按照中国药典2010年版规定的方法，在pH8.8磷酸盐缓冲溶液中进行，所述pH8.8的磷酸盐缓冲液是通过将氢氧化钠和磷酸二氢钾加水溶解，并用磷酸调pH至8.8而获得的。
试验结果见表e2。
美索舒利颗粒剂的制备工艺如下：
1)将美索舒利、羟丙基β-环糊精、甘露醇、微晶纤维素、阿斯巴甜和聚维酮分别干燥，并将主药(美索舒利)、辅料分别粉碎，然后，主药过200目筛，辅料过80目筛备用；
2)准确称取处方量的美索舒利、羟丙基β-环糊精、甘露醇、微晶纤维素、阿斯巴甜和聚维酮混合均匀，加75％乙醇溶液制软材，将软材过16目筛制成湿颗粒，40℃干燥，过16目筛整粒，测定颗粒主药含量，确定装量，测定重量差异，包装即得美索舒利颗粒剂。
表e1 处方筛选表
主药与辅料 处方e1 处方e2 处方e3 处方e4 处方e5 处方e6
美索舒利 50 50 50 50 50 50
羟丙基β-环糊精 / / 250 250 300 250
甘露醇 500 500 400 400 500 500
微晶纤维素 100 80 60 35 20 35
阿斯巴甜 / 5 10 15 20 25
聚维酮 40 60 80 100 100 100
75％乙醇溶液 100 100 100 100 100 100
注：“/”表示处方中不含有相应组分
表e2 处方筛选结果
Figure PCTCN2014085783-appb-000041
由上表e2的处方筛选结果综合来看，处方e4的颗粒的口感、混悬性、溶出度均最好。当且美索舒利：羟丙基β-环糊精：甘露醇的重量配比在1：5：8时，其溶出的效果最好。但是，美索舒利颗粒剂的溶出度还需要更进一步的提高，增加其在水中的溶解度。
发明人创造性的在原辅料的前处理上进行改进和优化，将美索舒利、与增溶剂、填充剂辅料混合，并先后进行两次微粉化处理，再利用湿法制粒进行颗粒剂的制备，具体制备工艺如下：
1)将美索舒利、羟丙基β-环糊精、甘露醇、微晶纤维素、阿斯巴甜、聚维酮，均分别干燥，
2)将处方量的美索舒利、羟丙基β-环糊精混合，微粉化处理1次，再加入甘露醇到上述微粉化处理的颗粒中混合，继续微粉化至粒径为1-100微米的颗粒，
3)将微晶纤维素、阿斯巴甜、聚维酮过80目筛备用；
4)将上述步骤2和步骤3中的原辅料混合均匀，加75％乙醇溶液制软材，将软材过16目筛制成湿颗粒，40℃干燥，过16目筛整粒，测定颗粒主药含量，确定装量，测定重量差异，包装成颗粒剂即得。
进一步的，发明人在处方e4的基础上，将美索舒利、羟丙基β-环糊精、甘露醇混合做微粉化处理，进一步筛选处方e7-处方e11，处方e7-处方e11见表e3，按照处方e7-处方e11制备获得的美索舒利颗粒剂的溶出度测定结果见表e4。
表e3 进一步的处方筛选表
Figure PCTCN2014085783-appb-000042
其中，处方e7中，美索舒利、羟丙基β-环糊精、甘露醇经2次微粉化处理后，测定的粒径为1-10微米；
处方e8中，美索舒利、羟丙基β-环糊精、甘露醇经2次微粉化处理后，测定的粒径为10-30微米；
处方e9中，美索舒利、羟丙基β-环糊精、甘露醇经2次微粉化处理后，测定的粒径为30-60微米；
处方e10中，美索舒利、羟丙基β-环糊精、甘露醇经2次微粉化处理后，测定的粒径为60-80微米；
处方e11中，美索舒利、羟丙基β-环糊精、甘露醇经2次微粉化处理后，测定的粒径为80-100微米。
表f4
指标 处方e7 处方e8 处方e9 处方e10 处方e11 处方e4
溶出度 88.2％ 89.5％ 92.5％ 90.8％ 90.1％ 77.7％
表e4可以看出，按照处方e7-处方e11制得的美索舒利颗粒剂的溶出度效果，均优于用一般前处理得到的美索舒利颗粒剂，溶出度达到药典规定要求。特别的，当美索舒利、羟丙基β-环糊精和甘露醇混合微粉化在30-60微米，且美索舒利：羟丙基β-环糊精：甘露醇的重量配比在1：5：8时，其溶出的效果最好。
另外，发明人对处方中辅料对主药的30天影响因素实验进行了实验，以考察处方中辅料与主药的药物相容性和对药物的稳定性影响，具体如下：
将按照处方e4制备获得的美索舒利颗粒剂暴露于培养皿中，分别于高温(60℃)、高湿(相对湿度92.5％)、光照条件下放置30，并于0天、5天、10天、和30天时取样，观察美索舒利颗粒剂的外观，并利用高效液相色谱法测定美索舒利颗粒剂中有关物质和含量，实验测定结果见表e5。
表e5 处方中辅料对主药的30天影响因素实验结果
试验条件 外观 有关物质(％) 含量(标示量％)
0天 黄色 0.26 99.7
光照5天 黄色 0.28 99.8
光照10天 黄色 0.29 98.9
光照30天 黄色 0.31 99.5
60℃5天 黄色 0.30 99.4
60℃10天 黄色 0.36 99.3
60℃30天 黄色 0.39 98.7
相对湿度92.5％5天 黄色 0.27 99.6
相对湿度92.5％10天 黄色 0.30 99.1
相对湿度92.5％30天 黄色 0.36 98.5
上述表e5中，有关物质是指在合成过程中产生的中间体、副产物等或储藏运输过程中所降解的产物。标示量是指主药理论上的投料量。含量是指主药占标示量的重量百分比。
由表e5的结果可知，处方中各辅料与主药的药物相容性良好，辅料对主药稳定性无影响。
发明人用同样的方法，研究了规格为25mg、75mg、100mg、125mg等不同规格的处方和制备工艺，都得到了与上面规格为50mg的处方和工艺相同的技术效果。
实施例e2
处方：
美索舒利25重量份、羟丙基β-环糊精125重量份、甘露醇200重量份、微晶纤维素17.5重量份、阿斯巴甜7.5重量份、聚维酮50重量份、75％乙醇适量。
制备工艺如下：
1)将美索舒利、羟丙基β-环糊精、甘露醇、微晶纤维素、阿斯巴甜、聚维酮，均分别干燥，
2)将处方量的美索舒利、羟丙基β-环糊精混合，微粉化处理1次，再加入甘露醇到上述微粉化处理的颗粒中混合，继续微粉化至粒径为10微米(μm)的颗粒，
3)将微晶纤维素、阿斯巴甜、聚维酮过80目筛备用；
4)将上述步骤2和步骤3中的原辅料混合均匀，加75％乙醇溶液制软材，将软材过16目筛制成湿颗粒，40℃干燥，过16目筛整粒，测定颗粒主药含量，确定装量，测定重量差异，包装成颗粒剂即得。
按照上述处方及制备方法，制备三批美索舒利颗粒剂样品，批号分别为130501、130502、130503，并按照常规方法，对所得到的美索舒利颗粒剂样品进行了加速6个月稳定性试验研究，研究数据见表e6。
表e6 三批美索舒利颗粒剂中试样品的加速6个月稳定性数据
Figure PCTCN2014085783-appb-000043
Figure PCTCN2014085783-appb-000044
表e6的结果表明，本发明的美索舒利颗粒剂经加速6个月稳定性试验，质量稳定。
实施例e3
处方：
美索舒利25重量份、羟丙基β-环糊精25重量份、甘露醇125重量份、微晶纤维素15重量份、阿斯巴甜10重量份、聚维酮25重量份、75％乙醇适量。
制备工艺如下：
1)将美索舒利、羟丙基β-环糊精、甘露醇、微晶纤维素、阿斯巴甜、聚维酮，均分别干燥，
2)将处方量的美索舒利、羟丙基β-环糊精混合，微粉化处理1次，再加入甘露醇到上述微粉化处理的颗粒中混合，继续微粉化至粒径为50微米(μm)的颗粒，
3)将微晶纤维素、阿斯巴甜、聚维酮过80目筛备用；
4)将上述步骤2和步骤3中的原辅料混合均匀，加75％乙醇溶液制软材，将软材过16目筛制成湿颗粒，40℃干燥，过16目筛整粒，测定颗粒主药含量，确定装量，测定重量差异，包装成颗粒剂即得。
实施例e4
处方：
美索舒利25重量份、羟丙基β-环糊精25重量份、甘露醇400重量份、微晶纤维素17.5重量份、阿斯巴甜5重量份、聚维酮50重量份、75％乙醇适量。
制备工艺如下：
1)将美索舒利、羟丙基β-环糊精、甘露醇、微晶纤维素、阿斯巴甜、聚维酮，均分别干燥，
2)将处方量的美索舒利、羟丙基β-环糊精混合，微粉化处理1次，再加入甘露醇到上述微粉化处理的颗粒中混合，继续微粉化至粒径为100微米(μm)的颗粒，
3)将微晶纤维素、阿斯巴甜、聚维酮过80目筛备用；
4)将上述步骤2和步骤3中的原辅料混合均匀，加75％乙醇溶液制软材，将软材过16目筛制成湿颗粒，40℃干燥，过16目筛整粒，测定颗粒主药含量，确定装量，测定重量差异，包装成颗粒剂即得。
实施例e5
处方：
美索舒利50重量份、羟丙基β-环糊精250重量份、甘露醇400重量份、微晶纤维素35重量份、阿斯巴甜15重量份、聚维酮100重量份、75％乙醇适量。
制备工艺同实施例e2。
实施例e6
处方：
美索舒利50重量份、羟丙基β-环糊精50重量份、甘露醇400重量份、微晶纤维素35重量份、阿斯巴甜15重量份、聚维酮50重量份、75％乙醇适量。
制备工艺同实施例e3。
实施例e7
处方：
美索舒利50重量份、羟丙基β-环糊精125重量份、甘露醇500重量份、微晶纤维素35重量份、阿斯巴甜15重量份、聚维酮100重量份、75％乙醇适量。
制备工艺同实施例e4。
实施例e8
处方：
美索舒利75重量份、羟丙基β-环糊精375重量份、甘露醇600重量份、微晶纤维素52.5重量份、阿斯巴甜21.5重量份、聚维酮150重量份、75％乙醇适量。
制备工艺同实施例e2。
实施例e9
处方：
美索舒利75重量份、羟丙基β-环糊精75重量份、甘露醇600重量份、微晶纤维素60重量份、阿斯巴甜25重量份、聚维酮100重量份、75％乙醇适量。
制备工艺同实施例e3。
实施例e10
处方：
美索舒利75重量份、羟丙基β-环糊精75重量份、甘露醇450重量份、微晶纤维素50重量份、阿斯巴甜25重量份、聚维酮150重量份、75％乙醇适量。
制备工艺同实施例e4。
实施例e11
处方：
美索舒利100重量份、羟丙基β-环糊精500重量份、甘露醇400重量份、微晶纤维素70重量份、阿斯巴甜30重量份、聚维酮200重量份、75％乙醇适量。
制备工艺同实施例e2。
实施例e12
处方：
美索舒利100重量份、羟丙基β-环糊精100重量份、甘露醇300重量份、微晶纤维素60重量份、阿斯巴甜30重量份、聚维酮150重量份、75％乙醇适量。
制备工艺同实施例e3。
实施例e13
处方：
美索舒利100重量份、羟丙基β-环糊精100重量份、甘露醇600重量份、微晶纤维素50重量份、阿斯巴甜40重量份、聚维酮100重量份、75％乙醇适量。
制备工艺同实施例e4。
实施例e14
处方：
美索舒利125重量份、羟丙基β-环糊精375重量份、甘露醇600重量份、微晶纤维素50重量份、阿斯巴甜20重量份、聚维酮200重量份、75％乙醇适量。
制备工艺同实施例e2。
实施例e15
处方：
美索舒利125重量份、羟丙基β-环糊精250重量份、甘露醇500重量份、微晶纤维素75重量份、阿斯巴甜12.5重量份、聚维酮100重量份、75％乙醇适量。
制备工艺同实施例e3。
实施例e16
处方：
美索舒利125重量份、羟丙基β-环糊精250重量份、甘露醇375重量份、微晶纤维素50重量份、阿斯巴甜25重量份、聚维酮150重量份、75％乙醇适量
制备工艺同实施例e4。
发明人用与实施例e2中相同的方法，对实施例e3-实施例e16所得的美索舒利颗粒剂进行了加速6个月的稳定性试验，结果表明，各处方所得的药品稳定性好，所得的美索舒利颗粒剂质量稳定。
以下美索舒利胶囊的实施例f1-f12，为按照1000粒处方量投料，以下实施例只是进行说明，并不限制发明范围。
实施例f1：美索舒利胶囊的处方研究
由于主药美索舒利几乎不溶于水，且主药量也较大，因此，处方工艺的难点在于提高 本品的溶出度。在本实施例中，对规格为50mg/粒的美索舒利胶囊的处方进行了研究，具体而言，由于美索舒利原料药水溶性及流动性均差，考虑加入水溶性辅料及崩解剂促进溶出，设计了9个处方，见表f1。
表f1 不同的处方设计
Figure PCTCN2014085783-appb-000045
注：在粘合剂的配制上，羟丙甲纤维素需加纯化水配制成4％的羟丙甲纤维素水溶液(g/g)，聚维酮K30需加纯化水配制成8％的聚维酮K30水溶液(g/g)，“-”表示不含有相应处方。
制备方法(湿法制粒)：
按表f1中的处方，采用湿法制粒工艺，分别制备样品，具体如下：
(1)原辅料前处理：将主药(美索舒利)、各辅料分别粉碎后，主药过60目筛，辅料过80目筛，备用；
(2)配粘合剂：
当处方中的粘合剂选择聚维酮K30时，称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液Ⅰ，备用；
当处方中的粘合剂选择羟丙甲纤维素时，称取4克羟丙甲纤维素于烧杯中，加纯化水96 克，搅拌至澄清，得4％羟丙甲纤维素水溶液Ⅰ，备用；
(3)混合：称取处方量的主药、填充剂混合均匀后，再加入崩解剂混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
溶出度测定：
按中国药典2010版溶出度项下的测定方法，测定上述9个处方在溶出介质中45分钟的溶出度，其中溶出介质为磷酸盐缓冲液(氢氧化钠2.3g，磷酸二氢钾7.65g，加水使溶解为1000ml，用磷酸调pH至8.8)，溶出度测定结果见表f2。
表f2 各处方胶囊的溶出度对比
处方 f1 f2 f3 f4 f5 f6 f7 f8 f9
溶出度(％) 80.5 71.0 70.7 80.6 71.5 69.1 72.2 80.0 71.2
从溶出结果看，所设计的9个处方在溶出介质中45分钟的溶出度显示，较优的处方为处方f1、处方f4、处方f8。由于美索舒利水溶性差，而羟丙甲纤维素有阻溶作用，可能会在样品留样期间影响溶出度，加之其在水中完全溶胀所需时间较长，不利于工业化生产，因此不优选其作为粘合剂。
而微晶纤维素不仅能作为填充剂，而且具备崩解剂的性能，选取微晶纤维素作为填充剂可达到好的溶出效果。故本研究确定以处方f1为基础，进一步考察筛选填充剂的比例、粘合剂的浓度，以及改进崩解剂的添加方式，对处方和制剂工艺进行进一步优化。
实施例f2：美索舒利胶囊的处方工艺优化
本研究根据中国药典2010版对胶囊的剂型要求，参照CDE颁布的《化学药物制剂研究基本技术指导原则》，结合胶囊剂的特点，以溶出度等为考察指标，对本品处方所使用辅料的种类和用量进行了进一步的筛选。
(1)填充剂的筛选
调整乳糖和微晶纤维素的比例和用量，考察稀释剂(在本文中，“填充剂”和“稀释剂”可以互换使用)不同比例及用量对胶囊成形性和溶出度的影响，具体处方和结果如下：
本研究采用乳糖和微晶纤维素的组合为稀释剂，乳糖和微晶纤维素不同比例的处方见表f3，表f3所示为制备1000粒美索舒利胶囊的处方量。按照表f3所示处方及上述实施例f1中所述的制备方法，制备美索舒利胶囊。其中处方f6-处方f10中，粘合剂的配制方法为：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液。
测定制备获得的美索舒利胶囊的溶出度，以便于筛选填充剂。溶出度测定结果见表f3。
表f3 填充剂的筛选处方及测定结果
Figure PCTCN2014085783-appb-000046
由表f3的结果可以看出，上述5个处方中，处方f12由于缺少了微晶纤维素，崩解性能稍差，溶出度低，而处方f1、f10、f11、f13的崩解和溶出度均较好，其中处方f11所得的溶出度最好，故选择乳糖和微晶纤维素的质量比为(0.5～5)：1，其中乳糖和微晶纤维素的质量比2:1为最佳比例。
(2)粘合剂的筛选
选取聚维酮K30作为粘合剂，并配制不同浓度的水溶液对其粘合效果进行了比较研究，具体如下：
按照表f4所示的处方以及实施例f1中的制备方法，制备获得美索舒利胶囊。
其中处方f14中，粘合剂的配制方法为：称取4克聚维酮K30于烧杯中，加纯化水96克，搅拌至澄清，得4％聚维酮K30水溶液；其中处方f15中，粘合剂的配制方法为：称取8克聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，得8％聚维酮K30水溶液；其中处方f16中，粘合剂的配制方法为：称取10克聚维酮K30于烧杯中，加纯化水90克，搅拌至澄清，得10％聚维酮K30水溶液；其中处方f17中，粘合剂的配制方法为：称取15克聚维酮K30于烧杯中，加纯化水85克，搅拌至澄清，得15％聚维酮K30水溶液。
制备过程中观察美索舒利制软材情况、以及美索舒利干颗粒情况，并测定制备获得的美索舒利胶囊的溶出度，处方和测定结果见表f4，其中，表f4所示处方为制备1000粒美索舒利胶囊的处方量。
表f4 粘合剂的筛选
Figure PCTCN2014085783-appb-000047
从表f4的结果可以看出，在处方f14中，当粘合剂浓度为4％时，软材松散不易起粘，由于得到的干颗粒细粉较多，会导致胶囊灌装时得到的胶囊剂含量均匀性不合格；在处方f17中当粘合剂用量达到25％时，所制得软材较硬，不易过筛，而且延长了崩解时间；而在处方f15、处方f16中，当粘合剂的浓度为10％、或15％时，所制得的软材干湿程度适中，易过筛且得到的颗粒圆整，流动性好，易于进行胶囊灌装。而且采用10％比例的粘合剂时，所得到的美索舒利胶囊的溶出度优于采用10％比例所得到的美索舒利胶囊。
(3)崩解剂的筛选
在本实施例中，考察了崩解剂的用量以及崩解剂的添加方式对美索舒利胶囊的影响，具体如下：
按照表f5所示的配方以及实施例f1中的制备方法，制备获得美索舒利胶囊。
需要说明的是，在本实施例中，崩解剂的添加方式为两种：内加法和外加法。
内加法是指在混合步骤时加入崩解剂，外加法是指总混步骤中，在加入润滑剂之前，先将干颗粒和崩解剂混合均匀。
当崩解剂进行内外加法时，按表f5中的处方，采用湿法制粒工艺，分别制备样品，制 备方法如下：
(1)原辅料前处理：将主药(美索舒利)、各辅料分别粉碎后，主药过60目筛，辅料过80目筛，备用；
(2)配粘合剂：称取10克聚维酮K30于烧杯中，加纯化水90克，搅拌至澄清，得10％聚维酮K30水溶液Ⅰ，备用；
(3)混合：称取处方量的主药、处方量的填充剂混合均匀后，再加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
然后测定制备获得的美索舒利胶囊的溶出度，测定结果见表f5。其中，表f5所示处方f18-处方f22的配方为制备1000粒美索舒利胶囊的处方量。
表f5 崩解剂的处方筛选
Figure PCTCN2014085783-appb-000048
从表f5的结果可以看出，处方f18、处方f19和处方f20溶出度结果差异不大，说明减少一定量的崩解剂仍可以保持较好的溶出，同时还可以节约成本。处方f21和处方f22的崩解剂均采用内外加法，溶出度明显提高。外加崩解剂可以促进颗粒的崩解，内加崩解剂则能加快颗粒的分散，有利于提高溶出度。从上述结果可以看出，采用崩解剂内外加法的工艺，相对于崩解剂只采用内加法的工艺，其溶出度明显提高，故确定崩解剂的用量及添加方式为：崩解剂的内加量为崩解剂处方量的1/2，外加量为崩解剂处方量的另1/2。因此，暂定处方为处方f21。
实施例f3：对美索舒利原料药粒径考察
按照如下步骤考察原料药的粒径对美索舒利胶囊的影响，具体如下：
以实施例f2中的处方f21为基础，对本发明的制备工艺进一步优化，以便进一步提高本发明所述美索舒利胶囊的溶出度。
具体地，按照处方f21，分别制备两组(A1组和1B组)美索舒利胶囊，制备A1组美索舒利胶囊的方法如下所述，B1组美索舒利胶囊的制备方法与A1组美索舒利胶囊的制备方法区别在于，主药美索舒利和辅料填充剂混合未进行微粉化处理。
A1组美索舒利胶囊的制备方法如下：
(1)原辅料前处理：将主药(美索舒利)和辅料填充剂混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取10克聚维酮K30于烧杯中，加纯化水90克，搅拌至澄清，得10％聚维酮K30水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃±5℃下干燥约2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮，再加入处方量硬脂酸镁，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
然后测定制备获得的两组美索舒利胶囊的溶出度，测定结果见表f6。
表f6
Figure PCTCN2014085783-appb-000049
由表f6的结果可知，先将美索舒利和乳糖混合进行微粉化，制得的美索舒利胶囊的溶出度可以显著得到改善。
实施例f4：美索舒利胶囊的制备
处方：见表f7
表f7
Figure PCTCN2014085783-appb-000050
制备工艺：
(1)原辅料前处理：将主药(美索舒利)50克和辅料填充剂乳糖80克、微晶纤维素40克混合进行微粉化(粒径在5微米至30微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取10克粘合剂聚维酮K30于烧杯中，加纯化水90克，搅拌至澄清，得10％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮6克混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮6克，再加入处方量硬脂酸镁2.5克，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
实施例f5：美索舒利胶囊的制备
处方：见表f8
表f8
Figure PCTCN2014085783-appb-000051
制备工艺：
(1)原辅料前处理：将主药(美索舒利)50克和辅料填充剂乳糖60克、微晶纤维素60克混合进行微粉化(粒径在30微米至70微米)、其余各辅料分别粉碎后过60目筛，备用；
(2)配粘合剂：称取12克粘合剂聚维酮K30于烧杯中，加纯化水88克，搅拌至澄清，制备得12％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮8克混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于55℃下干燥4h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮8克，再加入处方量硬脂酸镁2克，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
实施例f6：美索舒利胶囊的制备
处方：见表f9
表f9
Figure PCTCN2014085783-appb-000052
制备工艺：
(1)原辅料前处理：将主药(美索舒利)50克和辅料填充剂乳糖113克、微晶纤维素57克混合进行微粉化(粒径在70微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取8克粘合剂聚维酮K30于烧杯中，加纯化水92克，搅拌至澄清，制备得8％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮6克混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于65℃下干燥1h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮6克，再加入处方量硬脂酸镁2.4克，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
实施例f7：美索舒利胶囊的制备
处方：见表f10
表f10
Figure PCTCN2014085783-appb-000053
Figure PCTCN2014085783-appb-000054
制备工艺：
(1)原辅料前处理：将主药(美索舒利)50克和辅料填充剂乳糖100克、微晶纤维素100克混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取20克粘合剂聚维酮K30于烧杯中，加纯化水80克，搅拌至澄清，制备得20％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮6克混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于55℃下干燥3h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮6克，再加入处方量硬脂酸镁2.5克，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
实施例f8：美索舒利胶囊的制备
处方：见表f11
表f11
Figure PCTCN2014085783-appb-000055
Figure PCTCN2014085783-appb-000056
制备工艺：
(1)原辅料前处理：将主药(美索舒利)100克和辅料填充剂乳糖100克、微晶纤维素100克混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取15克粘合剂聚维酮K30于烧杯中，加纯化水85克，搅拌至澄清，制备得15％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮6克混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于55℃下干燥2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮6克，再加入处方量硬脂酸镁2.5克，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
实施例f9：美索舒利胶囊的制备
处方：见表f12
表f12
Figure PCTCN2014085783-appb-000057
制备工艺：
(1)原辅料前处理：将主药(美索舒利)100克和辅料填充剂乳糖100克、微晶纤维素100克混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取7克粘合剂聚维酮K30于烧杯中，加纯化水93克，搅拌至澄清，制备得7％聚维酮K30的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联聚维酮6克混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥2h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联聚维酮6克，再加入处方量硬脂酸镁2.5克，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
实施例f10：美索舒利胶囊的制备
处方：见表f13
表f13
组成 原辅料 处方量(g)
主药 美索舒利 25
填充剂 玉米淀粉 150
粘合剂 羟丙甲纤维素 5
崩解剂(内加) 交联羧甲基纤维素钠 2.5
崩解剂(外加) 交联羧甲基纤维素钠 2.5
润滑剂 硬脂酸镁 0.8
制备工艺：
(1)原辅料前处理：将主药(美索舒利)25克和辅料填充剂玉米淀粉150克混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取5克粘合剂羟丙甲纤维素于烧杯中，加纯化水45克，搅拌至澄清，制备得5％羟丙甲纤维素的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂交联羧甲基纤维素 钠2.5克混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥1h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂交联羧甲基纤维素钠2.5克，再加入处方量硬脂酸镁0.8克，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
实施例f11：美索舒利胶囊的制备
处方：见表f14
表f14
组成 原辅料 处方量(g)
主药 美索舒利 125
填充剂 甘露醇 50
粘合剂 甲基纤维素 10
崩解剂(内加) 羧甲基淀粉钠 10
崩解剂(外加) 羧甲基淀粉钠 10
润滑剂 硬脂酸镁 4
制备工艺：
(1)原辅料前处理：将主药(美索舒利)125克和辅料填充剂甘露醇50克混合进行微粉化(粒径在5微米至100微米)、其余各辅料分别粉碎后过80目筛，备用；
(2)配粘合剂：称取10克粘合剂甲基纤维素于烧杯中，加纯化水90克，搅拌至澄清，制备得10％甲基纤维素的粘合剂水溶液Ⅰ，备用；
(3)混合：将美索舒利和填充剂混合均匀后，加入需內加的崩解剂羧甲基淀粉钠10克混合均匀，得混合物Ⅱ；
(4)制软材及制粒：将处方量的粘合剂水溶液Ⅰ加入混合物Ⅱ中，制成软材，将所得软材过18目不锈钢筛制粒，得湿颗粒；
(5)干燥：将步骤(4)中所得到的药物湿颗粒于60℃下干燥1h；
(6)整粒：将经过干燥的药物颗粒过18目不锈钢筛整粒，得干颗粒；
(7)总混：干颗粒中加入处方量的需外加的崩解剂羧甲基淀粉钠10克，再加入处方量硬脂酸镁4克，混合均匀，得总混颗粒；
(8)胶囊灌装：将所述总混颗粒含量检测合格的药物混合物样品进行胶囊灌装。
实施例f12、质量评价
首先，检查实施例f4-实施例f11所得到的美索舒利胶囊的外观性状、重量差异，并测定实施例f4-实施例f11所得美索舒利胶囊的溶出度，测定结果如表f15：
表f15：
Figure PCTCN2014085783-appb-000058
从表f15的结果显示，各批样品的性状、重量差异、溶出度均符合要求，且溶出度较高。
影响因素实验：
接下来，对上述实施例f6制备获得美索舒利胶囊进行影响因素实验，具体如下：
将实施例f6制备获得的美索舒利胶囊袒露于培养皿中，分别在高温(60℃)、高湿(RH92.5％，25℃)、强光(4500lx±500lx)条件下放置10天，于第5、10天取样，观察制剂外观、含量、溶出度、有关物质，并与考察前样品的检查数据进行比较，检测结果见表f16。
表f16 美索舒利胶囊影响因素试验结果
Figure PCTCN2014085783-appb-000059
Figure PCTCN2014085783-appb-000060
影响因素试验结果表明：胶囊在高温、高湿、光照下放置10天，含量、有关物质无显著性变化，质量稳定，表明，本发明所述的处方可行，本发明所述的制备工艺合理、重现性好、本发明所得的美索舒利胶囊质量稳定性好。
以下美索舒利缓释胶囊的实施例g1-g8按照1000片处方量投料，以下实施例只是进行说明，并不限制发明范围。
实施例g1
(1)美索舒利载药丸芯的制备
处方：
载药丸芯的处方组成 重量份
美索舒利 100
交联聚维酮 10
微晶纤维素 100
羟丙甲基纤维素 50
制备方法：
将美索舒利原料超细粉碎(即微粉化处理)后与上述处方量中的其余辅料等量递加混合均匀，用4％羟丙甲基纤维素纯化水溶液作为粘合剂将上述混合好的粉末制成软材，采用挤出滚圆的方法制成载药丸芯。挤出机采用单螺杆径向屏式挤出，筛板孔径为0.8mm，螺杆转速为40r/min。挤出物在500r/min转速下在离心造粒机中滚成美索舒利载药丸芯，并将制得的载药丸芯于40℃下干燥，即得。
(2)包衣液的配制
①隔离层包衣液
隔离层包衣液的组成 重量份
聚维酮K30 18.5
滑石粉 3
无水乙醇 115
配制方法：将聚维酮K30加入无水乙醇中，搅拌溶胀，待聚维酮K30完全溶胀后，再将滑石粉加入溶液中，搅拌使其均匀分散，即得隔离层包衣液。
②缓释层包衣液
缓释层包衣液的组成 重量份
25％乙基纤维素水分散体 95
聚乙二醇4000 1
纯化水 144
配制方法：将25％(质量分数，g/g)乙基纤维素水分散体加入处方量的纯化水中，搅拌均匀，再将处方量的聚乙二醇4000加入上述溶液中，搅拌使其均匀分散，即得缓释层包衣液。
(3)载药丸芯包衣
将上述制备获得的载药丸芯置于流化床中，采用底喷包衣，进风风量30HZ，转盘转速250r/min，进风温度40℃，物料温度35℃，雾化压力1.5bar，喷液速度4g/min。在确保载药丸芯滚动流畅的状态下，将隔离层包衣液喷到载药丸芯表面，取样测定包衣增重3％停止喷液。继续通风干燥药丸15min，然后改喷缓释层包衣液，待包衣增重至20％时，停止包衣，干燥，即得美索舒利缓释微丸。
(4)熟化
将步骤(3)中得到的美索舒利缓释微丸置于35摄氏度真空恒温干燥箱中，熟化8个小时。
(5)灌装胶囊
将熟化完毕的美索舒利缓释微丸灌入1号空心胶囊中，即得本实施例的美索舒利缓释胶囊。
然后，对制备获得的美索舒利缓释胶囊进行溶出度测试，具体如下：
溶出度实验：以中国药典2010年版二部附录XC第一法装置，照中国药典2010年版二部附录XD第一法测定样品的溶出度。以水1000ml为溶出介质，转速100转，在1、2、4、8、10、12、16小时取样，测定制备获得的美索舒利缓释胶囊的溶出度，结果见表g1，其对应的溶出图见附图17。
表1
时间(小时) 溶出度(％)
0 0
1 48
2 58
4 69
6 78
8 82
12 88
16 87
实施例g2
(1)美索舒利载药丸芯的制备
处方：
载药丸芯的处方组成 重量份
美索舒利 50
交联羧甲基纤维素钠 15
淀粉 145
羟丙甲基纤维素 50
制备方法：
将美索舒利原料超细粉碎后与上述处方量中的其余辅料等量递加混合均匀，用4％羟丙甲基纤维素纯化水溶液作为粘合剂将上述混合好的粉末制成软材，采用挤出滚圆的方法制成载药丸芯。挤出机采用单螺杆径向屏式挤出，筛板孔径为0.8mm，螺杆转速为40r/min。挤出物在500r/min转速下在离心造粒机中滚成美索舒利载药丸芯，并将制得的载药丸芯于40℃下干燥，即得。
(2)包衣液的配制
①隔离层包衣液
隔离层包衣液的组成 重量份
聚维酮K30 25
滑石粉 2
无水乙醇 150
配制方法：同实施例g1。
②缓释层包衣液
Figure PCTCN2014085783-appb-000061
配制方法：同实施例g1。
(3)载药丸芯包衣：方法同实施例g1。
(4)熟化：将步骤(3)中得到的美索舒利缓释微丸置于30摄氏度真空恒温干燥箱中，熟化10个小时。
(5)灌装胶囊：将熟化完毕的美索舒利缓释微丸灌入1号空心胶囊中，即得本实施例的美索舒利缓释胶囊。
然后，对制备获得的美索舒利缓释胶囊进行溶出度测试，测定方法同实施例1，测定制备获得的美索舒利缓释胶囊的溶出度结果见表g2。
表g2
时间(小时) 溶出度(％)
0 0
1 47
2 59
4 72
6 76
8 83
12 86
16 87
实施例g3
(1)美索舒利载药丸芯的制备
处方：
载药丸芯的处方组成 重量份
美索舒利 50
低取代羟丙基纤维素 20
乳糖 140
羟丙甲基纤维素 30
制备方法：
将美索舒利原料超细粉碎后与上述处方量中的其余辅料等量递加混合均匀，用4％羟丙甲基纤维素纯化水溶液作为粘合剂将上述混合好的粉末制成软材，采用挤出滚圆的方法制成载药丸芯。挤出机采用单螺杆径向屏式挤出，筛板孔径为0.8mm，螺杆转速为40r/min。挤出物在500r/min转速下在离心造粒机中滚成美索舒利载药丸芯，并将制得的载药丸芯于40℃下干燥，即得。
(2)包衣液的配制
①隔离层包衣液
隔离层包衣液的组成 重量份
聚维酮K30 15
滑石粉 3
无水乙醇 130
配制方法：同实施例g1。
②缓释层包衣液
Figure PCTCN2014085783-appb-000062
配制方法：同实施例g1。
(3)载药丸芯包衣：方法同实施例g1。
(4)熟化：将步骤(3)中得到的美索舒利缓释微丸置于40摄氏度真空恒温干燥箱中，熟化6个小时。
(5)灌装胶囊：将熟化完毕的美索舒利缓释微丸灌入1号空心胶囊中，即得本实施例的美索舒利缓释胶囊。
然后，对制备获得的美索舒利缓释胶囊进行溶出度测试，测定方法同实施例g1，测定制备获得的美索舒利缓释胶囊的溶出度结果见表g3。
表g3
时间(小时) 溶出度(％)
0 0
1 50
2 57
4 72
6 84
8 85
12 83
16 82
实施例g4
(1)美索舒利载药丸芯的制备
处方：
载药丸芯的处方组成 重量份
美索舒利 75
羧甲基淀粉钠 15
糊精 120
羟丙基纤维素 40
制备方法：
将美索舒利原料超细粉碎后与上述处方量中的其余辅料等量递加混合均匀，用4％ 羟丙基纤维素纯化水溶液作为粘合剂将上述混合好的粉末制成软材，采用挤出滚圆的方法制成载药丸芯。挤出机采用单螺杆径向屏式挤出，筛板孔径为0.8mm，螺杆转速为40r/min。挤出物在500r/min转速下在离心造粒机中滚成美索舒利载药丸芯，并将制得的载药丸芯于40℃下干燥，即得。
(2)包衣液的配制
①隔离层包衣液
隔离层包衣液的组成 重量份
聚维酮K30 10
滑石粉 5.5
无水乙醇 120
配制方法：同实施例g1。
②缓释层包衣液
Figure PCTCN2014085783-appb-000063
配制方法：同实施例g1。
(3)载药丸芯包衣：方法同实施例g1。
(4)熟化：同实施例g1。
(5)灌装胶囊：同实施例g1。
然后，对制备获得的美索舒利缓释胶囊进行溶出度测试，测定方法同实施例g1，测定制备获得的美索舒利缓释胶囊的溶出度结果见表g4，其对应的溶出图见附图18。
表g4
时间(小时) 溶出度(％)
0 0
1 51
2 65
4 78
6 85
8 81
12 79
16 77
实施例g5
(1)美索舒利载药丸芯的制备
处方：
载药丸芯的处方组成 重量份
美索舒利 100
交联聚维酮 20
微晶纤维素 100
羧甲基纤维素钠 30
制备方法：
将美索舒利原料超细粉碎后与上述处方量中的其余辅料等量递加混合均匀，用4％羧甲基纤维素钠纯化水溶液作为粘合剂将上述混合好的粉末制成软材，采用挤出滚圆的方法制成载药丸芯。挤出机采用单螺杆径向屏式挤出，筛板孔径为0.8mm，螺杆转速为40r/min。挤出物在500r/min转速下在离心造粒机中滚成美索舒利载药丸芯，并将制得的载药丸芯于40℃下干燥，即得。
(2)包衣液的配制
①隔离层包衣液
隔离层包衣液的组成 重量份
聚维酮K30 25
滑石粉 2.5
无水乙醇 100
配制方法：同实施例g1。
②缓释层包衣液
Figure PCTCN2014085783-appb-000064
配制方法：同实施例g1。
(3)载药丸芯包衣：方法同实施例g1。
(4)熟化：同实施例g1。
(5)灌装胶囊：同实施例g1。
然后，对制备获得的美索舒利缓释胶囊进行溶出度测试，测定方法同实施例g1，测定制备获得的美索舒利缓释胶囊的溶出度结果见表g5。
表g5
时间(小时) 溶出度(％)
0 0
1 30
2 43
4 51
6 74
8 81
12 80
16 78
实施例g6
(1)美索舒利载药丸芯的制备
处方：
载药丸芯的处方组成 重量份
美索舒利 100
交联聚维酮 12
微晶纤维素 100
羟丙甲基纤维素 40
制备方法：
将美索舒利原料超细粉碎后与上述处方量中的其余辅料等量递加混合均匀，用4％羧甲基纤维素钠纯化水溶液作为粘合剂将上述混合好的粉末制成软材，采用挤出滚圆的方法制成载药丸芯。挤出机采用单螺杆径向屏式挤出，筛板孔径为0.8mm，螺杆转速为40r/min。挤出物在500r/min转速下在离心造粒机中滚成美索舒利载药丸芯，并将制得的载药丸芯于40℃下干燥，即得。
(2)包衣液的配制
①隔离层包衣液
隔离层包衣液的组成 重量份
聚维酮K30 18
滑石粉 1.3
无水乙醇 110
配制方法：同实施例g1。
②缓释层包衣液
Figure PCTCN2014085783-appb-000065
配制方法：同实施例g1。
(3)载药丸芯包衣：方法同实施例g1。
(4)熟化：同实施例g1。
(5)灌装胶囊：同实施例g1。
实施例g7
发明人对实施例g1中制备获得美索舒利缓释胶囊进行了10天影响因素测试。具体如下：
将100mg规格的美索舒利缓释胶囊(按照实施例g1方法制备)袒露于培养皿中，在高温(60℃)、高湿(RH92.5％，25℃)、强光(4500lx±500lx)条件下放置10天，于第5、10天取样，观察制剂外观、含量、溶出度、有关物质等项目，并与考察前样品的检查数据进行比较，结果如表g6：
表g6：
Figure PCTCN2014085783-appb-000066
上表的10天影响因素试验结果表明，美索舒利缓释胶囊在高温、高湿和光照条件下，质量是稳定的，其含量无明显降低、有关物质无明显上升，表明本发明的美索舒利分散片的质量稳定性好。
本发明人采用同样的方法，对实施例g2-实施例g6进行10天影响因素试验，结果均表明，本发明制备工艺得到的美索舒利缓释胶囊质量稳定性好。
实施例g8
以实施例g1中制备获得的美索舒利缓释胶囊为研究对象，按照常规方法，研究了美索舒利缓释胶囊在Beagle犬体内的药代动力学行为，药代动力学测试结果见图19。
由图19可以看出，缓释胶囊拥有十分平稳的血药浓度，避免或减小了血药峰谷现象的出现，有利于提高药物使用的安全性，减少服药次数，提高患者的顺应性。
在本发明的描述中，需要理解的是，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。在本发明的描述中，“多个”的含义是两个或两个以上，除非另有明确具体的限定。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (36)

  1. 微晶纤维素在制备美索舒利制剂中的用途。
  2. 根据权利要求1所述的用途，其特征在于，所述美索舒利制剂为选自胶囊剂、颗粒剂或片剂的口服固体制剂形式。
  3. 根据权利要求2所述的用途，其特征在于，所述片剂为选自薄膜衣片、口腔崩解片、分散片、缓释片中的至少一种。
  4. 根据权利要求2所述的用途，其特征在于，所述胶囊剂为胶囊、缓释胶囊中的至少一种。
  5. 一种用于美索舒利的辅料，其特征在于，包括：
    微晶纤维素作为填充剂。
  6. 根据权利要求5所述的辅料，其特征在于，所述填充剂进一步包括选自乳糖、糊精、蔗糖、淀粉和甘露醇中的至少一种，其中，所述淀粉为选自玉米淀粉、可压性淀粉和预胶化淀粉中的至少一种。
  7. 根据权利要求5或6所述的辅料，其特征在于，进一步包括：
    选自崩解剂、粘合剂、润滑剂、助悬剂、矫味剂、增溶剂、骨架缓释材料、溶剂和助流剂中的至少一种，
    其中，
    所述崩解剂为选自交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素和交联羧甲基纤维素钠中的至少一种；
    所述粘合剂为选自聚维酮K30、羟丙甲基纤维素、甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、淀粉浆、糊精中的至少一种；
    所述润滑剂为选自硬脂酸镁、微粉硅胶、硬脂酰富马酸钠、十二烷基硫酸钠、二氧化硅、聚乙二醇中的至少一种；
    所述助悬剂为选自聚维酮、羟丙甲基纤维素、羧甲基纤维素钠、微晶纤维素中的至少一种；
    所述矫味剂为选自阿斯巴甜、香橙香精、蔗糖、甜菊苷、阿司帕坦中的至少一种，
    所述增溶剂为选自羟丙基β-环糊精、泊洛沙姆188中的至少一种；
    所述骨架缓释是材料为选自羟丙甲基纤维素K4M、羟丙甲基纤维素K15M、羟丙甲基
    纤维素K100M，羟丙甲基纤维素E50、羟丙甲基纤维素E4M中的至少一种；
    所述溶剂为体积分数为75％的乙醇溶液；
    所述助流剂为微粉硅胶。
  8. 一种美索舒利制剂，其特征在于，包括：
    美索舒利；以及
    权利要求5-7中任一项所述的辅料。
  9. 根据权利要求8所述的美索舒利制剂，其特征在于，所述美索舒利制剂为选自胶囊剂、颗粒剂或片剂的口服固体制剂形式。
  10. 据权利要求9所述的美索舒利制剂，其特征在于，所述片剂为选自薄膜衣片、口腔崩解片、分散片、缓释片中的至少一种。
  11. 根据权利要求9所述的美索舒利制剂，其特征在于，所述胶囊剂为胶囊、缓释胶囊中的至少一种。
  12. 根据权利要求8-11中任一项所述的美索舒利制剂，其特征在于，按照重量份数，美索舒利薄膜衣片包括：
    所述美索舒利25-150重量份；
    所述填充剂50-200重量份；
    所述粘合剂6-12重量份；
    所述崩解剂5-20重量份；以及
    所述润滑剂0.8-4重量份。
  13. 根据权利要求8-11中任一项所述的美索舒利制剂，其特征在于，按照重量份数，美索舒利口腔崩解片包括：
    所述美索舒利25-125重量份；
    所述甘露醇20-60重量份；
    所述微晶纤维素30-70重量份；
    所述粘合剂5-40重量份；
    所述崩解剂2-30重量份；
    所述矫味剂5-20重量份；
    所述润滑剂0.5-10重量份；以及
    所述助流剂0.1-0.5重量份。
  14. 根据权利要求8-11中任一项所述的美索舒利制剂，其特征在于，按照重量份数，美索舒利分散片包括：
    所述美索舒利25-125重量份；
    所述矫味剂5-20重量份；
    所述填充剂60-150重量份；
    所述粘合剂5-30重量份；
    所述崩解剂2-20重量份；以及
    所述润滑剂0.5-3重量份。
  15. 根据权利要求8-11中任一项所述的美索舒利制剂，其特征在于，按照重量份数，美索舒利缓释片包括：
    所述美索舒利25～125重量份；
    所述骨架缓释材料80～127.5重量份；
    所述填充剂5～75重量份；
    所述润滑剂1.5～2.5重量份；
    所述增溶剂15～20重量份；以及
    所述崩解剂5～9重量份。
  16. 根据权利要求8-11中任一项所述的美索舒利制剂，其特征在于，按照重量份数，美索舒利颗粒剂包括：
    所述美索舒利25-125重量份；
    所述增溶剂25-500重量份；
    所述填充剂125-600重量份；
    所述助悬剂15-75重量份；
    所述矫味剂5-40重量份；
    所述粘合剂25-200重量份；以及
    所述溶剂10-200重量份。
  17. 根据权利要求8-11中任一项所述的美索舒利制剂，其特征在于，按照重量份数，美索舒利胶囊包括：
    所述美索舒利25-150重量份；
    所述填充剂50-200重量份；
    所述粘合剂5-20重量份；
    所述崩解剂5-20重量份；以及
    所述润滑剂0.8-4重量份。
  18. 根据权利要求8-11中任一项所述的美索舒利制剂，其特征在于，按照重量份数，美索舒利缓释胶囊包括：
    缓释微丸和空心胶囊，所述缓释微丸包括载药丸芯和包衣层，所述包衣层包括隔离层和缓释层，其中，所述载药丸芯包括：
    所述美索舒利50-100重量份；
    所述崩解剂10-20重量份；
    所述填充剂100-145重量份；以及
    所述粘合剂30-50重量份，
    所述隔离层包括：致孔剂、抗粘剂、以及隔离包衣层溶剂；
    所述缓释层包含高分子聚合物、增塑剂、以及纯化水。
  19. 根据权利要求18所述的美索舒利制剂，其特征在于，所述致孔剂聚维酮K30。
  20. 根据权利要求18所述的美索舒利制剂，其特征在于，所述抗粘剂为滑石粉。
  21. 根据权利要求18所述的美索舒利制剂，其特征在于，所述隔离层溶剂为无水乙醇。
  22. 根据权利要求18所述的美索舒利制剂，其特征在于，所述高分子聚合物为选自聚丙烯酸树脂、乙基纤维素中的至少一种。
  23. 根据权利要求18所述的美索舒利制剂，其特征在于，所述乙基纤维素为乙基纤维素水分散体。
  24. 根据权利要求18所述的美索舒利制剂，其特征在于，所述增塑剂为选自丙二醇、聚乙二醇4000、苯甲酸二甲酯、柠檬酸三乙酯的至少一种。
  25. 根据权利要求22所述的美索舒利制剂，其特征在于，所述聚丙烯酸树脂为选自
    Figure PCTCN2014085783-appb-100001
    RL30D、
    Figure PCTCN2014085783-appb-100002
    RS30D、
    Figure PCTCN2014085783-appb-100003
    RL100、
    Figure PCTCN2014085783-appb-100004
    RSPO、
    Figure PCTCN2014085783-appb-100005
    NE30D中的至少一种。
  26. 一种制备权利要求8-25中任一项所述的美索舒利制剂的方法，其特征在于，包括：
    将美索舒利进行微粉化处理，并将所得到的美索舒利微粉颗粒与权利要求5-7中任一项所述的辅料混合，以便获得药物混合物；
    将所述药物混合物制成胶囊剂、颗粒剂或片剂。
  27. 根据权利要求26所述的方法，其特征在于，所述美索舒利微粉颗粒的粒径为1-100微米。
  28. 根据权利要求26或27所述的方法，其特征在于，包括：
    (a1)将美索舒利和填充剂混合，并将所得到的混合物进行微粉化处理，以便获得粒径为5微米至100微米的混合物微粉颗粒，将崩解剂、粘合剂和润滑剂分别粉碎后过80目筛，备用；
    (a2)将所述粘合剂与纯化水混合，配制得质量分数为6％～12％的粘合剂水溶液aⅠ，备用；
    (a3)将所述混合物微粉颗粒与內加的崩解剂混合，得混合物aⅡ；
    (a4)将所述粘合剂水溶液aⅠ加入所述混合物aⅡ中，并将所得到的混合物制成软材，将所得软材过18目不锈钢筛制粒，以便获得湿颗粒；
    (a5)于55℃～65℃下，将所述湿颗粒干燥1～4h，然后过18目不锈钢筛整粒，以便获得干颗粒；
    (a6)将所述干颗粒与外加的崩解剂混合，再将所得到的混合物与硬脂酸镁混合，以便获得所述药物混合物；
    (a7)测定所述药物混合物的含药量，并计算理论片重，然后将所述药物混合物进行压片，以便获得所述美索舒利片芯；
    (a8)将包衣粉末加入纯化水中，配制成固含量为20％的包衣溶液，然后利用所述包衣溶液对所述美索舒利片芯进行包衣处理，以便获得美索舒利薄膜衣片。
  29. 根据权利要求26或27所述的方法，其特征在于，包括：
    (b1)将所述美索舒利进行微粉化，以便获得美索舒利微粉；
    (b2)将所述美索舒利微粉与助流剂和矫味剂混合；
    (b3)将所述填充剂进行微粉化，以便获得粒径为20-100微米的填充剂微粉；
    (b4)将所述步骤(b3)中所得到的混合物与所述崩解剂和所述粘合剂混合；
    (b5)将所述步骤(b4)中所得到的混合物与所述润滑剂混合，以便获得药物混合物；
    (b6)通过直接压片法将所述药物混合物制成美索舒利口腔崩解片。
  30. 根据权利要求26或27所述的方法，其特征在于，包括：
    (c1)将所述美索舒利溶于有机溶剂，以便获得有机相溶液；
    (c2)将所述填充剂和所述粘合剂溶于纯化水，以便获得水相溶液；
    (c3)将所述有机相溶液与所述水相溶液混合，以便获得混合的美索舒利混悬溶液；
    (c4)将所述混合的美索舒利混悬溶液进行均质后，进行喷雾干燥，以便获得喷雾干燥粉末；
    (c5)将所述喷雾干燥粉末与所述润滑剂、所述崩解剂和所述矫味剂混合，以便获得药物混合物；
    (c6)对所述药物混合物取样，并进行含量测定，测定结果合格后，将所述药物混合物直接粉末压片，以便获得美索舒利分散片。
  31. 根据权利要求26或27所述的方法，其特征在于，包括：
    (d1)将所述美索舒利溶于丙酮，并将羟丙基β环糊精水溶液与美索舒利丙酮溶液相混合，挥干溶剂，以便获得结晶粉末；
    (d2)将所述结晶粉末进行超细粉碎，并与骨架缓释材料、填充剂混合；
    (d3)将步骤(d2)中得到的混合物进行制粒，并将制得的颗粒进行干燥；
    (d4)将干燥后的颗粒与所述润滑剂和所述崩解剂混合，并将所得到的混合物进行压片。
  32. 根据权利要求31所述的方法，其特征在于，进一步包括：
    (d5)将所述步骤(d4)压片得到的片芯包薄膜衣，以便获得美索舒利缓释片。
  33. 根据权利要求26或27所述的方法，其特征在于，包括：
    (e1)将所述美索舒利和所述增溶剂混合，并将所得到的混合物进行微粉化处理；
    (e2)向步骤(e1)中得到的混合物中加入填充剂，并将所得到的混合物进行微粉化处理，以便获得微粉颗粒；
    (e3)将所述微粉颗粒和所述助悬剂、所述矫味剂、所述粘合剂以及所述溶剂混合；
    (e4)将步骤(e3)中所得到的混合物依次经制软材、制湿颗粒、干燥、整粒，以便获得美索舒利颗粒剂。
  34. 根据权利要求26或27所述的方法，其特征在于，包括：
    (f1)将所述美索舒利与所述填充剂混合，并将所得到的混合物进行微粉化处理至粒径为5-100微米，以便获得所述混合物微粉颗粒，将所述崩解剂、所述粘合剂、所述润滑剂过60目～80目筛，备用；
    (f2)将所述粘合剂与纯化水混合，以便获得所述粘合剂水溶液，所述粘合剂水溶液的质量分数为5％～20％；
    (f3)将所述混合物微粉颗粒与所述内加的崩解剂混合，以便获得所述第一混合物；
    (f4)将所述第一混合物与所述粘合剂水溶液混合，并将所得到的混合物进行制软材，将所得软材过18目筛制粒，以便获得所述湿颗粒；
    (f5)于55℃～65℃下，将所述湿颗粒进行干燥1～4小时，然后过18目筛整粒，以便获得所述干颗粒；
    (f6)将所述干颗粒与所述外加的崩解剂混合，以便获得第二混合物；
    (f7)将所述第二混合物与硬脂酸镁混合，以便获得所述药物混合物；
    (f8)将所述药物混合物进行含量检测，并将含量检测合格的所述药物混合物进行胶囊灌装，以便获得美索舒利胶囊。
  35. 根据权利要求26或27所述的方法，其特征在于，包括：
    (g1)将所述美索舒利超细粉碎后与所述填充剂、所述崩解剂和所述粘合剂混合，将所得到的混合物制成软材，并将所述软材通过挤出滚圆的方法制成所述载药丸芯；
    (g2)将致孔剂、抗粘剂和隔离层溶剂混合，以便获得所述隔离层包衣液；
    (g3)将高分子聚合物、增塑剂和纯化水混合，以便获得所述缓释层包衣液；
    (g4)将所述载药丸芯干燥后，置于流化床中，采用底喷包衣的方式，将所述隔离层包衣液喷于所述载药丸芯表面，以便在所述载药丸芯的表面形成所述隔离层；
    (g5)将表面形成有隔离层的载药丸芯干燥后，将所述缓释层包衣液喷于所述表面形成有隔离层的载药丸芯的表面，以便获得所述缓释微丸；
    (g6)于30～40℃，优选35℃下，将所述缓释微丸熟化6～10小时，优选6小时；
    (g7)将经过熟化的缓释微丸填充于空心胶囊中，以便获得美索舒利缓释胶囊。
  36. 一种治疗炎症、疼痛或类风湿性关节炎的方法，其特征在于，包括：对患者给药权利要求8-25中任一项所述的美索舒利制剂。
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