CN105435239B

CN105435239B - Mei Suoshuli Film coated tablets and preparation method thereof

Info

Publication number: CN105435239B
Application number: CN201410438840.6A
Authority: CN
Inventors: 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
Original assignee: Hubei Co Ltd Of Bio-Pharmaceutical Industry Institute For Research And Technology; Ren Fu Pharmaceutical Group Stock Co; Wuhan Guanggu Humanwell Biological Pharmaceutical Co Ltd
Current assignee: Hubei Co Ltd Of Bio-Pharmaceutical Industry Institute For Research And Technology; Ren Fu Pharmaceutical Group Stock Co; Wuhan Guanggu Humanwell Biological Pharmaceutical Co Ltd
Priority date: 2014-08-29
Filing date: 2014-08-29
Publication date: 2019-04-26
Anticipated expiration: 2034-08-29
Also published as: CN105435239A; WO2016029494A1

Abstract

The present invention provides microcrystalline celluloses to prepare the purposes in Mei Suoshuli preparation, the auxiliary material for Mei Suoshuli, Mei Suoshuli preparation and preparation method thereof, and the Mei Suoshuli quality of the pharmaceutical preparations is stable, Mei Suoshuli dissolution rate is high, bioavilability is high.

Description

Mei Suoshuli Film coated tablets and preparation method thereof

Technical field

The present invention relates to pharmaceutical fields, and in particular, to microcrystalline cellulose is preparing the purposes in Mei Suoshuli preparation, using In the auxiliary material of Mei Suoshuli, Mei Suoshuli preparation and preparation method thereof.

Background technique

Mei Suoshuli is by 1.1 class chemistry new drugs of Military Medical Science Institute and the cooperative development of people's good fortune Pharmaceutical Group.Mei Suo Shu Li is a kind of non-steroidal anti-inflammatory drugs (abbreviation NSAID), and main mechanism is inhibition cyclooxygenase (COX-2) activity, thus Inhibit arachidonic acid to ultimately generate prostacyclin (PG II), prostaglandin (PGE1, PGE2) and thromboxane A2 (TXA2), that is, subtracts The synthesis of the inflammatory mediators such as few prostaglandin, thromboxane, thus have the effects that antipyretic, analgesia, anti-inflammatory, detumescence well.Beauty Suo Shuli raw material is not soluble in water, sees report still without suitable Mei Suoshuli preparation at present.Thus, development efficacy is good, secondary work With the Mei Suoshuli preparation that small, dissolution rate is high, bioavilability is high and quality is stable, have very important significance.

However, grinding to the auxiliary material and Mei Suoshuli preparation and preparation method thereof for being used to prepare Mei Suoshuli preparation at present Study carefully, still has to be strengthened.

Summary of the invention

The present invention is directed to solve at least some of the technical problems in related technologies.For this purpose, of the invention One purpose is to propose a kind of good effect, Small side effects, the Mei Suoshu that dissolution rate is high, bioavilability is high and quality is stable Sharp preparation.

In one aspect of the invention, the present invention provides microcrystalline celluloses to prepare the purposes in Mei Suoshuli preparation. According to an embodiment of the invention, the Mei Suoshuli quality of the pharmaceutical preparations is stable, the dissolution rate of Mei Suoshuli is high, bioavilability is high.

According to an embodiment of the invention, the Mei Suoshuli preparation is selected from the oral solid of capsule, granule or tablet Body preparation form.Thereby, it is possible to meet the different needs of different patients, patient medication compliance is good.Inventors have found that when selection When filler of the microcrystalline cellulose as Mei Suoshuli preparation, only drugs compressibility is not good, and disintegration meets the requirements, and dissolution rate is high, And the hardness and unilateral finish of tablet can be improved.

According to an embodiment of the invention, the tablet is in Film coated tablets, oral disnitegration tablet, dispersible tablet, sustained release tablets At least one.Convenient to take as a result, patient compliance is good.

According to an embodiment of the invention, the capsule is at least one of capsule, spansule.The side of taking as a result, Just, patient compliance is good.

In another aspect of this invention, the present invention provides a kind of auxiliary materials for Mei Suoshuli.Reality according to the present invention Example is applied, the auxiliary material includes: microcrystalline cellulose as filler.Auxiliary material according to an embodiment of the present invention can be effective as a result, In preparation Mei Suoshuli preparation, and the Mei Suoshuli quality of the pharmaceutical preparations is stable, the dissolution rate of Mei Suoshuli is high, bioavilability It is high.

According to an embodiment of the invention, the filler further comprises selected from lactose, dextrin, sucrose, starch and sweet dew At least one of alcohol, wherein the starch is at least one in cornstarch, amylum pregelatinisatum and pregelatinized starch Kind.Thereby, it is possible to improve the compressibility of drug, reduce the dose deviations of main component, promote Mei Suoshuli preparation disintegration and Dissolution.

According to an embodiment of the invention, the auxiliary material further comprises: being selected from disintegrating agent, adhesive, lubricant, suspending At least one of agent, corrigent, solubilizer, skeleton slow-release material, solvent and glidant.

According to an embodiment of the invention, the disintegrating agent is selected from crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl At least one of base cellulose and croscarmellose sodium.As a result, Mei Suoshuli preparation can fater disintegration, be conducive to The dissolution of Mei Suoshuli.

According to an embodiment of the invention, described adhesive is selected from PVP K30, hypromellose, Methyl cellulose At least one of element, hydroxypropyl cellulose, sodium carboxymethylcellulose, starch slurry, dextrin.Adhesive effect is good as a result,.

According to an embodiment of the invention, the lubricant be selected from magnesium stearate, superfine silica gel powder, sodium stearyl fumarate, At least one of lauryl sodium sulfate, silica, polyethylene glycol.Lubricant effect is preferable as a result,.

According to an embodiment of the invention, the suspending agent is selected from povidone, hypromellose, carboxymethyl cellulose At least one of sodium, microcrystalline cellulose.

According to an embodiment of the invention, the corrigent is selected from Aspartame, fragrant citrus essence, sucrose, stevioside, A Si Pa is at least one of smooth.Mei Suoshuli preparation is good in taste as a result, and patient medication compliance is good.

According to an embodiment of the invention, the solubilizer be in hydroxypropylβ-cyclodextrin, PLURONICS F87 at least It is a kind of.Thereby, it is possible to be effectively improved the dissolubility of Mei Suoshuli.

According to an embodiment of the invention, it is selected from hypromellose K4M, hydroxypropyl that the skeleton sustained release, which is material, Cellulose K15M, hypromellose K100M, at least one in hypromellose E50, hypromellose E4M Kind.Thereby, it is possible to make Mei Suoshuli slow release, achieve the effect that be sustained for 24 hours.

According to an embodiment of the invention, the solvent is the ethanol solution that volume fraction is 75%.

According to an embodiment of the invention, the glidant is superfine silica gel powder.Be conducive to improve mobility as a result,.

In another aspect of the invention, the present invention provides a kind of Mei Suoshuli preparations.According to an embodiment of the invention, should Mei Suoshuli preparation includes: Mei Suoshuli；And mentioned-above auxiliary material.Inventors have found that Mei Suoshuli preparation of the invention Dissolution rate height, disintegration time section, Small side effects, quality are stablized, and can effectively play anti-inflammatory, analgesia, antipyretic effect, and prepare It is simple process, at low cost.

According to an embodiment of the invention, the Mei Suoshuli preparation is selected from the oral solid of capsule, granule or tablet Body preparation form.Thereby, it is possible to meet the different needs of different patients, patient medication compliance is good.

According to an embodiment of the invention, the capsule is at least one of capsule, spansule.It is convenient to take as a result, Patient compliance is good.

According to an embodiment of the invention, Mei Suoshuli Film coated tablets includes: the Mei Suoshuli 25-150 parts by weight；It is described Filler 50-200 parts by weight；Described adhesive 6-12 parts by weight；The disintegrating agent 5-20 parts by weight；And the lubricant 0.8-4 parts by weight.Inventors have found that Mei Suoshuli Film coated tablets dissolution rate height of the invention, disintegration time section, Small side effects, Quality is stablized, and can effectively play anti-inflammatory, analgesia, antipyretic effect, and preparation process is simple, at low cost.In addition, invention people's will Other places discovery, the Mei Suoshuli Film coated tablets comprising aforementioned proportion supplementary material have the pharmaceutical properties better than other ratios.

Inventor has found by many experiments, when selecting microcrystalline cellulose for the filler of Film coated tablets, not only drugs Compressibility is good, and disintegration rate is fast, and dissolution rate is high, and the hardness and unilateral finish of Film coated tablets can be improved.

Inventor by a large amount of experiment discovery, individually using lactose as filler when, industrial mass production will appear sliver and show As so the present invention selects not in the auxiliary material of diluent (" diluent " and " filler " may be used interchangeably in the present invention) Individually select lactose.And microcrystalline cellulose not only serves as filler, and has the performance of disintegrating agent, chooses microcrystalline cellulose It can reach good result of extraction.And inventors have found that when the combination for selecting microcrystalline cellulose or microcrystalline cellulose and lactose When for filler, only drugs compressibility is not good, and disintegration rate is fast, and dissolution rate is high, and the hardness of Film coated tablets and unilateral can be improved Finish.In addition, according to an embodiment of the invention, when as adhesive and using crospovidone using PVP K30 When for disintegrating agent, the disintegration rate of Mei Suoshuli Film coated tablets is very fast, and dissolution rate is higher.

According to an embodiment of the invention, Mei Suoshuli oral disnitegration tablet includes: the Mei Suoshuli 25-125 parts by weight；Institute State mannitol 20-60 parts by weight；The microcrystalline cellulose 30-70 parts by weight；Described adhesive 5-40 parts by weight；The disintegrating agent 2-30 parts by weight；The corrigent 5-20 parts by weight；The lubricant 0.5-10 parts by weight；And the glidant 0.1-0.5 Parts by weight.Mei Suoshuli oral disnitegration tablet disintegration time of the invention is fast as a result, and dissolution rate is good and quality is stablized.And the oral cavity Disintegration is dispersed into fine particle or powder rapidly in the oral cavity after disintegrated tablet is oral, the patient that is particularly suitable for dysphagia and old Year patient, and the oral disnitegration tablet before reaching gastrointestinal tract with fine particle or powder type presence, drug-eluting Accelerate, big in gastrointestinal tract area distributions, absorption point is more, and for insoluble drug such as Mei Suoshuli, its bioavilability can be improved.

Inventor is found surprisingly that, is mixed with microcrystalline cellulose as filler, resulting Mei Suoshuli using mannitol Oral disnitegration tablet is convenient to take, curative effect is obvious, in good taste, and is conducive to Mei Suoshuli oral disnitegration tablet fater disintegration.Moreover, by Filler of the microcrystalline cellulose as auxiliary is used in Mei Suoshuli oral disnitegration tablet of the invention, so that the dosage of mannitol It is minimized, to reduce the cost of entire prescription, and overcomes since gained mouth collapses caused by mannitol dosage is excessive The shortcomings that piece friability is higher, is not suitable for transport storage and uses.It is suitable for the application of tablet forming technique simultaneously, further reduced Cost.

In addition, Mei Suoshuli can be effectively prevent by the way that glidant superfine silica gel powder is added into Mei Suoshuli oral disnitegration tablet The material sticks that may cause with auxiliary material are added the superfine silica gel powder of very little ratio, can also effectively eliminate electrostatic, while can also increase The hydrophily of Jia Meisuoshuli drug.Meanwhile not only disintegration time is fast for Mei Suoshuli oral disnitegration tablet of the invention, dissolution rate Good, quality is stablized, and falls and sliver phenomenon there is no broken brittleness is higher, small block easily occurs, is conducive to industrialized production, fits Close long-term storage transport and use and extensive promotion and application.

According to an embodiment of the invention, Mei Suoshuli dispersible tablet includes: the Mei Suoshuli 25-125 parts by weight；It is described to rectify Taste agent 5-20 parts by weight；The filler 60-150 parts by weight；Described adhesive 5-30 parts by weight；The disintegrating agent 2-20 weight Part；And the lubricant 0.5-3 parts by weight.Inventors have found that Mei Suoshuli dispersion tablet quality of the invention is stable, disintegration symbol Close require, dissolution rapidly, Mei Suoshuli concentration be rapidly reached that stable state, content are uniform, oral administration biaavailability is high, patient in vivo Compliance is good.

Inventor realizes insoluble drug using solid dispersions technique in the form of dispersible tablet by many experiments The preparation of Mei Suoshuli dispersible tablet, improves the solution rate of drug, improves oral administration biaavailability, provides one for patient A new clinical application selection.And the Mei Suoshuli dispersible tablet including aforementioned proportion supplementary material has the drug better than other ratios Performance.

According to an embodiment of the invention, Mei Suoshuli sustained release tablets include: 25~125 parts by weight of Mei Suoshuli；It is described 80~127.5 parts by weight of skeleton slow-release material；5~75 parts by weight of filler；1.5~2.5 parts by weight of lubricant；Institute State 15~20 parts by weight of solubilizer；And 3~9 parts by weight of disintegrating agent.Inventors have found that Mei Suoshuli of the invention is sustained Piece can be realized 24 hours and be sustained, and quality is stable, bioavilability is high, compliance is good.

It should be noted that inventor utilizes the technologies such as ultra-fine grinding, solid dispersions, cyclodextrin encapsulated, using sustained release The form of matrix tablet, realize the preparation of insoluble drug Mei Suoshuli sustained release tablets, and improves Mei Suoshuli in water Solubility improves the absorption of drug in vivo, improves oral administration biaavailability, provides a new clinical use for patient Medicine selection.Moreover, on the one hand Mei Suoshuli sustained release tablets of the invention solve the problems, such as that Mei Suoshuli oral administration biaavailability is low, On the one hand being made into sustained release tablets reduces medicining times, improves the compliance of patient medication.The present invention is different from Mei Suoshuli Raw material is directly made into sustained release tablets, but first improves the dissolubility of Mei Suoshuli by solid dispersions technique, then be made into Sustained release tablets have not only achieved the purpose that slow release, also improve the bioavilability of drug in vivo.

According to an embodiment of the invention, Mei Suoshu Zhixieli granules agent includes: the Mei Suoshuli 25-125 parts by weight；The increasing Solvent 25-500 parts by weight；The filler 125-600 parts by weight；The suspending agent 15-75 parts by weight；The corrigent 5-40 Parts by weight；Described adhesive 25-200 parts by weight；And the solvent 10-200 parts by weight.Inventors have found that beauty of the invention The agent of Suo Shu Zhixieli granules can be effective for antipyretic, analgesia, anti-inflammatory, detumescence, and quality is stable, dissolve out, is in good taste, medication is complied with Property it is good, and also solve children due to only needing smaller dose to treat, and tablets and capsules are unfavorable for the deficiencies of separating administration Place is taken very convenient especially for patient that is old, young and having dysphagia.

Inventor is had found by many experiments, in Mei Suoshu Zhixieli granules agent, when the weight ratio of Mei Suoshuli and suspending agent When for 1:0.6-0.8, Mei Suoshuli is in good suspension, will not precipitate；In addition when the weight of Mei Suoshuli and corrigent When amount is than being 1:0.2-0.4, mouthfeel is best.The most preferably described Mei Suoshuli, suspending agent, corrigent weight ratio be 1:0.7: 0.3.The compliance problem of above very good solution children and gerontal patient to the medicine.

Further, inventor is found surprisingly that by experiment, Mei Suoshuli, solubilizer hydroxypropylβ-cyclodextrin is mixed After conjunction, carries out micronization processes 1 time, add filler into the particle of above-mentioned micronization processes, continue to be micronized to partial size For 1-100 microns of particle, and Mei Suoshuli: hydroxypropylβ-cyclodextrin: the weight proportion of filler in 1:1-10:5-16, this When, it is good in the result of extraction of granule Sino-U.S. Suo Shuli.When especially selection filler contains mannitol, the dissolution of Mei Suoshuli Better effect.Its reason may be: the Mei Suoshuli of micronization is mixed with hydroxypropylβ-cyclodextrin, in wet-granulation process Ethanol water it is wet under, hydroxypropylβ-cyclodextrin plays clathration, and inclusion compound has good wettability, therefore Drug has obtained solubilising, meanwhile, mannitol itself is pleasantly sweet, no hygroscopicity, fast drying, and chemical stability is good, and granulation property is good, and Water soluble adjuvant, the drug particle ambient absorption of micronization the particle of a large amount of mannitol, in this way it is prevented that Mei Suoshu The mutual aggregation of the fine drug particle of benefit, is present in it steadily in mixture.When mannitol is dissolved in water, Mei Suoshuli Tiny drug particle is just directly exposed in dissolution medium, and the speed for directly resulting in drug dissolution (and dissolution) is greatly speeded up. Therefore, the combined application of hydroxypropylβ-cyclodextrin and mannitol plays the dissolution (and dissolution) of Mei Suoshuli drug good Synergistic effect, the solubility and dissolution rate of the Mei Suoshuli drug greatly enhanced.

In addition, inventor has found: when the partial size of Mei Suoshuli, hydroxypropylβ-cyclodextrin and filler admixed finepowder are in 30- 60 microns, and Mei Suoshuli: hydroxypropylβ-cyclodextrin: for the weight proportion of filler in 1:5:8, the effect of dissolution is best.

According to an embodiment of the invention, the obtained Mei Suoshu Zhixieli granules agent of the present invention, each auxiliary material and main ingredient in prescription Drug compatibility it is good, auxiliary material is on main ingredient stability without influence.The accelerated 6 months stability examination of gained granule of the invention It tests, quality is stablized.

According to an embodiment of the invention, the Mei Suoshuli capsule includes: the Mei Suoshuli 25-150 parts by weight；It is described Filler 50-200 parts by weight；Described adhesive 5-20 parts by weight；The disintegrating agent 5-20 parts by weight；And the lubricant 0.8-4 parts by weight.Inventors have found that Mei Suoshuli capsule of the invention can effectively play anti-inflammatory, analgesia, antipyretic effect, And dissolution rate is high, bioavilability is high, Small side effects.

According to an embodiment of the invention, preferably the combination of lactose and microcrystalline cellulose is used as and fills out in Mei Suoshuli capsule Fill agent.It, can be effective when thereby, it is possible to promote the dissolution of Mei Suoshuli, the especially combination of selection lactose and microcrystalline cellulose The solubility of Mei Suoshuli is improved, and then improves the dissolution rate and bioavilability of Mei Suoshuli.Particularly, when lactose and crystallite The mass ratio of cellulose is (0.5~5): when 1, can effectively improve the solubility of Mei Suoshuli, and then improve Mei Suoshuli's Dissolution rate and bioavilability.

According to an embodiment of the invention, the Mei Suoshuli spansule includes: sustained release pellet and Capsules, it is described slow It includes separation layer and slow release layer that pellet, which is released, including load pill core and coatings, the coatings, wherein the load pill core packet It includes: 50~100 parts by weight of Mei Suoshuli；10~20 parts by weight of disintegrating agent；100~145 parts by weight of filler； And 30~50 parts by weight of described adhesive.Mei Suoshuli spansule of the invention can be realized slow release, and can be big The big oral administration biaavailability for improving insoluble drug Mei Suoshuli, and dosage and times for spraying can be effectively reduced, poison Side effect is lower, and the compliance of patient is preferable.In addition, Mei Suoshuli spansule of the invention is convenient to take, it only need to be every Day administration 1~2 time, and drug slow release, can effectively avoid blood concentration from rising and falling excessive and effective blood drug concentration occur It is fluctuated, and toxic side effect is small.

Inventor realizes indissoluble using the form of sustained release pellet using superfine technique etc. by a large amount of experiment The preparation of property drug Mei Suoshuli spansule, and the solubility of Mei Suoshuli is improved, improve the suction of drug in vivo It receives, improves the dissolution rate and oral administration biaavailability of Mei Suoshuli drug, and can be realized slowly releasing for Mei Suoshuli drug It puts, realization is administered one time a day, improves the compliance of patient, and the matter of Mei Suoshuli spansule of the present invention Amount is stablized, and provides a new clinical application selection for patient.

Moreover, sustained release pellet uniform particle sizes according to an embodiment of the present invention, drug release is steady, can sustained release 12 it is small When more than.Mei Suoshuli spansule according to an embodiment of the present invention is made of the uniform pellet of many particle sizes, is released Clearance is will be more stable, have preferable safety, stable blood concentration, reduce patient and the several of adverse reaction occur Rate.

According to an embodiment of the invention, the separation layer includes: pore-foaming agent, antiplastering aid and isolation coat layer solvent；Institute Stating slow release layer includes high molecular polymer, plasticizer and purified water.

According to an embodiment of the invention, the pore-foaming agent PVP K30.

According to an embodiment of the invention, the antiplastering aid is talcum powder.

According to an embodiment of the invention, the separation layer solvent is dehydrated alcohol.

According to an embodiment of the invention, the high molecular polymer is in polyacrylic resin, ethyl cellulose It is at least one.

According to an embodiment of the invention, the ethyl cellulose is Aquacoat,

According to an embodiment of the invention, the plasticizer be selected from propylene glycol, Macrogol 4000, benzoic acid dimethyl ester, At least one of triethyl citrate.

In still another aspect of the invention, the present invention provides a kind of methods for preparing mentioned-above Mei Suoshuli preparation. According to an embodiment of the invention, this method comprises: Mei Suoshuli is carried out micronization processes, and obtained Mei Suoshuli is micro- Atomized particles are mixed with mentioned-above auxiliary material, to obtain medicinal mixture；By the medicinal mixture be made capsule, Granula or tablet.Inventors have found that this method using invention can quickly and effectively prepare mentioned-above Mei Suoshu Sharp preparation, and it is easy to operate, it is convenient and efficient, it is suitble to industrialized production.Wherein, by carrying out Mei Suoshuli at micronization Reason, enables to Mei Suoshuli to be adequately dispersed in auxiliary material, and then can greatly improve the dissolution rate of Mei Suoshuli.

According to an embodiment of the invention, the partial size of the Mei Suoshuli micro powder granule is 1-100 microns.As a result, by the grain The dissolution rate of the Mei Suoshuli preparation of the Mei Suoshuli micro powder granule preparation of degree is substantially better than other granularities.

According to an embodiment of the invention, the method for preparing Mei Suoshuli preparation may include: (a1) for Mei Suoshuli and fill out Agent mixing is filled, and obtained mixture is subjected to micronization processes, to obtain the mixing that partial size is 5 microns to 100 microns Disintegrating agent, adhesive and lubricant are smashed it through 80 meshes by object micro powder granule respectively, spare；(a2) by described adhesive with Purified water mixing, the binder aqueous solution a I for being 6%~12% with obtained mass fraction are spare；(a3) mixture is micro- Powder particles are mixed with the interior disintegrating agent added, obtain mixture a II；(a4) the mixture a is added in described adhesive aqueous solution a I In II, and softwood is made in obtained mixture, gained softwood is crossed into the sieve granulation of 18 mesh stainless steels, to obtain wet granular； (a5) at 55 DEG C~65 DEG C, by the dry 1~4h of the wet granular, 18 mesh stainless steels is then crossed and sieve whole grain, to obtain dry Grain；(a6) dry particl is mixed with additional disintegrating agent, then obtained mixture is mixed with magnesium stearate, to obtain Obtain the medicinal mixture；(a7) content of dispersion of the medicinal mixture is measured, and is calculated the theoretical tablet weight, then by the drug Mixture carries out tabletting, to obtain the Mei Suoshuli label；(a8) coating powder is added in purified water, is configured to contain admittedly The Coating Solution that amount is 20%, is then coated processing to the Mei Suoshuli label using the Coating Solution, to obtain Obtain the Mei Suoshuli Film coated tablets.Inventor enables to the beauty of slightly solubility by the way that Mei Suoshuli is carried out micronization processes Suo Shuli adequately disperses in auxiliary material, in this way manufactured Mei Suoshuli Film coated tablets, and dissolution rate significant can obtain To improvement.

The invention will be added in two times in disintegrating agent point plus disintegrating agent and additional disintegrating agent both forms, Additional disintegrating agent can promote the disintegration of particle, and interior plus disintegrating agent can then accelerate the dispersion of particle, can greatly improve Mei Suoshu The dissolution rate of sharp Film coated tablets.Result described in the embodiment of the present invention can be seen that the work using addition inside and outside disintegrating agent Skill, relative to disintegrating agent only with the technique of interior addition, dissolution rate is significantly improved.Therefore determine dosage and the addition side of disintegrating agent Formula are as follows: the interior dosage of disintegrating agent is the 1/2 of disintegrating agent recipe quantity, and outer dosage is another the 1/2 of disintegrating agent recipe quantity.

According to an embodiment of the invention, hardness is controlled 5 when tabletting by slice weight control in ± 5% range of theoretical slice weight ~7kg.Mei Suoshuli Film coated tablets appearance, slice weight for obtaining as a result, etc. meet the requirements, and disintegration rate is fast, and dissolution rate is high.

According to an embodiment of the invention, the parameter of Cotton seeds can be with are as follows: average inlet air temperature is 85 DEG C, average piece bed temperature Degree is 41 DEG C, atomizing pressure 2.5bar, and average coating pan revolving speed is 15~23rpm, average 3~4g/min of material flow.By This, Mei Suoshuli Film coated tablets it is unilateral bright and clean, appearance meets the requirements.

By the preparation-obtained Mei Suoshuli Film coated tablets of the present invention, character, hardness, friability, tablet weight variation are accorded with It closes and requires, and dissolution rate is higher, and can reach 90%, meets the requirements.

According to an embodiment of the invention, the method for preparing Mei Suoshuli preparation may include: (b1) by the Mei Suoshuli It is micronized, to obtain Mei Suoshuli micro mist；(b2) the Mei Suoshuli micro mist is mixed with glidant and corrigent； (b3) filler is micronized, to obtain the filler micro mist that partial size is 20-100 microns；(b4) by the step Suddenly obtained mixture is mixed with the disintegrating agent and described adhesive in (b3)；It (b5) will be acquired in the step (b4) Mixture and the mix lubricant, to obtain medicinal mixture；(b6) drug is mixed by direct compression method Mei Suoshuli oral disnitegration tablet is made in object.

Inventor has found by long-term practice, when preparing Mei Suoshuli oral disnitegration tablet, first by Mei Suoshuli and filler After carrying out micronization processes, the large specific surface area constituted enables gained Mei Suoshuli oral disnitegration tablet fater disintegration.Especially It is when the combination using microcrystalline cellulose and mannitol is as filler, and first by Mei Suoshuli, microcrystalline cellulose, mannitol After mixing carries out micronization processes, the Mei Suoshuli oral disnitegration tablet disintegration rate prepared is very fast, and dissolution rate is preferable.

Using prescription and preparation process of the invention, finally can ensure that Mei Suoshuli oral disnitegration tablet have good mouthfeel and Disintegration, be conducive to oral disnitegration tablet can fater disintegration, dissolution rate is good and the quality of preparation is stablized, and is conducive to its industrial metaplasia It produces.Moreover, using Mei Suoshuli oral disnitegration tablet made from this method, disintegration time limited 15s-45s, hardness 5-8kg, friability Less than 0.5%, 10 minute, the amount of dissolution in pH8.8 phosphate buffer solution was greater than 85% to degree, and quality is stablized.Wherein, described The phosphate buffer of pH8.8 is obtained by the way that sodium hydroxide and potassium dihydrogen phosphate are dissolved in water, and with phosphoric acid tune pH to 8.8 ?.

According to an embodiment of the invention, the method for preparing Mei Suoshuli preparation may include: (c1) by the Mei Suoshuli It is dissolved in organic solvent, to obtain organic phase solution；(c2) filler and described adhesive are dissolved in purified water, to obtain Obtain aqueous phase solution；(c3) organic phase solution is mixed with the aqueous phase solution, is suspended to obtain the Mei Suoshuli of mixing Solution；(c4) it after the mixed Mei Suoshuli suspension solution being carried out homogeneous, is spray-dried, to be spray-dried Powder；(c5) spray-dried powders are mixed with the lubricant, the disintegrating agent and the corrigent, to obtain medicine Object mixture；(c6) medicinal mixture is sampled, and carries out assay, after measurement result is qualified, the drug is mixed The direct pressed powder of object is closed, to obtain Mei Suoshuli dispersible tablet.

According to an embodiment of the invention, Mei Suoshuli is dissolved in organic solvent, organic phase is formed, dissolution is slow added into In the aqueous phase solution for having filler and adhesive, Mei Suoshuli suspension solution is obtained, then the suspension solution is subjected to homogeneous, obtained The suspension solution particle arrived crushes more tiny and more uniform, after spray-dried, by gained spray-dried powders and profit Lubrication prescription, disintegrating agent and corrigent mixing, obtain medicinal mixture, after carrying out assay, by the direct powder of the medicinal mixture Tabletting, to obtain Mei Suoshuli dispersible tablet.Using the preparation process and technology of the present invention for preparing Mei Suoshuli preparation, The solubility that can effectively improve Mei Suoshuli helps to improve its absorption in vivo, and then improves Mei Suoshuli dispersion The dissolution rate and bioavilability of piece.Mei Suoshuli dispersible tablet of the present invention can reach in a short time 80% or more it is molten Out.

According to an embodiment of the invention, in method of the present invention, using solid dispersions technique with dispersible tablet Form realizes the preparation of insoluble drug Mei Suoshuli dispersible tablet, improves the solution rate of drug, improves oral bio Availability provides a new clinical application selection for patient.Meanwhile Mei Suoshu is prepared for by the way of powder vertical compression piece Sharp dispersible tablet, substantially increases production efficiency, reduces production cost.The Mei Suoshuli dispersion tablet quality prepared is stable, Disintegration meets the requirements, dissolve out rapidly, content is uniform, good mouthfeel, patient medication compliance are good.

According to an embodiment of the invention, the method for preparing Mei Suoshuli preparation may include: (d1) by the Mei Suoshuli It is dissolved in acetone, and hydroxypropyl beta cyclodextrin aqueous solution and Mei Suoshuli acetone soln are mixed, solvent is volatilized, to be tied Crystalline flour end；(d2) crystalline powder is subjected to ultra-fine grinding, and is mixed with skeleton slow-release material, filler；(d3) by step (d2) mixture obtained in is pelletized, and particle obtained is dried；(d4) by after drying particle and the profit Lubrication prescription and disintegrating agent mixing, and obtained mixture is subjected to tabletting.According to an embodiment of the invention, can be further It include: the label film coating that (d5) obtains the step (d4) tabletting, to obtain Mei Suoshuli sustained release tablets.Utilize this hair Bright this method can fast and effeciently prepare mentioned-above Mei Suoshuli sustained release tablets, and simple, convenient fast Victory, suitable industrialized production, meanwhile, the Mei Suoshuli for preparing sustained release tablet quality is stable, bioavilability is high, medication according to It is good from property, and effective acting time is longer.

According to an embodiment of the invention, the gross mass based on the label, according to mass percent meter, coating weight gain is 2%-3%.

According to an embodiment of the invention, label film coating described in step (5), coating powder material selection white are soluble in the stomach Type film coating pre-mix dose Opadry 81W68907.The preparation method of coating solution: coating powder purifying water dispersion is formulated into 15% solid content stirs 60 minutes.The technological parameter of coating are as follows: atomizing pressure 0.2MP (megapascal), thimble pressure 0.2MP, Coating pan revolving speed 15r/s, feed speed 3r/min, enters the wind frequency 1100Hz by 75 DEG C of inlet air temperature, and 35~45 DEG C of temperature of charge, Coating weight gain 2%~3% terminates.

According to an embodiment of the invention, the hardness of the Mei Suoshuli sustained release tablets is 5-8N (newton).Mei Suoshuli as a result, The dissolution rate of sustained release tablets is preferable.

According to an embodiment of the invention, inventor improves Mei Suoshuli in water molten based on the technology of solid dispersions Xie Du, while Mei Suoshuli sustained release tablets are prepared for using the mechanism that skeleton is sustained.The Mei Suoshuli sustained release prepared in aforementioned manners Piece and ordinary preparation in animal body in pharmacokinetic the result shows that, Mei Suoshuli sustained release tablets of the invention its in vivo 2~5 times of Increased Plasma Half-life, in vivo release curve shows that drug release is steady, can be realized 24 hours and stablizes release.Into One step, the above method combines solid dispersion technology with skeleton slow release method, on the one hand solves the oral life of Mei Suoshuli The low problem of object availability, being on the one hand made into sustained release tablets reduces medicining times, improves the compliance of patient medication.Moreover, This method is different from directly for Mei Suoshuli raw material being made into sustained release tablets, but first improves Mei Suoshu by solid dispersions technique The dissolubility of benefit, then sustained release tablets are made into, not only achieve the purpose that slow release, also improves the biology of drug in vivo Availability.

According to an embodiment of the invention, the method for preparing Mei Suoshuli preparation may include: (e1) by the Mei Suoshuli It is mixed with the solubilizer, and obtained mixture is subjected to micronization processes；(e2) it is mixed to obtained in step (e1) Filler is added in object, and obtained mixture is subjected to micronization processes, to obtain micro powder granule；It (e3) will be described micro- Powder particles and the suspending agent, the corrigent, described adhesive and solvent mixing；(e4) by gained in step (e3) To mixture successively through softwood processed, wet granular processed, drying, whole grain, to obtain Mei Suoshu Zhixieli granules agent.At micronization Reason, Ke Yi Shi get Mei Suoshuli are uniformly dispersed in raw mixture, prevent Mei Suoshuli fine particle from assembling, keep its stable It is present in mixture, and the dissolution rate of Mei Suoshuli can be effectively improved.

Since Mei Suoshuli is not soluble in water, if solution of granule agent is poor, molten according to general Preparation Technology of Granules States Pharmacopoeia specifications requirement is also far not achieved in out-degree.The above method of the invention mixes Mei Suoshuli and auxiliary material, and carries out twice Micronization processes recycle wet granulation to carry out the preparation of granule, the solubility and result of extraction of obtained Mei Suoshuli Good while in good taste, quality is stablized, and very good solution patient takes medicine inconvenient, compliance difference problem.But also it solves Children determined due to only smaller dose being needed to treat, and tablets and capsules are unfavorable for the deficiencies of separating administration place.

According to an embodiment of the invention, the method for preparing Mei Suoshuli preparation may include: (f1) by the Mei Suoshuli It is mixed with the filler, and it is 5-100 microns that obtained mixture, which is carried out micronization processes to partial size, to obtain Mixture micro powder granule is stated, the disintegrating agent, described adhesive, the lubricant are crossed into 60 mesh~80 meshes, it is spare；(f2) will Described adhesive is mixed with purified water, and to obtain described adhesive aqueous solution, the mass fraction of described adhesive aqueous solution is 5%~20%；(f3) the mixture micro powder granule is mixed with the interior disintegrating agent added, to obtain first mixing Object；(f4) first mixture is mixed with described adhesive aqueous solution, and obtained mixture is subjected to softwood processed, it will Gained softwood crosses the granulation of 18 meshes, to obtain the wet granular；(f5) at 55 DEG C~65 DEG C, the wet granular is done Dry 1~4 hour, 18 mesh sieves are crossed, then to obtain the dry particl；(f6) dry particl and described additional are collapsed Agent mixing is solved, to obtain the second mixture；(f7) second mixture is mixed with magnesium stearate, to obtain the medicine Object mixture；(f8) by the medicinal mixture carry out content detection, and by the medicinal mixture of content detection qualification into Row capsule is filling, to obtain the Mei Suoshuli capsule.Using this method of the invention, can quickly and effectively prepare Mentioned-above Mei Suoshuli capsule, and simple, convenient quick, is suitble to industrialized production, and by by Mei Suoshu Benefit carries out micronization processes, can effectively improve the dissolution rate and bioavilability of Mei Suoshuli.

Inventor passes through many experiments, it has unexpectedly been found that: by the way that the mixture of Mei Suoshuli and filler are carried out micro mist Change, the Mei Suoshuli bulk pharmaceutical chemicals of indissoluble can adequately can be dispersed in filler, especially when filler be lactose and When microcrystalline cellulose, the partial size of Mei Suoshuli and filler by micronization processes are 1-100 microns, the Mei Suoshuli energy It is adequately dispersed in hydrophilic lactose, thereby, it is possible to significantly improve the dissolution rate of Mei Suoshuli capsule.In addition, using wet Method granulating process, and it is creative disintegrating agent in prescription is used into inside and outside addition, additional disintegrating agent can promote collapsing for particle Solution, interior plus disintegrating agent can then accelerate the dispersion of particle.Relative to disintegrating agent only with the technique of interior addition, the present invention is using disintegration The dissolution rate of the resulting Mei Suoshuli capsule of the technique of addition significantly improves inside and outside agent.

According to an embodiment of the invention, the method for preparing Mei Suoshuli preparation may include: (g1) by the Mei Suoshuli It is mixed after ultra-fine grinding with the filler, the disintegrating agent and described adhesive, softwood is made in obtained mixture, and The load pill core is made by the method for extrusion spheronization in the softwood；(g2) by pore-foaming agent, antiplastering aid and separation layer solvent Mixing, to obtain the spacer layer coating liquid；(g3) high molecular polymer, plasticizer and purified water are mixed, to obtain The slow release layer coating solution；(g4) it by after load pill core drying, is placed in fluidized bed, it, will by the way of the spray coating of bottom The spacer layer coating liquid is sprayed on the load pill wicking surface, to form the separation layer on the surface for carrying pill core； (g5) after the load pill core for surface being formed with separation layer is dry, by the slow release layer coating solution be sprayed on the surface be formed with every The surface of the load pill core of absciss layer, to obtain the sustained release pellet；It (g6), will be described slow at preferably 35 DEG C in 30~40 DEG C Pellet is released to cure 6~10 hours, preferably 6 hours；(g7) sustained release pellet through overcuring is filled in Capsules, to obtain Obtain the Mei Suoshuli spansule.Using this method of the invention, mentioned-above beauty can be fast and effeciently prepared Suo Shuli spansule, and it is simple, convenient quick, it is suitble to industrialized production.And preparation-obtained beauty according to the present invention Suo Shuli spansule quality is stablized.

According to an embodiment of the invention, Mei Suoshuli raw material is adopted in the preparation method of Mei Suoshuli spansule of the present invention With micronization processes raw material, pill core is carried through extrusion spheronization technology preparation Mei Suoshuli, then using fluidized bed to load pill core The coating of separation layer and slow release layer is carried out, this process control is simple, is easy to the realization of industrialized production, and institute of the present invention Obtained Mei Suoshuli spansule is stable and controllable for quality.

According to an embodiment of the invention, realizing insoluble drug Mei Suoshuli sustained release glue using the form of sustained release pellet The preparation of capsule, and the solubility of Mei Suoshuli is improved, the absorption of drug in vivo is improved, Mei Suoshuli drug is improved Dissolution rate and oral administration biaavailability, and can be realized the slow release of Mei Suoshuli drug, realization is administered one time a day, mentions The high compliance of patient, provides a new clinical application for patient and selects.

According to an embodiment of the invention, the present invention is based on the technologies of solid dispersions to improve Mei Suoshuli in water molten Xie Du, while Mei Suoshuli spansule is prepared for using sustained release coating technology.Sustained release pellet uniform particle sizes therein, drug are released It keeps steady, it can be sustained release 12 hours or more.It is equal by many particle sizes with Mei Suoshuli spansule prepared by the present invention Even pellet composition, release behavior will be more stable, have higher safety than sustained release tablets, have more stable blood medicine Concentration reduces patient and the probability of adverse reaction occurs

Detailed description of the invention

Fig. 1 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli dispersible tablet；

Fig. 2 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli dispersible tablet；

Fig. 3 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli dispersible tablet；

Fig. 4 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli dispersible tablet；

Fig. 5 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli dispersible tablet；

Fig. 6 is shown according to one embodiment of present invention and comparative example d1, preparation gained Mei Suoshuli are sustained The dissolution determination comparing result figure of piece；

Fig. 7 is shown according to one embodiment of present invention and comparative example d2, preparation gained Mei Suoshuli are sustained The dissolution determination comparing result figure of piece；

Fig. 8 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli sustained release tablets；

Fig. 9 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli sustained release tablets；

Figure 10 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli sustained release tablets；

Figure 11 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli sustained release tablets；

Figure 12 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli sustained release tablets；

Figure 13 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli sustained release tablets；

Figure 14 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli sustained release tablets；

Figure 15 shows according to one embodiment of present invention, the dissolution determination result of Mei Suoshuli sustained release tablets；

Figure 16 shows that according to one embodiment of present invention the pharmacokinetics of Mei Suoshuli sustained release tablets and ordinary tablet is real Test result；

Figure 17 shows according to one embodiment of present invention, the dissolution rate test result of Mei Suoshuli spansule；

Figure 18 shows according to one embodiment of present invention, the dissolution rate test result of Mei Suoshuli spansule；With And

Figure 19 shows that according to one embodiment of present invention the pharmacokinetics of Mei Suoshuli spansule tests knot Fruit.

Specific embodiment

The embodiment of the present invention is described below in detail.The embodiments described below is exemplary, and is only used for explaining this hair It is bright, and be not considered as limiting the invention.Mei Suoshuli bulk pharmaceutical chemicals in embodiment are the original drug of 1.1 classes chemistry, are The self-control of people's good fortune Pharmaceutical Group.Particular technique or condition are not specified in embodiment, according to the literature in the art described skill Art or condition are carried out according to product description.Reagents or instruments used without specified manufacturer is that can pass through city Purchase the conventional products obtained.

The embodiment a1-a12 of following Mei Suoshuli Film coated tablets, to feed intake according to 1000 tablet recipe amounts, following embodiment It is only illustrated, is not intended to limit invention scope.

A1: Mei Suoshuli Film coated tablets formulation study of embodiment

Since main ingredient Mei Suoshuli is practically insoluble in water, and main ingredient amount is also larger, and therefore, the difficult point of formulation and technology is to mention The dissolution rate of high this product.In the present embodiment, the prescription for the Mei Suoshuli Film coated tablets that specification is 100mg/ piece is ground Study carefully, specifically, considering that water soluble adjuvant and disintegrating agent, which is added, to be promoted due to Mei Suoshuli raw material aqueous solubility and mobility inequality Into dissolution, 9 prescriptions are devised, a1 is shown in Table.

Table a1 different Formulations

Note: in the preparation of adhesive, hydroxypropyl methylcellulose need to add purified water be configured to 4% hydroxypropyl methylcellulose it is water-soluble Liquid (g/g), PVP K30 need to add purified water to be configured to 8% PVP K30 aqueous solution (g/g), and "-" expression is without respective sets Point.

By the prescription in table a1, using wet granulation technology, Mei Suoshuli label is first prepared, measures dissolution rate,

Preparation method is specific as follows:

(1) supplementary material pre-treatment: after main ingredient (Mei Suoshuli), each auxiliary material are crushed respectively, main ingredient crosses 60 meshes, auxiliary material mistake 80 meshes, it is spare；

(2) match adhesive:

When the adhesive in prescription selects PVP K30 (PVPK30), 8 grams of PVP K30s are weighed in beaker, are added pure Change 92 grams of water, stirs to clarify, obtain 8% PVP K30 aqueous solution I, it is spare；

When the adhesive in prescription selects hydroxypropyl methylcellulose, 4 grams of hydroxypropyl methylcelluloses are weighed in beaker, add purifying It 96 grams of water, stirs to clarify, obtains 4% hydroxypropyl methylcellulose aqueous solution I, it is spare；

(3) mix: the main ingredient that weighs recipe quantity, filler after mixing, add disintegrating agent crospovidone (PVPP) it is uniformly mixed, obtains mixture II；

(4) softwood processed and granulation: the binder aqueous solution I of recipe quantity is added in mixture II, softwood is made, by gained Softwood crosses the sieve granulation of 18 mesh stainless steels, obtains wet granular；

(5) it dries: drug wet granular obtained in step (4) is dried into about 2h at 60 DEG C ± 5 DEG C；

(6) whole grain: 18 mesh stainless steels sieve whole grain will be crossed by dry drug granule, obtains dry particl；

(7) total mix: being added recipe quantity magnesium stearate in dry particl, be uniformly mixed, obtain total mix particle；

(8) tabletting: according to content of dispersion measured by total mix particle, calculating the theoretical tablet weight, and tablet press machine is adjusted to suitable and is filled out Charge, control pressure make the tablet hardness of Film coated tablets within 5~7kg, and tabletting to obtain the final product.

Dissolution determination:

By the measuring method under 2010 editions dissolution rate items of Chinese Pharmacopoeia, above-mentioned 9 prescriptions are measured 45 points in dissolution medium The dissolution rate of clock, wherein dissolution medium is that (sodium hydroxide 2.30g, potassium dihydrogen phosphate 7.65g add water to make molten to phosphate buffer Solution is 1000ml, and with phosphoric acid tune pH to 8.8), dissolution determination the results are shown in Table a2.

The dissolution rate of each Film coated tablets Core formulation of table a2 compares

Prescription	a1	a2	a3	a4	a5	a6	a7	a8	a9
										Dissolution rate (%)	80.6	78.8	74.9	82.3	80.5	72.0	82.5	78.6	77.9

In terms of dissolution result, 9 designed prescriptions, 45 minutes dissolution rates in dissolution medium are shown, preferably prescription For prescription a1, prescription a4, prescription a5, prescription a7, dissolution rate has reached 80% or more.Due to Mei Suoshuli poorly water-soluble, And hypromellose is known as the molten effect of resistance, and dissolution rate may be influenced during sample keeps sample, its complete swelling in water in addition Required time is longer, is unfavorable for industrialized production, thus preferably its as adhesive.But due to previous experiments research shows that: When individually using lactose as filler, industrial mass production will appear sliver phenomenon, so the present invention is in the auxiliary material selection of diluent Do not select lactose.And microcrystalline cellulose not only serves as filler, and has the performance of disintegrating agent, choosing microcrystalline cellulose can Reach good result of extraction.

Therefore originally determine based on prescription a4 and prescription a7, it further investigates the optimum amount of screening filler, glue The concentration of mixture, and the addition manner of disintegrating agent is improved, prescription and preparation process are advanced optimized.

The Mei Suoshuli Film coated tablets prescription and process optimization of embodiment a2:100mg specification

This research is according to the Chinese Pharmacopoeia 2010 editions dosage form requirements to Film coated tablets, " the chemicals system promulgated referring to CDE Basic fundamental guideline is studied in agent ", the characteristics of combination film garment piece, with character, hardness, friability, disintegration time, dissolution rate Deng for inspection target, further screening has been carried out to the type and dosage of the used auxiliary material of this product prescription.

(1) screening of filler

The ratio and dosage of microcrystalline cellulose are adjusted, investigating diluent, (herein, " filler " and " diluent " can be with It is used interchangeably) influence of the different amounts to tabletting formability and dissolution rate, specific prescription and result be as follows:

Using microcrystalline cellulose as diluent, the prescription of microcrystalline cellulose different amounts is shown in Table a3, table a3 institute for this research It is shown as the recipe quantity of 1000 Mei Suoshuli Film coated tablets of preparation.According to preparation described in prescription shown in table a3 and embodiment a1 Method carries out pelletizing press sheet with 1000/batches of batches, and theoretical slice weight is 240mg, then measures the Mei Suoshuli prepared Hardness, friability, disintegration time and the dissolution rate of Film coated tablets screen filler.It the results are shown in Table a3.

The screening prescription and measurement result of table a3 filler

For microcrystalline cellulose by the dosage of above-mentioned 4 prescriptions, dissolution rate can reach 80% it can be seen from the result of table a3 More than, wherein best with the disintegration of prescription a12 and dissolution rate.

(2) screening of adhesive

PVP-K30 is chosen as adhesive, and the aqueous solution for preparing various concentration compares its bonding effect and grinds Study carefully, specific as follows:

According to prescription shown in table a4 and the preparation method in embodiment a1, Mei Suoshuli Film coated tablets is prepared Label observes Mei Suoshuli dry particl situation in preparation process, and measures the label of the Mei Suoshuli Film coated tablets prepared Hardness, friability, disintegration time and dissolution rate, prescription and measurement result are shown in Table a4, wherein prescription shown in table a4 be preparation The recipe quantity of the label of 1000 Mei Suoshuli Film coated tablets.

Wherein, in prescription a14, the preparation method of adhesive are as follows: weigh 4 grams of PVP K30s in beaker, add purified water It 96 grams, stirs to clarify, obtains 4% PVP K30 aqueous solution；Wherein in prescription a15, the preparation method of adhesive are as follows: weigh 8 grams PVP K30 adds 92 grams of purified water, stirs to clarify in beaker, obtains 8% PVP K30 aqueous solution；Wherein in prescription a16, The preparation method of adhesive are as follows: weigh 12 grams of PVP K30s in beaker, add 88 grams of purified water, stir to clarify, it is poly- to obtain 12% Tie up ketone K30 aqueous solution；Wherein in prescription a17, the preparation method of adhesive are as follows: weigh 6 grams of PVP K30s in beaker, add pure Change 94 grams of water, stirs to clarify, obtain 6% PVP K30 aqueous solution；Wherein in prescription a18, the preparation method of adhesive are as follows: claim It takes 15 grams of PVP K30s in beaker, adds 85 grams of purified water, stir to clarify, obtain 15% PVP K30 aqueous solution.

The screening of table a4 adhesive

It can be seen that from the result of table a4 when binder concn is 4%, softwood is dry, loosely, it has been not easy to glue, due to Obtained dry particl is small and loose, and fine powder is more, poor fluidity, be easy to cause tablet weight variation unqualified, poor compressibility, causes hard Spend relatively low, friability is high, is unable to satisfy coating demand；When binder dosage reaches 15%, obtained softwood is harder, is not easy Sieve, viscous sieve is more serious, and mostly strip, and extends disintegration time；And when the concentration of adhesive is 6%~12%, Obtained softwood dry and wet degree is moderate, the particle rounding for being easily sieved and obtaining, and uniformly, good fluidity is easy to carry out tabletting, obtain The inspection targets such as tablet hardness, friability, disintegration time to Film coated tablets are qualified, therefore, select adhesive for PVPK₃₀, Concentration is 6%~12%, the adhesive PVPK in prescription₃₀Dosage are as follows: 6g~12g/1000 piece.

(3) screening of disintegrating agent

In the present embodiment, the dosage of disintegrating agent and the addition manner of disintegrating agent have been investigated to Mei Suoshuli Film coated tablets The influence of label, specific as follows:

According to formula shown in table a5 and the preparation method in embodiment a1, Mei Suoshuli Film coated tablets piece is prepared Core.It should be noted that in the present embodiment, the addition manner of disintegrating agent is two kinds: interior addition and outer addition, interior addition be Disintegrating agent is added in step (3), outer addition refers to is added disintegrating agent in step (7).Then the Mei Suoshu prepared is measured Hardness, friability, disintegration time and the dissolution rate of sharp Film coated tablets label, measurement result are shown in Table 6.Wherein, it is formulated shown in table 5 For the recipe quantity for preparing 100 Mei Suoshuli Film coated tablets labels.

The prescription screening of table a5 disintegrating agent

The prescription screening experimental result of table a6 disintegrating agent

It can be seen that prescription a20 from the result of table a6 and prescription a21 dissolution results difference be little, illustrate to reduce certain The disintegrating agent of amount can still keep preferably dissolving out, while can be with save the cost.Using inside and outside addition, additional disintegrating agent can be with Promote the disintegration of particle, interior plus disintegrating agent can then accelerate the dispersion of particle, be conducive to improve dissolution rate.It can see from the above Out, the disintegration time of prescription a23 and dissolution rate are attained by optimal, therefore determine the dosage and addition manner of PVPP are as follows: interior to add 0.7g, additional 0.5g.Therefore, fixing tentatively best prescription is prescription a23.

According to formula shown in table a7 and the preparation method in embodiment a1, Mei Suoshuli piece is prepared.

It should be noted that in the present embodiment, the addition manner of disintegrating agent is two kinds: interior addition and outer addition.

Interior addition refers to is added disintegrating agent in mixing step, and outer addition refers in total mix step, be added lubricant it Before, first dry particl and disintegrating agent are uniformly mixed.

When disintegrating agent carries out inside and outside addition, sample is prepared using wet granulation technology respectively by the prescription in table a7, The preparation method is as follows:

(2) match adhesive: weighing 8 grams of PVP K30s in beaker, add 92 grams of purified water, stir to clarify, it is poly- to obtain 8% Ketone K30 aqueous solution I is tieed up, it is spare；

(3) mix: the filler of the main ingredient, recipe quantity that weigh recipe quantity after mixing, adds the disintegration added in needing Agent crospovidone is uniformly mixed, and obtains mixture II；

(7) total mix: being added the additional disintegrating agent crospovidone of the need of recipe quantity in dry particl, adds recipe quantity tristearin Sour magnesium is uniformly mixed, obtains total mix particle；

(8) tabletting: according to content of dispersion measured by total mix particle, calculating the theoretical tablet weight, and tablet press machine is adjusted to suitable and is filled out Charge, control pressure make Film coated tablets tablet hardness within 5~7kg, and tabletting to obtain the final product.

Then hardness, friability, disintegration time and the dissolution rate of the Mei Suoshuli Film coated tablets label prepared are measured, Measurement result is shown in Table a7.Wherein, the formula of prescription a24- prescription a28 shown in table a7 is the prescription for preparing 1000 Mei Suoshuli pieces Amount.

The prescription screening of table a7 disintegrating agent

It can be seen that prescription a24, prescription a25 from the result of table a7 and prescription a26 dissolution results difference be little, explanation Reducing a certain amount of disintegrating agent can still keep preferably dissolving out, while can be with save the cost.Prescription a27's and prescription a28 Disintegrating agent is all made of inside and outside addition, and dissolution rate significantly improves.Additional disintegrating agent can promote the disintegration of particle, and interior plus disintegrating agent is then The dispersion that can accelerate particle is conducive to improve dissolution rate.It can be seen from the results above that using the work of addition inside and outside disintegrating agent Skill, relative to disintegrating agent only with the technique of interior addition, dissolution rate is significantly improved.Therefore determine dosage and the addition side of disintegrating agent Formula are as follows: the interior dosage of disintegrating agent is the 1/2 of disintegrating agent recipe quantity, and outer dosage is another the 1/2 of disintegrating agent recipe quantity.Therefore, it fixes tentatively Prescription is prescription a28.

A3: Mei Suoshuli Film coated tablets preparation process of embodiment advanced optimizes experiment

1, Mei Suoshuli bulk pharmaceutical chemicals partial size is investigated

Influence of the partial size of Mei Suoshuli bulk pharmaceutical chemicals to Mei Suoshuli piece is investigated in accordance with the following steps, specific as follows:

Based on the prescription a28 in embodiment 2, preparation process of the invention is advanced optimized, further to mention The dissolution rate of high Mei Suoshuli Film coated tablets label of the present invention.

Specifically, according to prescription a28, two groups of (A group and B group) Mei Suoshuli Film coated tablets labels are prepared respectively, prepare A group The method of Mei Suoshuli Film coated tablets label is as described below, the preparation method and A group Mei Suoshuli film of B group Mei Suoshuli tablet The preparation method difference of tablet core is that the mixture of main ingredient Mei Suoshuli and auxiliary material filler does not carry out micronization processes. It is specific as follows:

A group Mei Suoshuli Film coated tablets label the preparation method is as follows:

(1) supplementary material pre-treatment: main ingredient (Mei Suoshuli) and filler microcrystalline cellulose are mixed and are micronized (partial size At 5 microns to 100 microns), remaining each auxiliary material smash it through 80 meshes respectively, it is spare；

(3) it mixes: after mixing by Mei Suoshuli and filler, the disintegrating agent crospovidone mixing added in needing is added Uniformly, mixture II is obtained；

Then the dissolution rate of the Mei Suoshuli Film coated tablets label prepared is measured, measurement result is shown in Table a8.

Table a8

By the result of table a8 it is found that relative to the Mei Suoshuli without micronization, first by Mei Suoshuli and filler crystallite Cellulose mixing is micronized, then the dissolution rate of Mei Suoshuli Film coated tablets label obtained can significantly be improved.

2, tablet forming technique is investigated

It is thick in conjunction with slice weight and suitable piece according to working condition, while to consider to meet friability requirement, using tablet press machine into Row tabletting.The hardness level of Film coated tablets label is controlled into the section shown in table a9, then measures the Film coated tablets of different hardness Friability, dissolution rate and the disintegration time of label, measurement result are shown in Table a9.

Table a9 investigates influence of the hardness to experimental result

It was found from the result of table a9: when range of the hardness of Film coated tablets label between 4~7kg, disintegration time and Dissolution rate is affected by it less；And when hardness is in 7~8kg, dissolution rate reduces；And when hardness is in 4~5kg, friability is big； In view of Film coated tablets label also need of coating, to the more demanding of friability, therefore, the hardness of Film coated tablets label is controlled It is comparatively ideal range in 5~7kg.

Wherein, prescription a30 is the Mei Suoshuli piece that specification is 50mg, prescription are as follows: Mei Suoshuli 50g, microcrystalline cellulose 170g, PVP K30 8g, crospovidone (interior to add) 6g, crospovidone (additional) 6g, magnesium stearate 2.5g.

Prescription a29 is the Mei Suoshuli piece that specification is 100mg, prescription are as follows: Mei Suoshuli 100g, microcrystalline cellulose 120g, PVP K30 8g, crospovidone (interior to add) 6g, crospovidone (additional) 6g, magnesium stearate 2.5g.

The preparation method is as follows:

(1) supplementary material pre-treatment: main ingredient (Mei Suoshuli) and auxiliary material filler are mixed and are micronized that (partial size is micro- 5 Rice to 100 microns), remaining each auxiliary material smash it through 80 meshes respectively, it is spare；

(8) tabletting: according to content of dispersion measured by total mix particle, calculating the theoretical tablet weight, and tablet press machine is adjusted to suitable and is filled out Charge, controlling pressure respectively makes Film coated tablets tablet hardness carry out tabletting within 4~5kg, 5~6kg, 6~7kg, 7~8kg Up to the Mei Suoshuli piece of above-mentioned different hardness.

3, art for coating is studied

In order to guarantee Film coated tablets quality and conveniently take, and Chang Mei Suoshuli label (heretofore described label, i.e., Refer to the Mei Suoshuli piece not being coated in above-described embodiment) the suitable clothing layer material of surface layer package, make in Film coated tablets Drug is isolated from the outside, and obtains being covered with the Film coated tablets of film-coating in Mei Suoshuli medical surfaces, to reach moisture-proof, keep away The stability that light, isolation air oxidation, enhancing drug save covers the bad odor in Film coated tablets and reduces medicine irritation Purpose.

(1) coating material are as follows: white stomach dissolution type Opadry 81W68907, Shanghai Colorcon Coating Technology Co., Ltd are raw It produces.

(2) coating solution is prepared

Coating powder is added in purified water, the solution of solid content 20% is configured to, with screw type stirring paddle stirring 45 minutes.The coating solution made can directly pump out use by peristaltic pump from liquid dispensing container.

(3) coating conditions

85 DEG C of inlet air temperature of setting, average piece bed tempertaure are 41 DEG C, coating pan 15~23r/min of revolving speed, spouting velocity 3~ 4g/min.After every weight gain to setting value, stop spray coating solution, drying of blowing a cold wind over is cooled to room temperature slice to piece temperature, uses film Packed good, weighing is taken a sample to check.

(4) screening of coating powder dosage

130804 batches of Mei Suoshuli Film coated tablets label samples of above-mentioned preparation are taken to weigh coating by the 5% of label weight Powder adds purified water that the solution that solid content is 20% is made, and investigates the coating effect of different coating weight gains, and investigation the results are shown in Table a10.

The screening of table a10 coating powder dosage

Coating weight gain	Coating effect (amplification sem observation)	Disintegration time (s)
			1.8%	Package is complete substantially for label, but edge is imperfect	78
3.0%	Coating tablet is fully wrapped around, and color is uniform, and edge is complete	105
			3.5%	Coating tablet is fully wrapped around, and color is uniform, and edge is complete	113
4.0%	Coating tablet is fully wrapped around, and color is uniform, and edge is complete	171

Table a10's the result shows that, coating powder dosage be label weight 3.0% or more when, coating tablet appearance has been able to satisfy It is required that and as coating powder dosage increases, disintegration time accordingly extends, and when coating powder dosage is 4.0%, disintegration time exists Accelerate extended possibility.Basic performance is carried out to the coating tablet that above-mentioned three kinds of appearances are met the requirements to evaluate as shown in following table a11:

The evaluation of table a11 coating tablet basic performance

Comprehensively consider in conjunction with the result of table a10 and table a11, controls coating weight gain in label weight when selection is coated 3.0%-3.5%, had not only been able to satisfy the appearance requirement of coating tablet, but also did not influenced disintegration time and dissolution rate, moreover it is possible to play preferable Shaded effect.

The preparation of a4: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 50g, microcrystalline cellulose 170g, PVP K30 8g, crospovidone (interior to add) 6g, crospovidone (additional) 6g, magnesium stearate 2.5g are made 1000 altogether.

Preparation method:

(2) match adhesive: weighing 8 grams of adhesive PVP K30s in beaker, add 92 grams of purified water, stir to clarify, obtain The binder aqueous solution I of 8% PVP K30, it is spare；

(5) it dries: drug wet granular obtained in step (4) is dried into 2h at 60 DEG C；

(9) it is coated: coating powder white stomach dissolution type Opadry 81W68907 being added in purified water, solid content is configured to For 20% Coating Solution, with screw type stirring paddle stirring 45 minutes.Label is carried out using common transformation coating pan Coating, get Mei Suoshuli Film coated tablets.Wherein, the major parameter of coating process is as follows: average inlet air temperature is 85 DEG C, average piece Bed tempertaure is 41 DEG C, atomizing pressure 2.5bar, and average coating pan revolving speed is 15~23rpm, average 3~4g/ of material flow Min, weight gain 3%~3.5%, obtains the Mei Suoshuli Film coated tablets.

(10) it packs: the Mei Suoshuli Film coated tablets being wrapped using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag Dress.

The preparation of a5: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 50g, microcrystalline cellulose 150g, PVP K30 8g, crospovidone (interior to add) 6g, crospovidone (additional) 6g, magnesium stearate 2.4g are made 1000 altogether.

Preparation method: with embodiment 5.

The preparation of a6: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 50g, microcrystalline cellulose 120g, PVP K30 10g, crospovidone (interior to add) 2.5g, crosslinking are poly- Dimension ketone (additional) 2.5g, magnesium stearate 1g is made 1000 altogether.

Preparation method: matching adhesive: weighing 10 grams of adhesive PVP K30s in beaker, adds 90 grams of purified water, stirring is extremely Clarification, obtains the binder aqueous solution I of 10% PVP K30；Remaining preparation method is the same as embodiment 4.

The preparation of a7: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 25g, microcrystalline cellulose 200g, PVP K30 6g, crospovidone (interior to add) 8g, crospovidone (additional) 8g, magnesium stearate 0.8g are made 1000 altogether.

Preparation method: matching adhesive: weighing 6 grams of adhesive PVP K30s in beaker, adds 94 grams of purified water, stirring is extremely Clarification, obtains the binder aqueous solution I of 6% PVP K30；Remaining preparation method is the same as embodiment 4.

The preparation of a8: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 75g, microcrystalline cellulose 150g, PVP K30 12g, crospovidone (interior to add) 10g are crosslinked poly- dimension Ketone (additional) 10g, magnesium stearate 4g is made 1000 altogether.

Preparation method: matching adhesive: weighing 12 grams of adhesive PVP K30s in beaker, adds 88 grams of purified water, stirring is extremely Clarification, obtains the binder aqueous solution I of 12% PVP K30；Remaining preparation method is the same as embodiment 4.

The preparation of a9: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 100g, microcrystalline cellulose 120g, PVP K30 7g, crospovidone (interior to add) 6g are crosslinked poly- dimension Ketone (additional) 6g, magnesium stearate 2.5g is made 1000 altogether.

Preparation method: matching adhesive: weighing 7 grams of adhesive PVP K30s in beaker, adds 93 grams of purified water, stirring is extremely Clarification, obtains the binder aqueous solution I of 7% PVP K30；Remaining preparation method is the same as embodiment 4.

The preparation of a10: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 100g, microcrystalline cellulose 120g, PVP K30 10g, crospovidone (interior to add) 7g are crosslinked poly- dimension Ketone (additional) 7g, magnesium stearate 3g is made 1000 altogether.

The preparation of a11: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 125g, microcrystalline cellulose 90g, PVP K30 7g, crospovidone (interior to add) 5g, crospovidone (additional) 5g, magnesium stearate 2g are made 1000 altogether.

Embodiment a12: quality evaluation

1, performance evaluation

Totally 8 samples described in a4- embodiment of embodiment of the present invention a11 carry out character, hardness, friability, the piece method of double differences Different, dissolution rate inspection the results are shown in Table a12 in order to carry out performance evaluation to the preparation-obtained Mei Suoshuli of the present invention.

The evaluation of table a12 Mei Suoshuli piece performance

Table a12 the results show that the character of 8 batches of samples, hardness, friability, tablet weight variation meet the requirements, and dissolution rate compared with Height, and can reach 90%, it meets the requirements.

2, influence factor experiment in 10 days:

Next, preparing Mei Suoshuli Film coated tablets to above-described embodiment a4 carries out influence factor experiment, specifically such as Under:

The Mei Suoshuli Film coated tablets (lot number 131205) of 50mg specification is uncovered in culture dish, high temperature (60 DEG C), It places 10 days under the conditions of high humidity (RH 92.5%, 25 DEG C), Qiang Guang (4500lx ± 500lx), was sampled in the 5th, 10 day, observation system The projects such as agent appearance, content, dissolution rate, related substance, weight-loss ratio, and be compared with the inspection data for investigating preceding sample, it examines Survey the results are shown in Table 13.

Wherein, impurity 1 is compound shown in formula I disclosed in Chinese invention patent application CN103553984A, structure Formula is as follows:

Table a13 Mei Suoshuli Film coated tablets (50mg/ piece) (lot number 131205) influence factor experiment investigation result

3, the selection of interior packaging material:

Next, to the Mei Suoshuli Film coated tablets of above-mentioned 50mg specification, 3 batches are produced, lot number is respectively 131206, 131207, the comparative studies of four kinds of packagings 131208, have been carried out respectively, and four kinds of quasi- choosing packagings are successively are as follows: polyvinyl chloride (PVC) bubble Cover, PVC bubble-cap+two-sided composite aluminium film bag, two-sided composite aluminium film bag and plastic bottle.Then, the thin of four kinds of packagings will be respectively adopted Film garment piece is placed 6 months under the conditions of temperature is 40 DEG C ± 2 DEG C, relative humidity is 75% ± 5%, accelerate 6 months Comparison is investigated, and respectively at the 0th, 1,2,3, sampling in June, has been carried out the detection of each inspection target of stability test, has been accelerated 6 months Experimental data is shown in Table a14.

Table a14 Mei Suoshuli Film coated tablets (50mg/ piece, PVC bubble-cap+two-sided composite aluminium film bag) accelerates experiment in 6 months As a result

After accelerating 6 months, the content of four kinds of packagings, related substance dissolution rate are all without significant changes.PVC blister package and modeling The piece sub-pieces of material bottle packaging is significantly increased again, and piece for prompting both to pack has the different degrees of moisture absorption, it may be possible to because For the poor air-tightness of plastic bottle and PVC blister package, it is affected by humidity.Although each finger of two-sided composite aluminium film bag packaging Mark variation is little, but due to not easy to maintain behind Kaifeng, so not using.PVC bubble-cap+two-sided composite membrane aluminium bag packaging piece, Appearance character, content, related substance and dissolution rate are all more stable.It can be seen that PVC bubble-cap+two-sided composite aluminium film bag packs water-fast steaming The long-time stability of this product can be effectively ensured in permeability to gas, favorable sealing property.Therefore, PVC bubble-cap+two-sided clad aluminum is selected Film bag is packaged as the optimal interior packaging material of Mei Suoshuli Film coated tablets.

The embodiment h1-h14 of following Mei Suoshuli Film coated tablets, to feed intake according to 1000 tablet recipe amounts, following embodiment It is only illustrated, is not intended to limit invention scope.

Embodiment h1: main ingredient and auxiliary material interaction are tested

In the present embodiment, whether there are interaction and preparation in main ingredient and prescription between selected auxiliary material to investigate Whether crystal form has change in the process, (public according to Chinese invention patent application CN103553984A embodiment 8 using liquid chromatography The Mei Suoshuli HPLC detection method opened) interaction between selected auxiliary material and main ingredient is studied.

Specifically, by independent auxiliary material, the mixture of main ingredient and each independent auxiliary material, the mixture of main ingredient and all auxiliary materials It is placed 10 days under the conditions of influence factor respectively, after comparing 0 day and 10 days, the character of mixture, the change in relation to substance and content Change.

1, the preparation of test sample

The lot number of bulk pharmaceutical chemicals (Mei Suoshuli): 101217 batches (self-control of Ren Fu Pharmaceutical Group joint-stock company, purity 99.8%), Mei Suoshuli bulk pharmaceutical chemicals are first crossed into 60 meshes, each auxiliary material crosses 80 meshes.

H1 sample: main ingredient and microcrystalline cellulose (mass ratio 1:5) mixture；

0.1g Mei Suoshuli bulk pharmaceutical chemicals and 0.5g microcrystalline cellulose are weighed, 60 meshes is crossed and mixes 3 times, number h is 1.

H2 sample: main ingredient and lactose (mass ratio 1:5) mixture；

0.1g Mei Suoshuli bulk pharmaceutical chemicals and 0.5g lactose are weighed, 60 meshes is crossed and mixes 3 times, number h is 2.

H3 sample: the mixture of main ingredient and PVP K30 (mass ratio 5:1)

0.5g Mei Suoshuli bulk pharmaceutical chemicals and 0.1g PVP K30 are weighed, 60 meshes is crossed and mixes 3 times, number h is 3.

H4 sample: main ingredient and crospovidone (mass ratio 5:2) mixture

0.5g Mei Suoshuli bulk pharmaceutical chemicals and 0.2g crospovidone are weighed, 60 meshes is crossed and mixes 3 times, number h is 4.

H5 sample: the mixture of main ingredient and magnesium stearate (mass ratio 20:1)

2g Mei Suoshuli bulk pharmaceutical chemicals and 0.1g magnesium stearate are weighed, 60 meshes is crossed and mixes 3 times, number h is 5.

H6 sample: main ingredient and mixed accessories (mass ratio 1:5) mixture；

Weigh 0.1g Mei Suoshuli bulk pharmaceutical chemicals and 0.5g mixture (wherein lactose 0.23g+ microcrystalline cellulose 0.23g+ Crospovidone 0.04g), it crosses 60 meshes and mixes 3 times, number h is 6.

2, test method

Above-mentioned h1-h6 sample is respectively placed in high temperature, high humidity and illumination condition lower 10 days, after comparing 0 day and 10 days, is mixed The character of conjunction object, the variation in relation to substance and content, test result are shown in Table h1.

Table h1 main ingredient and auxiliary material compatibility experiments result

3, conclusion

H1~h6 sample placed 10 days under high temperature, high humidity and illumination condition after measurement result, compared with 0 day, Character, content do not have significant change, and impurity 1 does not increase trend, and without generating new impurity, the results showed that, each auxiliary material with Compatibility is good between main ingredient, does not interact between Mei Suoshuli and each auxiliary material.

The formulation study of h2: Mei Suoshuli Film coated tablets of embodiment

Since main ingredient Mei Suoshuli is practically insoluble in water, and main ingredient amount is also larger, and therefore, the difficult point of formulation and technology is to mention The dissolution rate of high this product.In the present embodiment, the prescription for the Mei Suoshuli tablet that specification is 50mg/ piece is studied, is had For body, due to Mei Suoshuli raw material aqueous solubility and mobility inequality, considers that water soluble adjuvant is added and disintegrating agent promotion is molten Out, 9 prescriptions are devised, h2 is shown in Table.

Table h2 different Formulations

Note: in the preparation of adhesive, hydroxypropyl methylcellulose need to add purified water be configured to 4% hydroxypropyl methylcellulose it is water-soluble Liquid (g/g), PVP K30 need to add purified water be configured to 8% PVP K30 aqueous solution (g/g).

By the prescription in table h1, using wet granulation technology, Mei Suoshuli label is first prepared, measures dissolution rate,

Preparation method is specific as follows:

(2) match adhesive:

(8) tabletting: according to content of dispersion measured by total mix particle, calculating the theoretical tablet weight, and tablet press machine is adjusted to suitable and is filled out Charge, control pressure make tablet hardness within 5~7kg, and tabletting to obtain the final product.

Dissolution determination:

By the measuring method under 2010 editions dissolution rate items of Chinese Pharmacopoeia, above-mentioned 9 prescriptions are measured 45 points in dissolution medium The dissolution rate of clock, wherein dissolution medium is that (sodium hydroxide 2.30g, potassium dihydrogen phosphate 7.65g add water to make molten to phosphate buffer Solution is 1000ml, and with phosphoric acid tune pH to 8.8), dissolution determination the results are shown in Table h3.

The dissolution rate of each tablet formulation of table h3 compares

Prescription	1	2	3	4	5	6	7	8	9
										Dissolution rate (%)	81.3	71.6	70.9	80.2	72.3	71.1	72.8	80.6	71.9

In terms of dissolution result, 9 designed prescriptions, 45 minutes dissolution rates in dissolution medium are shown, preferably prescription For prescription h1, prescription h4, prescription h8.Due to Mei Suoshuli poorly water-soluble, and hypromellose is known as the molten effect of resistance, may be Sample influences dissolution rate during keeping sample, it is longer the time required to complete swelling in water in addition, is unfavorable for industrialized production, therefore Preferably its as adhesive.But due to previous experiments research shows that: when individually using lactose as filler, industrial mass production can go out Existing sliver phenomenon, so the present invention does not select lactose individually in the auxiliary material selection of diluent.But due to as filler Lactose good water solubility, and microcrystalline cellulose not only serves as filler, and has the performance of disintegrating agent, chooses lactose and crystallite Cellulose combination is used as diluent (herein, " filler " and " diluent " may be used interchangeably) simultaneously, reachable To good result of extraction.

Therefore originally determine based on prescription h1, further investigate the optimal proportion and dosage, bonding of screening filler The concentration of agent, and the addition manner of disintegrating agent is improved, prescription and preparation process are advanced optimized.

The Mei Suoshuli Film coated tablets prescription and process optimization of embodiment h3:50mg specification

Dosage form requirement of this research according to Chinese Pharmacopoeia 2010 editions to tablet, referring to CDE promulgation " chemicals medicine is ground Study carefully basic fundamental guideline ", it is to investigate with character, hardness, friability, disintegration time, dissolution rate etc. in conjunction with the characteristics of tablet Index further screens the type and dosage of the used auxiliary material of this product prescription.

(1) screening of diluent

In embodiment h2 on the basis of prescription h1, the ratio and dosage of lactose and microcrystalline cellulose are adjusted, investigates dilution The influence of agent different proportion and dosage to tabletting formability and dissolution rate, specific as follows:

According to preparation method described in prescription shown in table h4 and embodiment h2, pelletized with 1000/batches of batches, Then tabletting measures hardness, friability, disintegration time and the dissolution rate of the Mei Suoshuli tablet prepared, screen filler. It the results are shown in Table h4.

Wherein in prescription h10- prescription h14, the preparation method of adhesive are as follows: weigh 8 grams of PVP K30s in beaker, add It 92 grams of purified water, stirs to clarify, obtains 8% PVP K30 aqueous solution.

The screening prescription and measurement result of table h4 filler

It can be seen from the result of table h4 in above-mentioned h5 prescription, since lactose proportion is larger, micro- in prescription h12 Crystalline cellulose proportion is smaller, causes disintegrating property slightly worse, and dissolution rate is slightly lower, and the disintegration of prescription h10, h11, h13, h14 Preferable with dissolution rate, dissolution rate can reach 80% or more, therefore selecting the mass ratio of lactose and microcrystalline cellulose is (0.25 ~3): 1, wherein the resulting dissolution rate of prescription h10 is best and disintegration time is moderate, therefore it is preferred that lactose and microcrystalline cellulose most Good mass ratio is 0.5:1.

(2) selection of binder dosage

PVP K30 is chosen as adhesive, and the aqueous solution for preparing various concentration compares its bonding effect Research, investigates influence of the dosage of adhesive to Mei Suoshuli tablet, specific as follows:

According to prescription shown in table h5 and the preparation method in embodiment h2, Mei Suoshuli tablet is prepared, is prepared Observe Mei Suoshuli softwood in the process and the case where particle, and measure the hardness of the Mei Suoshuli tablet prepared, friability, Disintegration time and dissolution rate, prescription and measurement result are shown in Table h5,

Wherein, prescription shown in table h5 is the supplementary material dosage for preparing 1000 tablets of Mei Suoshuli tablets.

Wherein, in prescription h15, the preparation method of adhesive are as follows: weigh 4 grams of PVP K30s in beaker, add purified water It 96 grams, stirs to clarify, obtains 4% PVP K30 aqueous solution；Wherein in prescription h16, the preparation method of adhesive are as follows: weigh 8 grams PVP K30 adds 92 grams of purified water, stirs to clarify in beaker, obtains 8% PVP K30 aqueous solution；Wherein in prescription h17, The preparation method of adhesive are as follows: weigh 12 grams of PVP K30s in beaker, add 88 grams of purified water, stir to clarify, it is poly- to obtain 12% Tie up ketone K30 aqueous solution；Wherein in prescription h18, the preparation method of adhesive are as follows: weigh 6 grams of PVP K30s in beaker, add pure Change 94 grams of water, stirs to clarify, obtain 6% PVP K30 aqueous solution；Wherein in prescription h19, the preparation method of adhesive are as follows: claim It takes 15 grams of PVP K30s in beaker, adds 85 grams of purified water, stir to clarify, obtain 15% PVP K30 aqueous solution.

The prescription screening of table h5 binder dosage

It can be seen that in prescription h15 from the result of table h5, when binder concn is 4%, softwood is dry, easily it is sieved, Grain is small, and fine powder is more, it is insufficient to will lead to tablet toughness, and the tablet content uniformity obtained when tabletting is unqualified；In prescription h18 When binder dosage reaches 15%, obtained softwood is wetter, it is more difficult to be sieved, particle has strip, consolidation, and extends disintegration Time；The raising of binder dosage is to dissolution, mobility of particle without too big improvement result.And in prescription h16, prescription h17, When the concentration of adhesive is 6g (6%), 8g (8%) or 10g (10%), obtained softwood dry and wet degree is moderate, is easily sieved And obtained particle rounding, uniformly, good fluidity is easy to carry out tabletting.Therefore determine that the dosage of adhesive is 6~12g/1000 Piece.

(3) screening of disintegrating agent dosage

In the present embodiment, the dosage of disintegrating agent and the addition manner of disintegrating agent have been investigated to the shadow of Mei Suoshuli tablet It rings, specific as follows:

According to formula shown in table h6 and the preparation method in embodiment h2, Mei Suoshuli piece is prepared.

Interior addition is that disintegrating agent is added in mixing step, and outer addition refers in total mix step, before lubricant is added, First dry particl and disintegrating agent are uniformly mixed.

When disintegrating agent carries out inside and outside addition, Mei Suoshu is prepared using wet granulation technology respectively by the prescription in table h6 Sharp tablet, the preparation method is as follows:

(2) match adhesive: weighing 10 grams of PVP K30s in beaker, add 90 grams of purified water, stir to clarify, obtain 10% PVP K30 aqueous solution I, it is spare；

Then hardness, friability, disintegration time and the dissolution rate of the Mei Suoshuli tablet prepared, measurement result are measured It is shown in Table h6.Wherein, the formula of prescription h20- prescription h24 shown in table h6 is the recipe quantity for preparing 1000 Mei Suoshuli pieces.

The prescription screening of table h6 disintegrating agent

Note: "-" indicates not containing respective components

It can be seen that prescription h20, prescription h21 from the result of table h6 and prescription h22 dissolution results difference be little, explanation Reducing a certain amount of disintegrating agent can still keep preferably dissolving out, while can be with save the cost.Prescription h23's and prescription h24 Disintegrating agent is all made of inside and outside addition, and dissolution rate significantly improves.Additional disintegrating agent can promote the disintegration of particle, and interior plus disintegrating agent is then The dispersion that can accelerate particle is conducive to improve dissolution rate.It can be seen from the results above that using the work of addition inside and outside disintegrating agent Skill, relative to disintegrating agent only with the technique of interior addition, dissolution rate is significantly improved, and dissolution rate can be improved to 85% or more. Therefore determine the dosage and addition manner of disintegrating agent are as follows: the interior dosage of disintegrating agent is the 1/2 of disintegrating agent recipe quantity, and outer dosage is disintegration Another the 1/2 of agent recipe quantity.Therefore, fixing tentatively prescription is prescription h24.

Embodiment 4: preparation process advanced optimizes experiment

1, Mei Suoshuli bulk pharmaceutical chemicals partial size is investigated

Based on the prescription h24 in embodiment h3, preparation process of the invention is advanced optimized, further to mention The dissolution rate of high Mei Suoshuli piece of the present invention.

Specifically, according to prescription h24, two groups of (A group and B group) Mei Suoshuli tablets are prepared respectively, prepare A group Mei Suoshuli The method of tablet is as described below, and the preparation method of B group Mei Suoshuli tablet and the preparation method difference of A group Mei Suoshuli tablet exist In the mixture of main ingredient Mei Suoshuli and auxiliary material filler does not carry out micronization processes.It is specific as follows:

A group Mei Suoshuli tablet the preparation method is as follows:

Then the dissolution rate of the two groups of Mei Suoshuli tablets prepared is measured, measurement result is shown in Table h7.

Table h7

By the result of table h7 it is found that relative to the Mei Suoshuli without micronization, first by Mei Suoshuli and filler lactose, And microcrystalline cellulose mixing is micronized, then the dissolution rate of Mei Suoshuli tablet obtained can significantly be improved.

2, tablet forming technique is investigated

It is thick in conjunction with slice weight and suitable piece according to working condition, while to consider to meet friability requirement, using tablet press machine into Row tabletting.The hardness level of tablet is controlled into the section shown in table h8, then measures friability, the dissolution of the tablet of different hardness Degree and disintegration time, measurement result are shown in Table h8.

Table h8 investigates influence of the hardness to experimental result

It was found from the result of table h8: when range of the hardness of tablet between 4~7kg, disintegration time and dissolution rate by It influences little；And when hardness is in 7~8kg, dissolution rate reduces；And when hardness is in 4~5kg, friability is big；In view of piece Agent also need of coating, to the more demanding of friability, therefore, it is comparatively ideal range that the hardness of tablet, which is controlled in 5~7kg,.

Wherein, prescription h24 is the Mei Suoshuli piece that specification is 50mg, prescription are as follows: Mei Suoshuli 50g, lactose 50g, it is micro- Crystalline cellulose 100g, PVP K30 8g, crospovidone (interior to add) 6g, crospovidone (additional) 6g, magnesium stearate 2.5g.

Prescription h25 is the Mei Suoshuli piece that specification is 100mg, prescription are as follows: Mei Suoshuli 100g, lactose 40g, crystallite are fine Tie up element 80g, PVP K30 8g, crospovidone (interior to add) 6g, crospovidone (additional) 6g, magnesium stearate 2.5g.

The preparation method is as follows:

(8) tabletting: according to content of dispersion measured by total mix particle, calculating the theoretical tablet weight, and tablet press machine is adjusted to suitable and is filled out Charge, controlling pressure respectively makes tablet hardness carry out tabletting within 4~5kg, 5~6kg, 6~7kg, 7~8kg up to above-mentioned The Mei Suoshuli piece of different hardness.

3, art for coating is studied

In order to guarantee tablet quality and conveniently take, (label herein refers to above-mentioned implementation to Chang Mei Suoshuli label The Mei Suoshuli tablet not being coated in example) the suitable clothing layer material of surface layer package, so that the drug in tablet is isolated from the outside, It obtains being covered with the tablet of film-coating in Mei Suoshuli medical surfaces, to reach moisture-proof, be protected from light, completely cut off air oxidation, enhancing The stability that drug saves covers the bad odor in tablet and reduces the purpose of medicine irritation.

(2) coating solution is prepared

(3) coating conditions

(4) screening of coating powder dosage

When taking the prescription and technique, especially tabletting according to prescription h25, control pressure makes tablet hardness within 5~7kg The Mei Suoshuli piece sample that progress tabletting obtains weighs coating powder by the 5% of label weight, adds purified water that solid content is made and is 20% solution, investigates the coating effect of different coating weight gains, and investigation the results are shown in Table h9.

The screening of table h9 coating powder dosage

Coating weight gain	Coating effect (amplification sem observation)	Disintegration time (s)
			1.8%	Package is complete substantially for label, but edge is imperfect	80
3.0%	Coating tablet is fully wrapped around, and color is uniform, and edge is complete	101
			3.5%	Coating tablet is fully wrapped around, and color is uniform, and edge is complete	112
4.0%	Coating tablet is fully wrapped around, and color is uniform, and edge is complete	166

Table h9's the result shows that, coating powder dosage be label weight 3.0% or more when, coating tablet appearance, which has been able to satisfy, to be wanted It asks, and as coating powder dosage increases, disintegration time accordingly extends, when coating powder dosage is 4.0%, disintegration time, which exists, to be added The extended possibility of speed.Basic performance is carried out to the coating tablet that above-mentioned three kinds of appearances are met the requirements to evaluate as shown in following table h10:

The evaluation of table h10 coating tablet basic performance

Comprehensively consider in conjunction with the result of table h9 and table h10, controls coating weight gain in label weight when selection is coated 3.0%-3.5%, had not only been able to satisfy the appearance requirement of coating tablet, but also did not influenced disintegration time and dissolution rate, moreover it is possible to play preferable Shaded effect.

The preparation of h5: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 50g, lactose 50g, microcrystalline cellulose 100g, PVP K30 8g, crospovidone (interior to add) 6g are handed over Connection povidone (additional) 6g, magnesium stearate 2.5g is made 1000 altogether.

Preparation method:

(1) supplementary material pre-treatment: main ingredient (Mei Suoshuli) and auxiliary material filler lactose, microcrystalline cellulose mixing are carried out micro- Dusting (partial size is at 5 microns to 100 microns), remaining each auxiliary material smash it through 80 meshes respectively, spare；

(9) it is coated: coating powder white stomach dissolution type Opadry 81W68907 being added in purified water, solid content is configured to For 20% Coating Solution, with screw type stirring paddle stirring 45 minutes.Label is carried out using common transformation coating pan Coating, get Mei Suoshuli Film coated tablets.Wherein, the major parameter of coating process is as follows: average inlet air temperature is 85 DEG C, average piece Bed tempertaure is 41 DEG C, atomizing pressure 2.5bar, and average coating pan revolving speed is 15~23rpm, average 3~4g/ of material flow Min, weight gain 3%~3.5%, obtains the Mei Suoshuli tablet.

(10) it packs: the Mei Suoshuli tablet being packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.

The preparation of h6: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 50g, lactose 113g, microcrystalline cellulose 57g, PVP K30 8g, crospovidone (interior to add) 6g are handed over Connection povidone (additional) 6g, magnesium stearate 2.4g is made 1000 altogether.

Preparation method:

(5) it dries: drug wet granular obtained in step (4) is dried into 4h at 55 DEG C；

(10) it packs: the Mei Suoshuli tablet being packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag

The preparation of h7: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 50g, lactose 135g, microcrystalline cellulose 45g, PVP K30 8g, crospovidone (interior to add) 8g are handed over Connection povidone (additional) 8g, magnesium stearate 2g is made 1000 altogether.

(5) it dries: drug wet granular obtained in step (4) is dried into 1h at 65 DEG C；

The preparation of h8: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 25g, lactose 30g, microcrystalline cellulose 120g, PVP K30 6g, crospovidone (interior to add) 3g are handed over Connection povidone (additional) 3g, magnesium stearate 2g is made 1000 altogether.

Preparation method:

With adhesive: weighing 6 grams of adhesive PVP K30s in beaker, add 94 grams of purified water, stir to clarify, obtain 6% The binder aqueous solution I of PVP K30；Remaining preparation method is the same as embodiment 5.

The preparation of h9: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 25g, cornstarch 200g, hydroxypropyl methylcellulose 6g, croscarmellose sodium (interior to add) 2.5g, Croscarmellose sodium (additional) 2.5g, magnesium stearate 0.8g is made 1000 altogether.

Preparation method:

(1) supplementary material pre-treatment: main ingredient (Mei Suoshuli) and auxiliary material filler cornstarch are mixed and are micronized (grain Diameter is at 5 microns to 100 microns), remaining each auxiliary material smash it through 80 meshes respectively, it is spare；

(2) match adhesive: weighing 6 grams of adhesive hydroxypropyl methylcelluloses in beaker, add 94 grams of purified water, stir to clear Clearly, the binder aqueous solution I of 6% hydroxypropyl methylcellulose is obtained, it is spare；

The preparation of h10: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 100g, lactose 40g, microcrystalline cellulose 80g, PVP K30 12g, crospovidone (interior to add) 7g, Crospovidone (additional) 7g, magnesium stearate 3g is made 1000 altogether.

Preparation method: matching adhesive: weighing 12 grams of adhesive PVP K30s in beaker, adds 88 grams of purified water, stirring is extremely Clarification, obtains the binder aqueous solution I of 12% PVP K30；Remaining preparation method is the same as embodiment h5.

The preparation of h11: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 100g, lactose 80g, microcrystalline cellulose 40g, PVP K30 7g, crospovidone (interior to add) 6g are handed over Connection povidone (additional) 6g, magnesium stearate 2.5g is made 1000 altogether.

Preparation method: matching adhesive: weighing 7 grams of adhesive PVP K30s in beaker, adds 93 grams of purified water, stirring is extremely Clarification, obtains the binder aqueous solution I of 7% PVP K30；Remaining preparation method is the same as embodiment h5.

The preparation of h12: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 125g, mannitol 50g, methylcellulose 10g, crospovidone (interior to add) 7g, crospovidone are (outer Add) 7g, magnesium stearate 4g is made 1000 altogether.

Preparation method:

(1) supplementary material pre-treatment: main ingredient (Mei Suoshuli) and auxiliary material filler mannitol are mixed and are micronized (partial size At 5 microns to 100 microns), remaining each auxiliary material smash it through 80 meshes respectively, it is spare；

(2) match adhesive: weighing 10 grams of adhesive methylcellulose in beaker, add 90 grams of purified water, stir to clarify, The binder aqueous solution I of 10% hydroxypropyl methylcellulose is obtained, it is spare；

The preparation of h13: Mei Suoshuli Film coated tablets of embodiment

Prescription:

Mei Suoshuli 125g, lactose 60g, microcrystalline cellulose 60g, PVP K30 10g, sodium carboxymethyl starch (interior to add) 10g, sodium carboxymethyl starch (additional) 10g, magnesium stearate 3g are made 1000 altogether.

Preparation method:.

(3) it mixes: after mixing by Mei Suoshuli and filler, it is mixed that the disintegrating agent carboxymethyl base sodium starch added in needing is added It closes uniformly, obtains mixture II；

(7) total mix: the additional disintegrating agent carboxymethyl base sodium starch of the need of recipe quantity is added in dry particl, it is hard to add recipe quantity Fatty acid magnesium is uniformly mixed, obtains total mix particle；

Embodiment h14: quality evaluation

1, performance evaluation

Totally 9 samples described in h5- embodiment of embodiment of the present invention h13 carry out character, hardness, friability, the piece method of double differences Different, dissolution rate inspection the results are shown in Table h11 in order to carry out performance evaluation to the preparation-obtained Mei Suoshuli of the present invention

The evaluation of table h11 Mei Suoshuli piece performance

Table h11 the results show that the character of 9 batches of samples, hardness, friability, tablet weight variation meet the requirements, and dissolution rate compared with Height, and can reach 90%, it meets the requirements.

2, influence factor experiment in 10 days:

Next, preparing Mei Suoshuli piece (Film coated tablets) to above-described embodiment h11 carries out influence factor experiment, tool Body is as follows:

The Mei Suoshuli Film coated tablets (lot number 131101) of 100mg specification is uncovered in culture dish, high temperature (60 DEG C), It places 10 days under the conditions of high humidity (RH 92.5%, 25 DEG C), Qiang Guang (4500lx ± 500lx), was sampled in the 5th, 10 day, observation system The projects such as agent appearance, content, dissolution rate, related substance, weight-loss ratio, and be compared with the inspection data for investigating preceding sample, it examines Survey the results are shown in Table h12.

Table h12 Mei Suoshuli Film coated tablets (100mg/ piece) (lot number 131101) influence factor test result

Influence factor test result shows: Film coated tablets is placed 10 days under high temperature, high humidity, illumination, content, related substance No conspicuousness variation, quality is basicly stable, shows that prescription science is feasible, rational technology, favorable reproducibility.But 10 days films of high humidity There is the slight moisture absorption on garment piece surface, and dissolution rate is declined, and prompts selection when packing it is noted that moisture-proof.Therefore, product needs to seal It is stored at dry.

3, the selection of interior packaging material:

Next, to the Mei Suoshuli Film coated tablets of above-mentioned 100mg specification, 3 batches are produced, lot number is respectively 131201, 131202, the comparative studies of four kinds of packagings 131203, have been carried out respectively, and four kinds of quasi- choosing packagings are successively are as follows: polyvinyl chloride (PVC) bubble Cover, PVC bubble-cap+two-sided composite aluminium film bag, two-sided composite aluminium film bag and plastic bottle.Then, the thin of four kinds of packagings will be respectively adopted Film garment piece is placed 6 months under the conditions of temperature is 40 DEG C ± 2 DEG C, relative humidity is 75% ± 5%, accelerate 6 months Comparison is investigated, and respectively at the 1st, 2,3, sampling in June, has been carried out the detection of each inspection target of stability test, has been accelerated 6 months realities It tests data and is shown in Table h13.

Table h13 Mei Suoshuli Film coated tablets (100mg/ piece, PVC bubble-cap+two-sided composite aluminium film bag) accelerates experiment in 6 months As a result

The embodiment b1-b13 of following Mei Suoshuli oral disnitegration tablet is implemented below to feed intake according to 1000 tablet recipe amounts Example is only illustrated, and is not intended to limit invention scope.

Embodiment b1:

Prescription: 25 grams of Mei Suoshuli, 20 grams of mannitol, 30 grams of microcrystalline cellulose, 5 grams of PVP K30, low-substituted hydroxypropyl 2 grams of cellulose, 5 grams of Aspartame, 0.5 gram of silica, 1000 oral cavities Mei Suoshuli are made altogether and collapse by 0.1 gram of superfine silica gel powder Solve piece.

Preparation method: the dosage form is produced using conventional tablet pharmaceutical equipment and direct compression method technique is used to prepare, specific to prepare Method is as follows:

The Mei Suoshuli of recipe quantity is micronized by step 1, and the partial size after micronization is 1-30 microns, and micro mist is added Silica gel is uniformly mixed；After finely ground 80 mesh of mistake of Aspartame, Mei Suoshuli, superfine silica gel powder and Aspartame are uniformly mixed；

The mannitol of recipe quantity and microcrystalline cellulose are micronized by step 2, and the partial size after micronization is 120-200 Micron；Low-substituted hydroxypropyl cellulose is crossed into 80 meshes, PVP K30 crosses 40 meshes, weighs respectively by recipe quantity and by above-mentioned suitable Sequence sequentially adds to be mixed in the hybrid medicine in above-mentioned steps 1；

Step 3, the silica that recipe quantity is added in gained hybrid medicine into above-mentioned steps 2, sieving mixes, in progress Mesosome content detection uses the tabletting of direct tablet compressing technology to get Mei Suoshuli oral disnitegration tablet after determining slice weight.

Embodiment b2:

Prescription: 25 grams of Mei Suoshuli, 20 grams of mannitol, 40 grams of microcrystalline cellulose, 10 grams of PVP K30, low-substituted hydroxypropyl 2 grams of cellulose, 5 grams of Aspartame, 0.5 gram of silica, 1000 oral cavities Mei Suoshuli are made altogether and collapse by 0.1 gram of superfine silica gel powder Solve piece.

Preparation method:

Mei Suoshuli oral disnitegration tablet is prepared using method identical with embodiment b1, difference is: by Mei Suoshuli into Partial size after row micronization is 60-100 microns, and the partial size after mannitol and microcrystalline cellulose are micronized is 10-60 microns.

Embodiment b3:

Prescription: 50 grams of Mei Suoshuli, 40 grams of mannitol, 60 grams of microcrystalline cellulose, 15 grams of sodium carboxymethylcellulose, crosslinking are poly- 10 grams of ketone, 10 grams of fragrant citrus essence, 2 grams of magnesium stearate are tieed up, 0.2 gram of superfine silica gel powder, 1000 Mei Suoshuli Orally disintegratings are made altogether Piece.

Preparation method:

The Mei Suoshuli of recipe quantity is micronized by step 1, and the partial size after micronization is 30-60 microns, and micro mist is added Silica gel is uniformly mixed；After finely ground 80 mesh of mistake of fragrant citrus essence, Mei Suoshuli, superfine silica gel powder and fragrant citrus essence are uniformly mixed；

The mannitol of recipe quantity and microcrystalline cellulose are micronized by step 2, and the partial size after micronization is that 60-120 is micro- Rice；Crospovidone is crossed into 80 meshes, sodium carboxymethylcellulose crosses 40 meshes, weighed respectively by recipe quantity and by said sequence according to It is mixed in the secondary hybrid medicine being added in above-mentioned steps 1；

Step 3, the magnesium stearate that recipe quantity is added in gained hybrid medicine into above-mentioned steps 2, sieving mixes, in progress Mesosome content detection uses the tabletting of direct tablet compressing technology to get Mei Suoshuli oral disnitegration tablet after determining slice weight.

Embodiment b4:

Prescription: 50 grams of Mei Suoshuli, 40 grams of mannitol, 60 grams of microcrystalline cellulose, 15 grams of PVP K30, crospovidone 12 grams, 10 grams of Aspartame, 2 grams of magnesium stearate, are made 1000 Mei Suoshuli oral disnitegration tablets altogether by 0.2 gram of superfine silica gel powder.

Preparation method:

The Mei Suoshuli of recipe quantity is micronized by step 1, and the partial size after micronization is 30-60 microns, and micro mist is added Silica gel is uniformly mixed；After finely ground 80 mesh of mistake of Aspartame, Mei Suoshuli, superfine silica gel powder and Aspartame are uniformly mixed；

The mannitol of recipe quantity and microcrystalline cellulose are micronized by step 2, and the partial size after micronization is that 60-120 is micro- Rice；Crospovidone is crossed into 80 meshes, PVP K30 crosses 40 meshes, weighs by recipe quantity and successively adds respectively by said sequence Enter and is mixed in the hybrid medicine in above-mentioned steps 1；

Embodiment b5:

Prescription: 50 grams of Mei Suoshuli, 40 grams of mannitol, 60 grams of microcrystalline cellulose, 15 grams of sodium carboxymethylcellulose, crosslinking are poly- 12 grams of ketone, 10 grams of fragrant citrus essence, 2 grams of polyethylene glycol are tieed up, 0.2 gram of superfine silica gel powder, 1000 Mei Suoshuli Orally disintegratings are made altogether Piece.

Preparation method: with embodiment b3.

Embodiment b6:

Prescription: 75 grams of Mei Suoshuli, 30 grams of mannitol, 60 grams of microcrystalline cellulose, 5 grams of hydroxypropyl methylcellulose, carboxymethyl form sediment 0.3 gram of superfine silica gel powder, 1000 Mei Suoshuli Orally disintegratings are made in 15 grams of powder sodium, 15 grams of Aspartame, 5 grams of polyethylene glycol altogether Piece.

Preparation method:

The Mei Suoshuli of recipe quantity is micronized by step 1, and the partial size after micronization is 1-30 microns, and micro mist is added Silica gel is uniformly mixed；By finely ground 80 mesh of mistake of Aspartame, Mei Suoshuli, superfine silica gel powder and Aspartame are uniformly mixed；

The mannitol of recipe quantity and microcrystalline cellulose are micronized by step 2, and the partial size after micronization is that 60-120 is micro- Rice；Sodium carboxymethyl starch is crossed into 80 meshes, hydroxypropyl methylcellulose crosses 40 meshes, weighed respectively by recipe quantity and by said sequence according to It is mixed in the secondary hybrid medicine being added in above-mentioned steps 1；

Step 3, the polyethylene glycol that recipe quantity is added in gained hybrid medicine into above-mentioned steps 2, sieving mixes, in progress Mesosome content detection uses the tabletting of direct tablet compressing technology to get Mei Suoshuli oral disnitegration tablet after determining slice weight.

Embodiment b7:

Prescription: 75 grams of Mei Suoshuli, 30 grams of mannitol, 60 grams of microcrystalline cellulose, 25 grams of hydroxypropyl methylcellulose, carboxymethyl form sediment 0.3 gram of superfine silica gel powder, 1000 Mei Suoshuli Orally disintegratings are made in 15 grams of powder sodium, 15 grams of Aspartame, 5 grams of polyethylene glycol altogether Piece.

Preparation method: with embodiment b6.

Embodiment b8:

Prescription: 100 grams of Mei Suoshuli, 40 grams of mannitol, 60 grams of microcrystalline cellulose, 40 grams of PVP K30, the poly- dimension of crosslinking 0.4 gram of superfine silica gel powder, 1000 Mei Suoshuli oral disnitegration tablets are made in 12 grams of ketone, 10 grams of Aspartame, 6 grams of magnesium stearate altogether.

Preparation method:

The Mei Suoshuli of recipe quantity is micronized by step 1, and the partial size after micronization is 30-60 microns, and micro mist is added Silica gel is uniformly mixed；By finely ground 80 mesh of mistake of Aspartame, Mei Suoshuli, superfine silica gel powder and Aspartame are uniformly mixed；

The mannitol of recipe quantity and microcrystalline cellulose are micronized by step 2, and the partial size after micronization is that 10-60 is micro- Rice；Crospovidone is crossed into 80 meshes, PVP K30 crosses 40 meshes, weighs by recipe quantity and successively adds respectively by said sequence Enter and is mixed in the hybrid medicine in above-mentioned steps 1；

Embodiment b9:

Prescription: 100 grams of Mei Suoshuli, 35 grams of mannitol, 70 grams of microcrystalline cellulose, 30 grams of PVP K30, the poly- dimension of crosslinking 0.4 gram of superfine silica gel powder, 1000 Mei Suoshuli oral disnitegration tablets are made in 12 grams of ketone, 10 grams of Aspartame, 6 grams of magnesium stearate altogether.

Preparation method: with embodiment b8.

Embodiment b10:

Prescription: 100 grams of Mei Suoshuli, 60 grams of mannitol, 60 grams of microcrystalline cellulose, 40 grams of PVP K30, the poly- dimension of crosslinking 0.4 gram of superfine silica gel powder, 1000 Mei Suoshuli oral disnitegration tablets are made in 10 grams of ketone, 15 grams of fragrant citrus essence, 6 grams of magnesium stearate altogether.

Preparation method:

The Mei Suoshuli of recipe quantity is micronized by step 1, and the partial size after micronization is 30-60 microns, and micro mist is added Silica gel is uniformly mixed；By finely ground 80 mesh of mistake of fragrant citrus essence, Mei Suoshuli, superfine silica gel powder and fragrant citrus essence are uniformly mixed；

The mannitol of recipe quantity and microcrystalline cellulose are micronized by step 2, and the partial size after micronization is that 30-60 is micro- Rice；Crospovidone is crossed into 80 meshes, PVP K30 crosses 40 meshes, weighs by recipe quantity and successively adds respectively by said sequence Enter and is mixed in the hybrid medicine in above-mentioned steps 1；

Embodiment b11:

Prescription: 125 grams of Mei Suoshuli, 30 grams of mannitol, 45 grams of microcrystalline cellulose, 30 grams of hydroxypropyl cellulose, crosslinking carboxylic 0.5 gram of superfine silica gel powder, 1000 Mei Suoshuli are made in 30 grams of sodium carboxymethylcellulose pyce, 20 grams of fragrant citrus essence, 0 gram of silica 1 altogether Oral disnitegration tablet.

Preparation method:

The mannitol of recipe quantity and microcrystalline cellulose are micronized by step 2, and the partial size after micronization is 100-150 Micron；Croscarmellose sodium is crossed into 80 meshes, hydroxypropyl cellulose crosses 40 meshes, weighs respectively by recipe quantity and by upper It states and is mixed in the hybrid medicine sequentially sequentially added in above-mentioned steps 1；

Embodiment b12:

Prescription: 125 grams of Mei Suoshuli, 60 grams of mannitol, 60 grams of microcrystalline cellulose, 20 grams of hydroxypropyl cellulose, crosslinking carboxylic 0.5 gram of superfine silica gel powder, 1000 Mei Suoshuli are made in 30 grams of sodium carboxymethylcellulose pyce, 20 grams of fragrant citrus essence, 0 gram of silica 1 altogether Oral disnitegration tablet.

Preparation method: with embodiment b11.

Embodiment b13:

Using following test method and test equipment, to the Mei Suoshuli prepared in embodiment b1- embodiment b12 Hardness, disintegration time limited, friability and the dissolution rate of oral disnitegration tablet are measured, specific as follows:

A, Determination of Hardness:

Mei Suoshuli oral disnitegration tablet 10 (n=10) are taken, uses YD-1 tablet hardness tester (the new daylight in Tianjin respectively Analytical instrumentation techniques Co., Ltd) measurement tablet hardness.

B, disintegration time mensuration, using static disintegration method.

Mei Suoshuli oral disnitegration tablet 1 is taken, is placed in 10ml test tube (test tube internal diameter is 13mm), 2ml is filled in test tube Water, water temperature are 37 DEG C, and tablet should be disintegrated in 1 minute, be dispersed in water.Sieving is poured out, is rinsed every time with water 2ml, in two times Test tube and sieve, sieve that can all by aperture less than 710 μm.6 (n=6) is checked according to the above method, should meet regulation.

C, friability measures, and is tested according to the tablet friability inspection technique of Chinese Pharmacopoeia version annex X G in 2010.

D, dissolution determination: using RCZ-8A intelligence digestion instrument, and the condition for dissolving out measurement is as follows

Dissolving-out method: mug paddle method；

Temperature: 37 DEG C ± 0.5 DEG C；

Revolving speed: 75 revs/min；

Dissolution medium: pH8.8 phosphate buffer, volume 1000ml；

Final sampling time point is 30 minutes.

Dissolution determination method is specific as follows:

(1) prepared by reference substance solution

Mei Suoshuli reference substance 25.0mg is weighed into 250ml measuring bottle, after adding methanol about 8ml being completely dissolved, is added molten Medium and constant volume out, shake up.Precision pipettes in the volumetric flask of 5.0ml to 25ml, with dissolution medium constant volume, obtains every 1ml In Mei Suoshuli reference substance solution containing about 20 μ g.

(2) prepared by test solution

It by the method under " dissolution test method " item, was sampled respectively at 5,15,25,35,45,60 minutes, filtration is accurate It is appropriate to draw subsequent filtrate, is diluted to every 1ml containing about 20 μ g Mei Suoshuli with dissolution medium.

(3) dissolution determination

According to the dissolution of the Mei Suoshuli oral disnitegration tablet sample prepared in upper method measurement embodiment b1- embodiment b12 Degree.

E, influence factor measurement in 10 days, the Mei Suoshuli oral disnitegration tablet that will be prepared in embodiment b1- embodiment b12 It uncovers in culture dish, in high temperature (60 DEG C), high humidity (RH 92.5%, 25 DEG C), the decentralization of Qiang Guang (4500lx ± 500lx) condition It sets 10 days, and when 0 day, 5 days and 10 days, using liquid disclosed in 201310476323.3 embodiment 8 of Chinese invention patent application The total impurities content of phase chromatography measurement Mei Suoshuli oral disnitegration tablet.

The disintegration time limited of the Mei Suoshuli oral disnitegration tablet prepared in embodiment b1- embodiment b12, friability, medicine Sheet hardness, dissolution determination the results are shown in Table b1, and influence factor measurement in 10 days is shown in Table b2.

Table b1: disintegration time limited, friability, tablet hardness, dissolution rate numerical value

From the above-mentioned all data measured: Mei Suoshuli oral disnitegration tablet of the invention, disintegration time limited 15s- 45s, hardness 5-8kg, less than 0.5%, 10 minute, the amount of dissolution was greater than 85% to friability in pH8.8 phosphate buffer solution.

B2:10 days influence factor experimental results of table

Above data illustrates: the Mei Suoshuli oral disnitegration tablet obtained using prescription and preparation process of the invention, warp After crossing influence factor experiment in 10 days, quality is still highly stable.

Comparative example b1:

Compared with preparation process of the invention, in comparative example b1 have following difference: (1) Mei Suoshuli raw material, And mannitol, microcrystalline cellulose, without micronization processes, (2) superfine silica gel powder is not added, (3) prepare U.S. rope using wet granulation Shu Li oral disnitegration tablet.

Prescription: 50 grams of Mei Suoshuli, 40 grams of mannitol, 60 grams of microcrystalline cellulose, 15 grams of PVP K30, crospovidone 12 grams, 10 grams of Aspartame, 2 grams of magnesium stearate, are made 1000 Mei Suoshuli oral disnitegration tablets altogether.

Preparation process is as follows:

1) match adhesive: taking the PVP K30 of recipe quantity, the solution that mass fraction 10% is made in purified water is added, it is spare.

2) it mixes: each auxiliary material is crossed into 80 meshes respectively, Mei Suoshuli crosses 60 meshes, weighs supplementary material by recipe quantity, will be former Auxiliary material is after mixing, spare.

3) softwood processed and granulation: the supplementary material after taking sieving to mix is added 10% PVP K30 aqueous solution, softwood processed, Granulation crosses 18 meshes and obtains wet granular.

4) dry and whole grain: wet granular being divided in disk, is placed in baking oven, and dry at 60 ± 5 DEG C, per half an hour is turned over It is dynamic primary, it is taken out after about 2h, 18 mesh sieves obtain dry particl, weighing.

5) total mix: according to dry particl weight, magnesium stearate is added, is uniformly mixed.

6) tabletting: according to content of dispersion measured by total mix particle, calculating the theoretical tablet weight, and tablet press machine is adjusted to suitable filling Amount, control pressure make piece hardness within 5~8kg, and tabletting is up to Mei Suoshuli oral disnitegration tablet.

Disintegrating method method: 37 DEG C of hot water 2ml is added in 10ml test tube, gently puts into tablet to be measured, starts simultaneously at Timing observes and records the complete disintegration time of tablet, and measurement is terminated in 1min, and whether observation tablet is disintegrated completely.

Test result: according to the requirement of Chinese oral disnitegration tablet key Quality Control, comparative example tests prescription and preparation The resulting tablet of method in hardness when (taking 4kg, 5kg, 6kg, 7kg and 8kg) within 4~8kg, cannot in 1min completely Disintegration.And hardness be 1kg and 2kg when, disintegration time limited is respectively 50s, 55s, and friability is also higher, respectively 1.1%, 1.5%.

And (the embodiment b1- embodiment of Mei Suoshuli oral disintegrating tablet obtained by direct tablet compressing technical solution according to the present invention B12) when hardness is within the scope of 5-8kg, disintegration time limited 15s-45s, friability is dissolved out less than 0.5%, and quality is steady It is fixed.

The embodiment c1-c14 of following Mei Suoshuli dispersible tablet feeds intake according to 1000 tablet recipe amounts, following embodiment only into Row explanation, is not intended to limit invention scope.

Embodiment c1

Prescription:

25 parts by weight of Mei Suoshuli, 5 parts by weight of aspartame, 60 parts by weight of microcrystalline cellulose, 5 weight of hypromellose Measure part, 2 parts by weight of sodium carboxymethyl starch, 0.5 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 25ml acetone and obtains A liquid, by the microcrystalline cellulose of recipe quantity, hydroxyl Third methylcellulose, which is dissolved in 100ml purified water, obtains B liquid；

(2) A liquid is slowly added in B liquid while stirring, obtains the Mei Suoshuli suspension solution of mixing；

(3) suspension solution is first subjected to homogeneous with homogenizer, then is spray-dried, collect powder；

(4) powder is uniformly mixed with the magnesium stearate of recipe quantity, aspartame, sodium carboxymethyl starch, obtains mixed-powder, The sample of mixed-powder is taken, and carries out assay, after content is qualified, carries out tabletting；

(5) mixed-powder obtained in (4) is directly added into rotary pelleting machine, direct powder compression, sheet hardness control In 5~7N to get Mei Suoshuli dispersible tablet.

Dissolution experiments:

With Chinese Pharmacopoeia two the second subtraction units of annex XC of version in 2010, according to two annex XD of Chinese Pharmacopoeia version in 2010 The dissolution rate for the Mei Suoshuli dispersible tablet that the measurement of one method prepares.Specifically, using water 9000ml as dissolution medium, revolving speed 100 Turn, sampled at 5,10,15,30,45,60 minutes, measure the dissolution rate of Mei Suoshuli dispersible tablet, measurement result is shown in Fig. 1.

Embodiment c2

Prescription:

25 parts by weight of Mei Suoshuli, 10 parts by weight of sucrose, 30 parts by weight of lactose, 50 parts by weight of microcrystalline cellulose, povidone 5 Parts by weight, 3 parts by weight of crospovidone, 0.5 parts by weight of superfine silica gel powder

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 25ml ethyl alcohol and obtains A liquid, by the lactose of recipe quantity, microcrystalline cellulose Element, povidone are dissolved in 100ml purified water and obtain B liquid；

(4) powder is uniformly mixed with the superfine silica gel powder of recipe quantity, sucrose, crospovidone, obtains mixed-powder, take mixing The sample of powder, and assay is carried out, after content is qualified, carry out tabletting；

Embodiment c3

Prescription:

50 parts by weight of Mei Suoshuli, 10 parts by weight of aspartame, 100 parts by weight of microcrystalline cellulose, hypromellose 10 parts by weight, 5 parts by weight of sodium carboxymethyl starch, 1 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 50ml ethyl alcohol and obtains A liquid, by the microcrystalline cellulose of recipe quantity, hydroxyl Third methylcellulose, which is dissolved in 120ml purified water, obtains B liquid；

Dissolution experiments: experimental method is shown in Fig. 2 with embodiment c1, the dissolution determination result of Mei Suoshuli dispersible tablet.

Embodiment c4

Prescription:

50 parts by weight of Mei Suoshuli, 80 parts by weight of mannitol, 8 parts by weight of hydroxypropyl cellulose, are handed over 10 parts by weight of stevioside Join 6 parts by weight of sodium carboxymethylcellulose, 1 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 50ml acetone and obtains A liquid, by the mannitol of recipe quantity, hydroxypropyl Cellulose, which is dissolved in 120ml purified water, obtains B liquid；

(4) powder is uniformly mixed with the magnesium stearate of recipe quantity, stevioside, croscarmellose sodium, must be mixed Powder takes the sample of mixed-powder, and carries out assay, after content is qualified, carries out tabletting；

Embodiment c5

Prescription:

50 parts by weight of Mei Suoshuli, 10 parts by weight of aspartame, 100 parts by weight of starch, 8 parts by weight of dextrin, low substitution hydroxyl 6 parts by weight of propyl cellulose, 1 parts by weight of fumaric acid sodium

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 50ml acetone and obtains A liquid, the starch of recipe quantity, dextrin are dissolved in B liquid is obtained in 120ml purified water；

(4) powder is uniformly mixed with the fumaric acid sodium of recipe quantity, aspartame, low-substituted hydroxypropyl cellulose, is obtained mixed Powder is closed, takes the sample of mixed-powder, and carry out assay, after content is qualified, carries out tabletting；

Embodiment c6

Prescription:

50 parts by weight of Mei Suoshuli, 20 parts by weight of sucrose, 110 parts by weight of lactose, 10 parts by weight of hypromellose, carboxylic 6 parts by weight of methyl starch sodium, 1 parts by weight of lauryl sodium sulfate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 50ml ethyl alcohol and obtains A liquid, by the lactose of recipe quantity, hydroxypropyl Cellulose, which is dissolved in 120ml purified water, obtains B liquid；

(4) powder is uniformly mixed with the lauryl sodium sulfate of recipe quantity, sucrose, sodium carboxymethyl starch, obtains mixed powder End takes the sample of mixed-powder, and carries out assay, after content is qualified, carries out tabletting；

Embodiment c7

Prescription:

75 parts by weight of Mei Suoshuli, 15 parts by weight of stevioside, 120 parts by weight of microcrystalline cellulose, hypromellose 12 Parts by weight, 8 parts by weight of sodium carboxymethyl starch, 1.5 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 75ml acetone and obtains A liquid, by the microcrystalline cellulose of recipe quantity, hydroxyl Third methylcellulose, which is dissolved in 150ml purified water, obtains B liquid；

(4) powder is uniformly mixed with the magnesium stearate of recipe quantity, stevioside, sodium carboxymethyl starch, obtains mixed-powder, takes The sample of mixed-powder, and assay is carried out, after content is qualified, carry out tabletting；

Dissolution experiments: experimental method is shown in Fig. 3 with embodiment c1, the dissolution determination result of Mei Suoshuli dispersible tablet.

Embodiment c8

Prescription:

75 parts by weight of Mei Suoshuli, 15 parts by weight of aspartame, 135 parts by weight of microcrystalline cellulose, 12 parts by weight of povidone, 8 parts by weight of sodium carboxymethyl starch, 1.5 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 75ml acetone and obtains A liquid, by the microcrystalline cellulose of recipe quantity, gathered Dimension ketone, which is dissolved in 150ml purified water, obtains B liquid；

Embodiment c9

Prescription:

100 parts by weight of Mei Suoshuli, 20 parts by weight of aspartame, 70 parts by weight of lactose, 80 parts by weight of microcrystalline cellulose, hydroxyl Third methylcellulose, 15 parts by weight, 5 parts by weight of sodium carboxymethyl starch, 2 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 100ml ethyl alcohol and obtains A liquid, by the lactose of recipe quantity, microcrystalline cellulose Element, hypromellose are dissolved in 150ml purified water and obtain B liquid；

Dissolution experiments: experimental method is shown in Fig. 4 with embodiment c1, the dissolution determination result of Mei Suoshuli dispersible tablet.

Embodiment c10

Prescription:

100 parts by weight of Mei Suoshuli, 20 parts by weight of aspartame, 130 parts by weight of microcrystalline cellulose, hypromellose 15 parts by weight, 10 parts by weight of sodium carboxymethyl starch, 2 parts by weight of superfine silica gel powder

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 100ml acetone and obtains A liquid, by the microcrystalline cellulose of recipe quantity, hydroxyl Third methylcellulose, which is dissolved in 150ml purified water, obtains B liquid；

(4) powder is uniformly mixed with the superfine silica gel powder of recipe quantity, aspartame, sodium carboxymethyl starch, obtains mixed-powder, The sample of mixed-powder is taken, and carries out assay, after content is qualified, carries out tabletting；

Embodiment c11

Prescription:

100 parts by weight of Mei Suoshuli, 20 parts by weight of sucrose, 30 parts by weight of lactose, 120 parts by weight of microcrystalline cellulose, hydroxypropyl 15 parts by weight of methylcellulose, 15 parts by weight of sodium carboxymethyl starch, 2 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 100ml acetone and obtains A liquid, by the lactose of recipe quantity, microcrystalline cellulose Element, hypromellose are dissolved in 150ml purified water and obtain B liquid；

(4) powder is uniformly mixed with the magnesium stearate of recipe quantity, sucrose, sodium carboxymethyl starch, obtains mixed-powder, taken mixed The sample of powder is closed, and carries out assay, after content is qualified, carries out tabletting；

Embodiment c12

Prescription:

100 parts by weight of Mei Suoshuli, 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 hypromellose, 12 parts by weight of crospovidone, 2 parts by weight of magnesium stearate

Preparation method:

(4) powder is uniformly mixed with the magnesium stearate of recipe quantity, aspartame, crospovidone, obtains mixed-powder, takes The sample of mixed-powder, and assay is carried out, after content is qualified, carry out tabletting；

Embodiment c13

Prescription:

125 parts by weight of Mei Suoshuli, 20 parts by weight of aspartame, 70 parts by weight of lactose, 55 parts by weight of microcrystalline cellulose, hydroxyl Third methylcellulose, 25 parts by weight, 5 parts by weight of sodium carboxymethyl starch, 3 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 125ml acetone and obtains A liquid, by the lactose of recipe quantity, microcrystalline cellulose Element, hypromellose are dissolved in 150ml purified water and obtain B liquid；

Dissolution experiments: experimental method is shown in Fig. 5 with embodiment c1, the dissolution determination result of Mei Suoshuli dispersible tablet.

Embodiment c14

Prescription:

125 parts by weight of Mei Suoshuli, 20 parts by weight of aspartame, 150 parts by weight of microcrystalline cellulose, 30 parts by weight of dextrin, 20 parts by weight of crospovidone, 3 parts by weight of magnesium stearate

Preparation method:

(1) above-mentioned recipe quantity Mei Suoshuli is dissolved in 125ml acetone and obtains A liquid, by the microcrystalline cellulose of recipe quantity, paste Essence, which is dissolved in 150ml purified water, obtains B liquid；

The embodiment d1-d17 of following Mei Suoshuli sustained release tablets feeds intake according to 1000 tablet recipe amounts, following embodiment only into Row explanation, is not intended to limit invention scope.

Embodiment d1:

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	100g
Hydroxypropyl beta cyclodextrin	15g
		Microcrystalline cellulose	25g
Hypromellose K4M	100g
		Sodium carboxymethyl starch	7.5g
Magnesium stearate	2.5g

The present invention uses the technology of solid dispersions, by wet granulation technology, then the plain piece film coating that will be pressed, system It is standby to obtain Mei Suoshuli sustained release tablets, the preparation method is as follows:

1. above-mentioned recipe quantity Mei Suoshuli is dissolved in 50ml acetone and obtains A liquid, the hydroxypropyl beta cyclodextrin of recipe quantity is molten B liquid is obtained in 40ml purified water；

2. A liquid is slowly added in B liquid while stirring, powder is collected after solution is volatilized；

3. by being uniformly mixed after powder ultra-fine grinding with the microcrystalline cellulose of recipe quantity and hypromellose K4M；

4. the mixed-powder in 3. is added in wet granulator, mix 15 minutes, by mixed powder in stirring speed Pure water granulation 90s is carried out under the conditions of degree 3r/s, cutting speed 10r/s, particle obtained is 90 minutes dry at 60 DEG C；

5. the magnesium stearate and sodium carboxymethyl starch of the particle addition recipe quantity after dry, after mixing tabletting, piece are hard Degree control is in 5~8N；

6. the plain piece film coating that will be pressed.The preparation method of coating solution: coating powder purifying water dispersion is formulated into 15% solid content stirs 60 minutes.The technological parameter of coating are as follows: atomizing pressure 0.2MP (megapascal), thimble pressure 0.2MP, Coating pan revolving speed 15r/s, feed speed 3r/min, enters the wind frequency 1100Hz by 75 DEG C of inlet air temperature, and 35~45 DEG C of temperature of charge, Coating weight gain 2%~3% terminates.

Dissolution experiments:

With Chinese Pharmacopoeia two the second subtraction units of annex XC of version in 2010, according to two annex XD of Chinese Pharmacopoeia version in 2010 The dissolution rate for the Mei Suoshuli sustained release tablets that the measurement of one method prepares.Using the buffer salt 1000ml of pH6.8 as solvent, revolving speed 50 Turn, sampled at 1,4,8,12,16,20,24 hour, measures the dissolution rate of Mei Suoshuli sustained release tablets, as a result see Fig. 6.

Comparative example d1

Prescription:

Comparative example does not use the technology of solid dispersions, passes through wet granulation technology, then the plain piece packet that will be pressed Mei Suoshuli sustained release tablets are prepared in film-coating, the preparation method is as follows:

1. by being mixed after above-mentioned recipe quantity Mei Suoshuli raw material ultra-fine grinding with microcrystalline cellulose and hypromellose K4M It closes uniform；

2. above-mentioned uniformly mixed powder is added in wet granulator, mix 15 minutes, then, in mixing speed 3r/ S, under cutting speed 10r/s, pure water granulation 90s, particle obtained drying 90 minutes at 60 DEG C；

3. the sodium carboxymethyl starch and magnesium stearate of the particle addition recipe quantity after dry, after mixing tabletting, piece are hard Degree control is in 5~8N；

4. the plain piece film coating that will be pressed.The preparation method of coating solution: coating powder purifying water dispersion is formulated into 15% solid content stirs 60 minutes.The technological parameter of coating are as follows: atomizing pressure 0.2MP (megapascal), thimble pressure 0.2MP, Coating pan revolving speed 15r/s, feed speed 3r/min, enters the wind frequency 1100Hz by 75 DEG C of inlet air temperature, and 35~45 DEG C of temperature of charge, Coating weight gain 2%~3% terminates.

Dissolution experiments: measuring method is shown in Fig. 6 with embodiment d1, measurement result.

D1 of the embodiment of the present invention uses the technology of solid dispersions Mei Suoshuli sustained release tablets are prepared, and compares real Applying a d1 does not use the technology of solid dispersions that Mei Suoshuli sustained release tablets are prepared.Embodiment d1 and comparison through the invention Embodiment d1 difference gained Mei Suoshuli sustained release tablets, the dissolution determination result of the two is compared, the results showed that, pass through system The technology of standby solid dispersions can significantly improve whole dissolution rate of the Mei Suoshuli in sustained release tablets, therefore preferably using solid Preparation method of the technical method of body dispersion as Mei Suoshuli sustained release tablets.

Comparative example d2

Prescription:

Compared with embodiment d1 of the present invention, do not pasted using solubilizer hydroxypropyl beta ring in the prescription of comparative example d2 Essence, but use PLURONICS F87.

Comparative example d2 also uses the technology of solid dispersions, by wet granulation technology, then the plain piece packet that will be pressed Mei Suoshuli sustained release tablets are prepared in film-coating, and preparation method is the same as embodiment d1.

Dissolution experiments: measuring method is shown in Fig. 7 with embodiment d1, measurement result.

Embodiment d1 and comparative example d2 difference gained Mei Suoshuli sustained release tablets through the invention, by the dissolution of the two Degree measurement result compares, the results showed that, by using solubilizer hydroxypropyl beta cyclodextrin, Mei Suoshuli can be significantly improved Dissolution rate in sustained release tablets.Whether hydroxypropyl beta cyclodextrin is taken to include, the final concentration of drug release will be directly influenced, because Take hydroxypropyl beta cyclodextrin inclusion that can effectively improve the dissolution rate of Mei Suoshuli in this prescription.

Embodiment d2

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	100g
Hydroxypropyl beta cyclodextrin	20g
		Microcrystalline cellulose	38.5g
Hypromellose K4M	80g
		Sodium carboxymethyl starch	9g
Magnesium stearate	1.5g

Preparation method is the same as embodiment d1.

Dissolution experiments: measuring method measures dissolution results and sees Fig. 8 with embodiment d1.

Embodiment d3

Prescription:

Preparation method is the same as embodiment d1.

Dissolution experiments: measuring method is shown in Fig. 9 with embodiment d1, measurement result.

Embodiment d4

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	100g
Hydroxypropyl beta cyclodextrin	15g
		Microcrystalline cellulose	25g
Hypromellose K15M	100g
		Sodium carboxymethyl starch	7.5g
Magnesium stearate	2.5g

Preparation method is the same as embodiment d1.

Dissolution experiments: measuring method is shown in Figure 10 with embodiment d1, measurement result.

Embodiment d5

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	100g
Hydroxypropyl beta cyclodextrin	18g
		Microcrystalline cellulose	25g
Hypromellose K100M	100g
		Sodium carboxymethyl starch	7.5g
Magnesium stearate	2g

Preparation method is the same as embodiment d1.

Dissolution experiments: measuring method is shown in Figure 11 with embodiment d1, measurement result.

Embodiment d6

Prescription:

Preparation method is the same as embodiment d1.

Dissolution experiments: measuring method is shown in Figure 12 with embodiment d1, measurement result.

Embodiment d7

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	25g
Hydroxypropyl beta cyclodextrin	15g
		Microcrystalline cellulose	75g
Hypromellose K4M	127.5g
		Sodium carboxymethyl starch	5g
Magnesium stearate	2.5g

Preparation method is the same as embodiment d1.

Dissolution experiments: measuring method is shown in Figure 13 with embodiment d1, measurement result.

Embodiment d8

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	50g
Hydroxypropyl beta cyclodextrin	15g
		Microcrystalline cellulose	65g
Hypromellose K4M	110g
		Sodium carboxymethyl starch	7.5g
Magnesium stearate	2g

Preparation method is the same as embodiment d1.

Dissolution experiments: measuring method is shown in Figure 14 with embodiment d1, measurement result.

Embodiment d9

Prescription:

Preparation method is the same as embodiment d1.

Embodiment d10

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	125g
Hydroxypropyl beta cyclodextrin	20g
		Microcrystalline cellulose	7.5g
Hypromellose K4M	90g
		Sodium carboxymethyl starch	5g
Magnesium stearate	2.5g

Preparation method is the same as embodiment d1.

Embodiment d11:

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	100g
Hydroxypropyl beta cyclodextrin	16g
		Lactose	25g
Hypromellose K15M	100g
		Crospovidone	7.5g
Superfine silica gel powder	2.5g

Preparation method is the same as embodiment d1.

Embodiment d12:

Prescription:

Preparation method is the same as embodiment d1.

Embodiment d13:

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	100g
Hydroxypropyl beta cyclodextrin	15g
		Starch	25g
Hypromellose E50	100g
		Croscarmellose sodium	7.5g
Fumaric acid sodium	2.5g

Preparation method is the same as embodiment d1.

Embodiment d14:

Prescription:

Prescription	Recipe quantity
		Mei Suoshuli	100g
Hydroxypropyl beta cyclodextrin	15g
		Microcrystalline cellulose	25g
Hypromellose E4M	100g
		Sodium carboxymethyl starch	7.5g
Magnesium stearate	2g

Preparation method is the same as embodiment d1.

Dissolution experiments: measuring method is shown in Figure 15 with embodiment d1, measurement result.

It can be seen that influence of the selection difference of skeleton slow-release material to drug release very by the result of Fig. 6-Figure 15 Greatly, by the comparison of dissolved corrosion, preferably hypromellose K4M is skeleton slow-release material.Dissolution degree

Embodiment d15: the medicine stability test of Mei Suoshuli sustained release tablets of the present invention

1, influence factor experiment in 10 days: the Mei Suoshuli sustained release tablets of the 100mg specification prepared in embodiment d1 are shielded It is exposed in culture dish, respectively under the conditions of high temperature (60 DEG C), high humidity (RH 92.5%, 25 DEG C), Qiang Guang (4500lx ± 500lx) It places 10 days, was sampled in the 0th, 5,10 day, the projects such as observation formulation aesthetics, content, dissolution rate, related substance, weight-loss ratio, and with The inspection data of sample are compared before investigating, and influence factor experimental result is as shown in following table d1 within 10 days.

Table d1

10 days influence factor test results of upper table d1 show that Mei Suoshuli sustained release tablets are steady under high temperature and illumination condition Fixed, and under super-humid conditions, sustained release tablets have the phenomenon that moisture absorption, and dissolution rate decreases, therefore should consider in finished product packing Moisture-proof problem stores under the conditions of hermetically drying.

2, stability test: accelerate test within 6 months:

Inventor has carried out the research of packaging material to Mei Suoshuli sustained release tablets, and selecting packaging material is PVC bubble-cap+two-sided multiple Close aluminum foil bag.By packaged Mei Suoshuli sustained release tablets temperature is 40 DEG C ± 2 DEG C, relative humidity is 75% ± 5% test bar It is placed 6 months under part, accelerate investigation in 6 months, respectively at the 1st, 2,3, sampling in June, it is each to have carried out stability test The detection of inspection target, detailed results see the table below d2.

Table d2:

Show that Mei Suoshuli sustained release tablets of the invention are referring mainly to by the acceleration 6 months stability experiment data of table d2 Not significant change is put on, shows that Mei Suoshuli sustained release tablet products quality of the invention is reliable and stable.PVC bubble-cap adds double The packaged form of face composite aluminium film bag, can satisfy product demand.

Embodiment d16: the prescription screening of Mei Suoshuli sustained release tablets of the present invention is studied

Prescription screening research is carried out by taking Mei Suoshuli 100mg piece as an example, Mei Suoshuli sustained-release tablet recipe screens table, is shown in Table D3, the selection result are shown in Table d4.

Table d3:

Table d4:

Prescription screening is that foundation is judged with Dissolution of Sustained Release Tablet release profiles, from dissolution rate, the Da Feng of above 6 prescriptions Time, rate of release measurement result it can be concluded that, if take hydroxypropyl beta cyclodextrin to include, drug release will be directly influenced Final concentration, therefore take hydroxypropyl beta cyclodextrin inclusion that can effectively improve the solubility of Mei Suoshuli.In addition hydroxypropyl The dosage of cellulose will directly influence the rate of release of sustained release tablets in the medium, therefore as needed can be by adjusting hydroxypropyl The dosage of methylcellulose obtains specific release behavior, and the weight proportion of Mei Suoshuli and hypromellose is in 1:1 Meet prescription demand.Microcrystalline cellulose is smaller in the upper role of specific release behavior adjusting as filler.It is overall next It says, the composition of prescription d6 is than preferably, can satisfy the demand to Mei Suoshuli sustained release tablets.And main ingredient Mei Suoshuli and skeleton The weight proportion of slow-release material hypromellose release behavior when 1:1 is most ideal, with hydroxypropyl beta cyclodextrin pair In the case that Mei Suoshuli carries out inclusion processing, dissolve out more excellent.

Embodiment d17

Using the Mei Suoshuli sustained release tablets prepared in embodiment d1 as research object, compared Mei Suoshuli sustained release tablets with Mei Suoshuli piece (through the embodiment of the present invention the prescription of a9 and technique preparation) in the intracorporal pharmacokinetics behavior of Beagle dog, The pharmacokinetic studies the result is shown in Figure 16 of Mei Suoshuli sustained release tablets and Mei Suoshuli piece.

The AUC of Mei Suoshuli sustained release tablets it can be seen from the result of Figure 16_0-∞It is bigger than Mei Suoshuli ordinary tablet, and partly decline Phase is obviously prolonged, and has achieved the purpose that initial design sustained release tablets, provides steady effective blood concentration, avoid or reduces blood The appearance of medicine peak valley phenomenon is conducive to improve the safety that drug uses, reduces medicining times, improve the compliance of patient.

The e1-e16 of following Mei Suoshu Zhixieli granules agent, to feed intake according to 1000 bags of recipe quantities, following embodiment is only carried out Illustrate, is not intended to limit invention scope.

The prescription screening and optimum preparation condition of e1: Mei Suoshu Zhixieli granules agent of embodiment

In the present embodiment, by taking 50mg Mei Suoshu Zhixieli granules agent as an example (i.e. specification: 50mg), to the place of Mei Suoshu Zhixieli granules agent Side and preparation process optimize, specific as follows:

Tentatively consider from dissolution rate of the mouthfeel of particle, suspension ability and particle etc., is related to Mei Suoshu Zhixieli granules agent Prescription, specific prescription is shown in Table e1, then prepares Mei Suoshu Zhixieli granules according to prescription shown in table e1 and following preparation methods Then character, mouthfeel and the dissolution rate of the Mei Suoshu Zhixieli granules agent prepared are conventionally observed and are detected in agent, In, mouthfeel is attempted by volunteer oral.Dissolution determination is according to method as defined in Chinese Pharmacopoeia version in 2010, in pH8.8 phosphorus It is carried out in hydrochlorate buffer solution, the phosphate buffer of the pH8.8 is water-soluble by adding sodium hydroxide and potassium dihydrogen phosphate Solution, and obtained with phosphoric acid tune pH to 8.8.

Test result is shown in Table e2.

The preparation process of Mei Suoshu Zhixieli granules agent is as follows:

1) Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol, microcrystalline cellulose, Aspartame and povidone are done respectively It is dry, and main ingredient (Mei Suoshuli), auxiliary material are crushed respectively, then, main ingredient crosses 200 meshes, and it is spare that auxiliary material crosses 80 meshes；

2) Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol, microcrystalline cellulose, the Aspartame of recipe quantity are accurately weighed It is uniformly mixed with povidone, adds 75% ethanol solution softwood, softwood crossed into 16 meshes, wet granular is made, 40 DEG C of dryings cross 16 Mesh sieve measures particle drug content, determines loading amount, measures weight differential, packs up to the agent of Mei Suoshu Zhixieli granules.

Table e1 prescription screening table

Main ingredient and auxiliary material	Prescription e1	Prescription e2	Prescription e3	Prescription e4	Prescription e5	Prescription e6
							Mei Suoshuli	50	50	50	50	50	50
Hydroxypropylβ-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
							75% ethanol solution	100	100	100	100	100	100

Note: "/" indicates not containing respective components in prescription

Table e2 prescription screening result

By upper table e2 prescription screening result in general, the mouthfeel of the particle of prescription e4, suspension ability, dissolution rate are most It is good.When and Mei Suoshuli: hydroxypropylβ-cyclodextrin: the weight proportion of mannitol in 1:5:8, dissolution effect it is best.But It is that the dissolution rate of Mei Suoshu Zhixieli granules agent also needs further to improve, increases its solubility in water.

Inventor is creative to be improved and optimizes in the preceding processing of supplementary material, by Mei Suoshuli, with solubilizer, fill out The mixing of agent auxiliary material is filled, and successively carries out micronization processes twice, wet granulation is recycled to carry out the preparation of granule, it is specific to prepare Technique is as follows:

1) by Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol, microcrystalline cellulose, Aspartame, povidone, distinguish It is dry,

2) Mei Suoshuli of recipe quantity, hydroxypropylβ-cyclodextrin are mixed, micronization processes 1 time, adds mannitol and arrive It is mixed in the particle of above-mentioned micronization processes, continues to be micronized to the particle that partial size is 1-100 microns,

3) that microcrystalline cellulose, Aspartame, povidone are crossed 80 meshes is spare；

4) supplementary material in above-mentioned steps 2 and step 3 is uniformly mixed, adds 75% ethanol solution softwood, by softwood mistake Wet granular is made in 16 meshes, and 16 mesh sieves are crossed in 40 DEG C of dryings, measure particle drug content, determine loading amount, measures weight difference It is different, it is packaged into granule to obtain the final product.

Further, inventor mixes Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol on the basis of prescription e4 Micronization processes are done, further screen prescription e7- prescription e11, prescription e7- prescription e11 is shown in Table e3, according to prescription e7- prescription e11 The dissolution determination of the Mei Suoshu Zhixieli granules agent prepared the results are shown in Table e4.

The further prescription screening table of table e3

Wherein, in prescription e7, Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol after 2 micronization processes, measurement Partial size is 1-10 microns；

In prescription e8, after 2 micronization processes, the partial size of measurement is for Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol 10-30 microns；

In prescription e9, after 2 micronization processes, the partial size of measurement is for Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol 30-60 microns；

In prescription e10, Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol are after 2 micronization processes, the partial size of measurement It is 60-80 microns；

In prescription e11, Mei Suoshuli, hydroxypropylβ-cyclodextrin, mannitol are after 2 micronization processes, the partial size of measurement It is 80-100 microns.

Table f4

Index	Prescription e7	Prescription e8	Prescription e9	Prescription e10	Prescription e11	Prescription e4
							Dissolution rate	88.2%	89.5%	92.5%	90.8%	90.1%	77.7%

Table e4 can be seen that the dissolution rate effect according to Mei Suoshu Zhixieli granules agent made from prescription e7- prescription e11, excellent In the Mei Suoshu Zhixieli granules agent obtained with general pre-treatment, dissolution rate reaches States Pharmacopoeia specifications requirement.Particularly, when Mei Suoshuli, Hydroxypropylβ-cyclodextrin and mannitol admixed finepowder are at 30-60 microns, and Mei Suoshuli: hydroxypropylβ-cyclodextrin: mannitol Weight proportion in 1:5:8, dissolution effect it is best.

In addition, inventor tests 30 day influence factors of the auxiliary material in prescription to main ingredient, to investigate prescription The drug compatibility of middle auxiliary material and main ingredient and stability influence to drug, specific as follows:

The Mei Suoshu Zhixieli granules agent prepared according to prescription e4 is exposed in culture dish, respectively at high temperature (60 DEG C), 30 are placed under high humidity (relative humidity 92.5%), illumination condition, and is sampled when 0 day, 5 days, 10 days and 30 days, and U.S. rope is observed The appearance of easypro Zhixieli granules agent, and utilize in high effective liquid chromatography for measuring Mei Suoshu Zhixieli granules agent in relation to substance and content, experiment Measurement result is shown in Table e5.

30 day influence factor experimental results of the auxiliary material to main ingredient in table e5 prescription

Experimental condition	Appearance	Related substance (%)	Content (labelled amount %)
				0 day	Yellow	0.26	99.7
Illumination 5 days	Yellow	0.28	99.8
				Illumination 10 days	Yellow	0.29	98.9
Illumination 30 days	Yellow	0.31	99.5
				60 DEG C 5 days	Yellow	0.30	99.4
60 DEG C 10 days	Yellow	0.36	99.3
				60 DEG C 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

In above-mentioned table e5, related substance refers to that the intermediate generated in the synthesis process, by-product etc. or storage transported The product degraded in journey.Labelled amount refers to the theoretic inventory of main ingredient.Content refers to that main ingredient accounts for the weight percent of labelled amount Than.

By the result of table e5 it is found that the drug compatibility of each auxiliary material and main ingredient is good in prescription, auxiliary material is to main ingredient stability Without influence.

The same method of inventor has studied the prescription that specification is the different sizes such as 25mg, 75mg, 100mg, 125mg And preparation process, all obtain technical effect identical with prescription and technique that specification above is 50mg.

Embodiment e2

Prescription:

25 parts by weight of Mei Suoshuli, 125 parts by weight of hydroxypropylβ-cyclodextrin, 200 parts by weight of mannitol, microcrystalline cellulose 17.5 parts by weight, 7.5 parts by weight of Aspartame, 50 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is as follows:

2) Mei Suoshuli of recipe quantity, hydroxypropylβ-cyclodextrin are mixed, micronization processes 1 time, adds mannitol and arrive It is mixed in the particle of above-mentioned micronization processes, continues to be micronized to the particle that partial size is 10 microns (μm),

According to above-mentioned prescription and preparation method, three batches of Mei Suoshu Zhixieli granules agent samples are prepared, lot number is respectively 130501, 130502,130503, and conventionally, obtained Mei Suoshu Zhixieli granules agent sample has been carried out to accelerate 6 months stabilizations Property experimental study, data are shown in Table e6.

6 months stability datas of acceleration of test agent in tri- batches of Mei Suoshu Zhixieli granules agent of table e6

Table e6's the result shows that, the accelerated stability test in 6 months of Mei Suoshu Zhixieli granules agent of the invention, quality stablize.

Embodiment e3

Prescription:

25 parts by weight of Mei Suoshuli, 25 parts by weight of hydroxypropylβ-cyclodextrin, 125 parts by weight of mannitol, microcrystalline cellulose 15 Parts by weight, 10 parts by weight of Aspartame, 25 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is as follows:

2) Mei Suoshuli of recipe quantity, hydroxypropylβ-cyclodextrin are mixed, micronization processes 1 time, adds mannitol and arrive It is mixed in the particle of above-mentioned micronization processes, continues to be micronized to the particle that partial size is 50 microns (μm),

Embodiment e4

Prescription:

25 parts by weight of Mei Suoshuli, 25 parts by weight of hydroxypropylβ-cyclodextrin, 400 parts by weight of mannitol, microcrystalline cellulose 17.5 parts by weight, 5 parts by weight of Aspartame, 50 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is as follows:

2) Mei Suoshuli of recipe quantity, hydroxypropylβ-cyclodextrin are mixed, micronization processes 1 time, adds mannitol and arrive It is mixed in the particle of above-mentioned micronization processes, continues to be micronized to the particle that partial size is 100 microns (μm),

Embodiment e5

Prescription:

50 parts by weight of Mei Suoshuli, 250 parts by weight of hydroxypropylβ-cyclodextrin, 400 parts by weight of mannitol, microcrystalline cellulose 35 Parts by weight, 15 parts by weight of Aspartame, 100 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e2.

Embodiment e6

Prescription:

50 parts by weight of Mei Suoshuli, 50 parts by weight of hydroxypropylβ-cyclodextrin, 400 parts by weight of mannitol, microcrystalline cellulose 35 Parts by weight, 15 parts by weight of Aspartame, 50 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e3.

Embodiment e7

Prescription:

50 parts by weight of Mei Suoshuli, 125 parts by weight of hydroxypropylβ-cyclodextrin, 500 parts by weight of mannitol, microcrystalline cellulose 35 Parts by weight, 15 parts by weight of Aspartame, 100 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e4.

Embodiment e8

Prescription:

75 parts by weight of Mei Suoshuli, 375 parts by weight of hydroxypropylβ-cyclodextrin, 600 parts by weight of mannitol, microcrystalline cellulose 52.5 parts by weight, 21.5 parts by weight of Aspartame, 150 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e2.

Embodiment e9

Prescription:

75 parts by weight of Mei Suoshuli, 75 parts by weight of hydroxypropylβ-cyclodextrin, 600 parts by weight of mannitol, microcrystalline cellulose 60 Parts by weight, 25 parts by weight of Aspartame, 100 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e3.

Embodiment e10

Prescription:

75 parts by weight of Mei Suoshuli, 75 parts by weight of hydroxypropylβ-cyclodextrin, 450 parts by weight of mannitol, microcrystalline cellulose 50 Parts by weight, 25 parts by weight of Aspartame, 150 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e4.

Embodiment e11

Prescription:

100 parts by weight of Mei Suoshuli, 500 parts by weight of hydroxypropylβ-cyclodextrin, 400 parts by weight of mannitol, microcrystalline cellulose 70 parts by weight, 30 parts by weight of Aspartame, 200 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e2.

Embodiment e12

Prescription:

100 parts by weight of Mei Suoshuli, 100 parts by weight of hydroxypropylβ-cyclodextrin, 300 parts by weight of mannitol, microcrystalline cellulose 60 parts by weight, 30 parts by weight of Aspartame, 150 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e3.

Embodiment e13

Prescription:

100 parts by weight of Mei Suoshuli, 100 parts by weight of hydroxypropylβ-cyclodextrin, 600 parts by weight of mannitol, microcrystalline cellulose 50 parts by weight, 40 parts by weight of Aspartame, 100 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e4.

Embodiment e14

Prescription:

125 parts by weight of Mei Suoshuli, 375 parts by weight of hydroxypropylβ-cyclodextrin, 600 parts by weight of mannitol, microcrystalline cellulose 50 parts by weight, 20 parts by weight of Aspartame, 200 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e2.

Embodiment e15

Prescription:

125 parts by weight of Mei Suoshuli, 250 parts by weight of hydroxypropylβ-cyclodextrin, 500 parts by weight of mannitol, microcrystalline cellulose 75 parts by weight, 12.5 parts by weight of Aspartame, 100 parts by weight of povidone, 75% appropriate amount of ethanol.

Preparation process is the same as embodiment e3.

Embodiment e16

Prescription:

125 parts by weight of Mei Suoshuli, 250 parts by weight of hydroxypropylβ-cyclodextrin, 375 parts by weight of mannitol, microcrystalline cellulose 50 parts by weight, 25 parts by weight of Aspartame, 150 parts by weight of povidone, 75% appropriate amount of ethanol

Preparation process is the same as embodiment e4.

Inventor with identical method in embodiment e2, to the resulting Mei Suoshu Zhixieli granules of embodiment e3- embodiment e16 Agent accelerate stability test in 6 months, the results showed that, each resulting stability of drug products of prescription is good, resulting Mei Suoshu Zhixieli granules agent quality is stablized.

The embodiment f1-f12 of following Mei Suoshuli capsule, to feed intake according to 1000 recipe quantities, following embodiment is It is illustrated, is not intended to limit invention scope.

The formulation study of f1: Mei Suoshuli capsule of embodiment

Since main ingredient Mei Suoshuli is practically insoluble in water, and main ingredient amount is also larger, and therefore, the difficult point of formulation and technology is to mention The dissolution rate of high this product.In the present embodiment, the prescription for the Mei Suoshuli capsule for being 50mg/ to specification is studied, and is had For body, due to Mei Suoshuli raw material aqueous solubility and mobility inequality, considers that water soluble adjuvant is added and disintegrating agent promotion is molten Out, 9 prescriptions are devised, f1 is shown in Table.

Table f1 different Formulations

Note: in the preparation of adhesive, hydroxypropyl methylcellulose need to add purified water be configured to 4% hydroxypropyl methylcellulose it is water-soluble Liquid (g/g), PVP K30 need to add purified water to be configured to 8% PVP K30 aqueous solution (g/g), and "-" indicates not containing corresponding Prescription.

Preparation method (wet granulation):

Sample is prepared using wet granulation technology respectively by the prescription in table f1, specific as follows:

(2) match adhesive:

When the adhesive in prescription selects PVP K30,8 grams of PVP K30s are weighed in beaker, add purified water 92 Gram, it stirs to clarify, obtains 8% PVP K30 aqueous solution I, it is spare；

(3) mix: the main ingredient that weighs recipe quantity, filler after mixing, add disintegrating agent and are uniformly mixed, must mix Object II；

(8) capsule is filling: it is filling that the qualified medicinal mixture sample of total mix granule content detection is carried out capsule.

Dissolution determination:

By the measuring method under 2010 editions dissolution rate items of Chinese Pharmacopoeia, above-mentioned 9 prescriptions are measured 45 points in dissolution medium The dissolution rate of clock, wherein dissolution medium is that (sodium hydroxide 2.3g, potassium dihydrogen phosphate 7.65g add water to make to dissolve to phosphate buffer For 1000ml, with phosphoric acid tune pH to 8.8), dissolution determination the results are shown in Table f2.

The dissolution rate of each prescription capsule of table f2 compares

Prescription	f1	f2	f3	f4	f5	f6	f7	f8	f9
										Dissolution rate (%)	80.5	71.0	70.7	80.6	71.5	69.1	72.2	80.0	71.2

In terms of dissolution result, 9 designed prescriptions, 45 minutes dissolution rates in dissolution medium are shown, preferably prescription For prescription f1, prescription f4, prescription f8.Due to Mei Suoshuli poorly water-soluble, and hypromellose is known as the molten effect of resistance, may be Sample influences dissolution rate during keeping sample, it is longer the time required to complete swelling in water in addition, is unfavorable for industrialized production, therefore Preferably its as adhesive.

And microcrystalline cellulose not only serves as filler, and has the performance of disintegrating agent, chooses microcrystalline cellulose conduct The result of extraction that filler can reach.Therefore originally determine based on prescription f1, further investigate the ratio of screening filler Example, the concentration of adhesive, and the addition manner of disintegrating agent is improved, prescription and preparation process are advanced optimized.

The formulation and technology of f2: Mei Suoshuli capsule of embodiment optimizes

Dosage form requirement of this research according to Chinese Pharmacopoeia 2010 editions to capsule, referring to CDE promulgation " chemicals medicine is ground Study carefully basic fundamental guideline ", in conjunction with the characteristics of capsule, with dissolution rate etc. for inspection target, this product prescription is used auxiliary The type and dosage of material have carried out further screening.

(1) screening of filler

The ratio and dosage of lactose and microcrystalline cellulose are adjusted, diluent (herein, " filler " and " dilution are investigated Agent " may be used interchangeably) influence of different proportion and dosage to capsule formability and dissolution rate, specific prescription and result be as follows:

This research is combined into diluent, the place of lactose and microcrystalline cellulose different proportion using the group of lactose and microcrystalline cellulose Fang Jianbiao f3, table f3 show the recipe quantity of 1000 Mei Suoshuli capsules of preparation.According to prescription shown in table f3 and above-mentioned implementation Preparation method described in example f1, prepares Mei Suoshuli capsule.Wherein in prescription f6- prescription f10, the preparation method of adhesive Are as follows: 8 grams of PVP K30s are weighed in beaker, adds 92 grams of purified water, stirs to clarify, and obtain 8% PVP K30 aqueous solution.

The dissolution rate of the Mei Suoshuli capsule prepared is measured, in order to screen filler.Dissolution determination result is shown in Table f3.

The screening prescription and measurement result of table f3 filler

It can be seen from the result of table f3 in above-mentioned 5 prescriptions, prescription f12 is due to having lacked microcrystalline cellulose, disintegration Can be slightly worse, dissolution rate is low, and the disintegration of prescription f1, f10, f11, f13 and dissolution rate are preferable, and wherein prescription f11 is resulting molten Out-degree is best, therefore selects the mass ratio of lactose and microcrystalline cellulose for (0.5~5): 1, the wherein matter of lactose and microcrystalline cellulose Amount is optimal proportion than 2:1.

(2) screening of adhesive

PVP K30 is chosen as adhesive, and the aqueous solution for preparing various concentration compares its bonding effect Research, specific as follows:

According to prescription shown in table f4 and the preparation method in embodiment f1, Mei Suoshuli capsule is prepared.

Wherein in prescription f14, the preparation method of adhesive are as follows: weigh 4 grams of PVP K30s in beaker, add purified water 96 Gram, it stirs to clarify, obtains 4% PVP K30 aqueous solution；Wherein in prescription f15, the preparation method of adhesive are as follows: weigh 8 grams and gather Ketone K30 is tieed up in beaker, adds 92 grams of purified water, stirs to clarify, obtain 8% PVP K30 aqueous solution；Wherein in prescription f16, glue The preparation method of mixture are as follows: weigh 10 grams of PVP K30s in beaker, add 90 grams of purified water, stir to clarify, obtain 10% poly- dimension Ketone K30 aqueous solution；Wherein in prescription f17, the preparation method of adhesive are as follows: weigh 15 grams of PVP K30s in beaker, add purifying It 85 grams of water, stirs to clarify, obtains 15% PVP K30 aqueous solution.

Mei Suoshuli softwood situation and Mei Suoshuli dry particl situation are observed in preparation process, and are measured preparation and obtained The dissolution rate of the Mei Suoshuli capsule obtained, prescription and measurement result are shown in Table f4, wherein prescription shown in table f4 is 1000 beauty of preparation The recipe quantity of Suo Shuli capsule.

The screening of table f4 adhesive

It can be seen that in prescription f14 from the result of table f4, when binder concn is 4%, softwood has loosely been not easy It is viscous, since obtained dry particl fine powder is more, will lead to capsule it is filling when obtained capsule agent content uniformity it is unqualified；Locating In square f17 when binder dosage reaches 25%, obtained softwood is harder, is not easy to be sieved, and extend disintegration time；And In prescription f15, prescription f16, when the concentration of adhesive is 10% or 15%, obtained softwood dry and wet degree is moderate, easy mistake The particle rounding for sieving and obtaining, good fluidity are easy to carry out capsule filling.And when using the adhesive of 10% ratio, gained The dissolution rate of the Mei Suoshuli capsule arrived is better than using the obtained Mei Suoshuli capsule of 10% ratio.

(3) screening of disintegrating agent

In the present embodiment, the dosage of disintegrating agent and the addition manner of disintegrating agent have been investigated to the shadow of Mei Suoshuli capsule It rings, specific as follows:

According to formula shown in table f5 and the preparation method in embodiment f1, Mei Suoshuli capsule is prepared.

Interior addition refers to, and disintegrating agent is added in mixing step, and outer addition refers in total mix step, be added lubricant it Before, first dry particl and disintegrating agent are uniformly mixed.

When disintegrating agent carries out inside and outside addition, sample is prepared using wet granulation technology respectively by the prescription in table f5, The preparation method is as follows:

Then the dissolution rate of the Mei Suoshuli capsule prepared is measured, measurement result is shown in Table f5.Wherein, place shown in table f5 The formula of square f18- prescription f22 is the recipe quantity for preparing 1000 Mei Suoshuli capsules.

The prescription screening of table f5 disintegrating agent

It can be seen that prescription f18, prescription f19 from the result of table f5 and prescription f20 dissolution results difference be little, explanation Reducing a certain amount of disintegrating agent can still keep preferably dissolving out, while can be with save the cost.Prescription f21's and prescription f22 Disintegrating agent is all made of inside and outside addition, and dissolution rate significantly improves.Additional disintegrating agent can promote the disintegration of particle, and interior plus disintegrating agent is then The dispersion that can accelerate particle is conducive to improve dissolution rate.It can be seen from the results above that using the work of addition inside and outside disintegrating agent Skill, relative to disintegrating agent only with the technique of interior addition, dissolution rate is significantly improved, therefore determines dosage and the addition side of disintegrating agent Formula are as follows: the interior dosage of disintegrating agent is the 1/2 of disintegrating agent recipe quantity, and outer dosage is another the 1/2 of disintegrating agent recipe quantity.Therefore, it fixes tentatively Prescription is prescription f21.

Embodiment f3: Mei Suoshuli bulk pharmaceutical chemicals partial size is investigated

Influence of the partial size of bulk pharmaceutical chemicals to Mei Suoshuli capsule is investigated in accordance with the following steps, specific as follows:

Based on the prescription f21 in embodiment f2, preparation process of the invention is advanced optimized, further to mention The dissolution rate of high Mei Suoshuli capsule of the present invention.

Specifically, according to prescription f21, two groups of (A1 group and 1B group) Mei Suoshuli capsules, the U.S. rope of preparation A1 group are prepared respectively The method of Shu Li capsule is as described below, the preparation method of B1 group Mei Suoshuli capsule and the preparation method of A1 group Mei Suoshuli capsule Difference is that main ingredient Mei Suoshuli and the mixing of auxiliary material filler do not carry out micronization processes.

A1 group Mei Suoshuli capsule the preparation method is as follows:

Then the dissolution rate of the two groups of Mei Suoshuli capsules prepared is measured, measurement result is shown in Table f6.

Table f6

It is micronized by the result of table f6 it is found that first mixing Mei Suoshuli and lactose, Mei Suoshuli capsule obtained Dissolution rate can significantly be improved.

The preparation of f4: Mei Suoshuli capsule of embodiment

Prescription: it is shown in Table f7

Table f7

Preparation process:

(1) supplementary material pre-treatment: by 50 grams of main ingredient (Mei Suoshuli) and 80 grams of auxiliary material filler lactose, microcrystalline cellulose 40 Gram mixing is micronized (partial size is at 5 microns to 30 microns), remaining each auxiliary material smashes it through 80 meshes respectively, spare；

(2) match adhesive: weighing 10 grams of adhesive PVP K30s in beaker, add 90 grams of purified water, stir to clarify, The binder aqueous solution I of 10% PVP K30 is obtained, it is spare；

(3) it mixes: after mixing by Mei Suoshuli and filler, 6 grams of disintegrating agent crospovidone added in needing is added It is uniformly mixed, obtains mixture II；

(7) total mix: the need of addition recipe quantity are additional in dry particl 6 grams of disintegrating agent crospovidone add recipe quantity It 2.5 grams of magnesium stearate, is uniformly mixed, obtains total mix particle；

The preparation of f5: Mei Suoshuli capsule of embodiment

Prescription: it is shown in Table f8

Table f8

Preparation process:

(1) supplementary material pre-treatment: by 50 grams of main ingredient (Mei Suoshuli) and 60 grams of auxiliary material filler lactose, microcrystalline cellulose 60 Gram mixing is micronized (partial size is at 30 microns to 70 microns), remaining each auxiliary material smashes it through 60 meshes respectively, spare；

(2) match adhesive: weighing 12 grams of adhesive PVP K30s in beaker, add 88 grams of purified water, stir to clarify, It is prepared into the binder aqueous solution I of 12% PVP K30, it is spare；

(3) it mixes: after mixing by Mei Suoshuli and filler, 8 grams of disintegrating agent crospovidone added in needing is added It is uniformly mixed, obtains mixture II；

(7) total mix: the need of addition recipe quantity are additional in dry particl 8 grams of disintegrating agent crospovidone add recipe quantity It 2 grams of magnesium stearate, is uniformly mixed, obtains total mix particle；

The preparation of f6: Mei Suoshuli capsule of embodiment

Prescription: it is shown in Table f9

Table f9

Preparation process:

(1) supplementary material pre-treatment: by 50 grams of main ingredient (Mei Suoshuli) and 113 grams of auxiliary material filler lactose, microcrystalline cellulose 57 grams of mixing are micronized (partial size is at 70 microns to 100 microns), remaining each auxiliary material smashes it through 80 meshes respectively, spare；

(2) match adhesive: weighing 8 grams of adhesive PVP K30s in beaker, add 92 grams of purified water, stir to clarify, make The standby binder aqueous solution I for obtaining 8% PVP K30, it is spare；

(7) total mix: the need of addition recipe quantity are additional in dry particl 6 grams of disintegrating agent crospovidone add recipe quantity It 2.4 grams of magnesium stearate, is uniformly mixed, obtains total mix particle；

The preparation of f7: Mei Suoshuli capsule of embodiment

Prescription: it is shown in Table f10

Table f10

Preparation process:

(1) supplementary material pre-treatment: by 50 grams of main ingredient (Mei Suoshuli) and 100 grams of auxiliary material filler lactose, microcrystalline cellulose 100 grams of mixing are micronized (partial size is at 5 microns to 100 microns), remaining each auxiliary material smashes it through 80 meshes respectively, spare；

(2) match adhesive: weighing 20 grams of adhesive PVP K30s in beaker, add 80 grams of purified water, stir to clarify, It is prepared into the binder aqueous solution I of 20% PVP K30, it is spare；

(5) it dries: drug wet granular obtained in step (4) is dried into 3h at 55 DEG C；

The preparation of f8: Mei Suoshuli capsule of embodiment

Prescription: it is shown in Table f11

Table f11

Preparation process:

(1) supplementary material pre-treatment: by 100 grams of main ingredient (Mei Suoshuli) and 100 grams of auxiliary material filler lactose, microcrystalline cellulose 100 grams of mixing are micronized (partial size is at 5 microns to 100 microns), remaining each auxiliary material smashes it through 80 meshes respectively, spare；

(2) match adhesive: weighing 15 grams of adhesive PVP K30s in beaker, add 85 grams of purified water, stir to clarify, It is prepared into the binder aqueous solution I of 15% PVP K30, it is spare；

(5) it dries: drug wet granular obtained in step (4) is dried into 2h at 55 DEG C；

The preparation of f9: Mei Suoshuli capsule of embodiment

Prescription: it is shown in Table f12

Table f12

Preparation process:

(2) match adhesive: weighing 7 grams of adhesive PVP K30s in beaker, add 93 grams of purified water, stir to clarify, make The standby binder aqueous solution I for obtaining 7% PVP K30, it is spare；

The preparation of f10: Mei Suoshuli capsule of embodiment

Prescription: it is shown in Table f13

Table f13

Composition	Supplementary material	Recipe quantity (g)
			Main ingredient	Mei Suoshuli	25
Filler	Cornstarch	150
			Adhesive	Hydroxypropyl methylcellulose	5
Disintegrating agent (interior to add)	Croscarmellose sodium	2.5
			Disintegrating agent (additional)	Croscarmellose sodium	2.5
Lubricant	Magnesium stearate	0.8

Preparation process:

(1) supplementary material pre-treatment: the 150 grams of mixing of 25 grams of main ingredient (Mei Suoshuli) and auxiliary material filler cornstarch are carried out Micronization (partial size is at 5 microns to 100 microns), remaining each auxiliary material smash it through 80 meshes respectively, spare；

(2) match adhesive: weighing 5 grams of adhesive hydroxypropyl methylcelluloses in beaker, add 45 grams of purified water, stir to clear Clearly, it is prepared into the binder aqueous solution I of 5% hydroxypropyl methylcellulose, it is spare；

(3) it mixes: after mixing by Mei Suoshuli and filler, the disintegrating agent cross-linked carboxymethyl fiber added in needing is added 2.5 grams of plain sodium are uniformly mixed, and obtain mixture II；

(5) it dries: drug wet granular obtained in step (4) is dried into 1h at 60 DEG C；

(7) total mix: the need of addition recipe quantity are additional in dry particl 2.5 grams of disintegrating agent croscarmellose sodium, then It is added 0.8 gram of recipe quantity magnesium stearate, is uniformly mixed, obtains total mix particle；

The preparation of f11: Mei Suoshuli capsule of embodiment

Prescription: it is shown in Table f14

Table f14

Composition	Supplementary material	Recipe quantity (g)
			Main ingredient	Mei Suoshuli	125
Filler	Mannitol	50
			Adhesive	Methylcellulose	10
Disintegrating agent (interior to add)	Sodium carboxymethyl starch	10
			Disintegrating agent (additional)	Sodium carboxymethyl starch	10
Lubricant	Magnesium stearate	4

Preparation process:

(1) supplementary material pre-treatment: the 50 grams of mixing of 125 grams of main ingredient (Mei Suoshuli) and auxiliary material filler mannitol are carried out micro- Dusting (partial size is at 5 microns to 100 microns), remaining each auxiliary material smash it through 80 meshes respectively, spare；

(2) match adhesive: weighing 10 grams of adhesive methylcellulose in beaker, add 90 grams of purified water, stir to clarify, It is prepared into the binder aqueous solution I of 10% methylcellulose, it is spare；

(3) it mixes: after mixing by Mei Suoshuli and filler, the disintegrating agent carboxymethyl base sodium starch 10 added in needing is added Gram be uniformly mixed, obtain mixture II；

(7) total mix: 10 grams additional of disintegrating agent carboxymethyl base sodium starch of the need of recipe quantity is added in dry particl, adds prescription 4 grams of magnesium stearate of amount is uniformly mixed, obtains total mix particle；

Embodiment f12, quality evaluation

Firstly, check the appearance character of the obtained Mei Suoshuli capsule of embodiment f4- embodiment f11, weight differential, and The dissolution rate of Mei Suoshuli capsule obtained by embodiment f4- embodiment f11 is measured, measurement result such as table f15:

Table f15:

From table f15's the results show that character of each batch of sample, weight differential, dissolution rate meet the requirements, and dissolution rate compared with It is high.

Influence factor experiment:

Next, preparing Mei Suoshuli capsule to above-described embodiment f6 carries out influence factor experiment, it is specific as follows:

The Mei Suoshuli capsule that embodiment f6 is prepared is uncovered in culture dish, respectively in high temperature (60 DEG C), high humidity It places 10 days under the conditions of (RH 92.5%, 25 DEG C), Qiang Guang (4500lx ± 500lx), was sampled in the 5th, 10 day, observed outside preparation Sight, content, dissolution rate, related substance, and be compared with the inspection data for investigating preceding sample, testing result is shown in Table f16.

Table f16 Mei Suoshuli capsule influence factor test result

Influence factor test result shows: capsule is placed 10 days under high temperature, high humidity, illumination, and content, related substance are without aobvious Write property variation, quality stablize, show that prescription of the present invention is feasible, preparation process of the present invention rationally, reproducibility Resulting Mei Suoshuli capsule quality stability good, of the invention is good.

The embodiment g1-g8 of following Mei Suoshuli spansule feeds intake according to 1000 tablet recipe amounts, and following embodiment is It is illustrated, is not intended to limit invention scope.

Embodiment g1

(1) Mei Suoshuli carries the preparation of pill core

Prescription:

Carry the composition of pill core	Parts by weight
		Mei Suoshuli	100
Crospovidone	10
		Microcrystalline cellulose	100
Hypromellose	50

Preparation method:

Mei Suoshuli raw material ultra-fine grinding (i.e. micronization processes) is passed with remaining auxiliary material equivalent in above-mentioned recipe quantity afterwards Add uniformly mixed, use 4% hypromellose purification of aqueous solutions that softwood is made in the above-mentioned powder mixed as adhesive, Load pill core is made using the method for extrusion spheronization.Using single screw rod, radially screen formula squeezes out extruder, hole diameter of sieve (perforated) plate 0.8mm, Screw speed is 40r/min.Extrudate is rolled into Mei Suoshuli in centrifugal granulator under 500r/min revolving speed and carries pill core, and By load pill core obtained at 40 DEG C dry to get.

(2) preparation of coating solution

1. spacer layer coating liquid

The composition of spacer layer coating liquid	Parts by weight
		PVP K30	18.5
Talcum powder	3
		Dehydrated alcohol	115

Preparation method: PVP K30 is added to absolute ethanol, stirring swelling, after PVP K30 complete swelling, then Talcum powder is added in solution, stirring keeps its evenly dispersed to get spacer layer coating liquid.

2. slow release layer coating solution

The composition of slow release layer coating solution	Parts by weight
		25% Aquacoat	95
Macrogol 4000	1
		Purified water	144

Preparation method: 25% (mass fraction, g/g) Aquacoat being added in the purified water of recipe quantity, It stirs evenly, then the Macrogol 4000 of recipe quantity is added in above-mentioned solution, stirring keeps its evenly dispersed to get slow release layer packet Clothing liquid.

(3) pill core coating is carried

The above-mentioned load pill core prepared is placed in fluidized bed, is sprayed and is coated the bottom of using, intake volume 30HZ, turntable turns Fast 250r/min, 40 DEG C of inlet air temperature, 35 DEG C of temperature of charge, atomizing pressure 1.5bar, hydrojet speed 4g/min.Ensuring to carry medicine In the state that capsule core rolls smoothness, spacer layer coating liquid is sprayed onto and carries pill wicking surface, coating weight gain 3% is measured by sampling and stops spray Liquid.Continue aeration-drying pill 15min, then change spray slow release layer coating solution, when coating weight gain is to 20%, stops coating, do It is dry to get Mei Suoshuli sustained release pellet.

(4) it cures

Mei Suoshuli sustained release pellet obtained in step (3) is placed in 35 degrees Celsius of vacuum constant temperature drying boxes, cures 8 Hour.

(5) filling capsule

The Mei Suoshuli sustained release pellet that curing finishes is poured into the Mei Suoshuli in No. 1 Capsules to get the present embodiment Spansule.

Then, dissolution rate test is carried out to the Mei Suoshuli spansule prepared, specific as follows:

Dissolution experiments: with Chinese Pharmacopoeia two the first subtraction units of annex XC of version in 2010, according to Chinese Pharmacopoeia version in 2010 The dissolution rate of two the first method of annex XD measurement samples.Using water 1000ml as dissolution medium, 100 turns of revolving speed, 1,2,4,8,10, 12, it samples within 16 hours, measures the dissolution rate of the Mei Suoshuli spansule prepared, the results are shown in Table g1, corresponding dissolution Figure is shown in attached drawing 17.

Table 1

Embodiment g2

(1) Mei Suoshuli carries the preparation of pill core

Prescription:

Carry the composition of pill core	Parts by weight
		Mei Suoshuli	50
Croscarmellose sodium	15
		Starch	145
Hypromellose	50

Preparation method:

It is uniformly mixed, uses by progressively increasing after Mei Suoshuli raw material ultra-fine grinding with remaining auxiliary material equivalent in above-mentioned recipe quantity As adhesive softwood is made in the above-mentioned powder mixed by 4% hypromellose purification of aqueous solutions, using extrusion spheronization Method load pill core is made.Using single screw rod, radially screen formula squeezes out extruder, hole diameter of sieve (perforated) plate 0.8mm, and screw speed is 40r/min.Extrudate is rolled into Mei Suoshuli in centrifugal granulator under 500r/min revolving speed and carries pill core, and by load obtained Pill core at 40 DEG C dry to get.

(2) preparation of coating solution

1. spacer layer coating liquid

The composition of spacer layer coating liquid	Parts by weight
		PVP K30	25
Talcum powder	2
		Dehydrated alcohol	150

Preparation method: with embodiment g1.

2. slow release layer coating solution

Preparation method: with embodiment g1.

(3) carry pill core coating: method is the same as embodiment g1.

(4) it cures: Mei Suoshuli sustained release pellet obtained in step (3) is placed in 30 degrees Celsius of vacuum constant temperature drying boxes In, cure 10 hours.

(5) filling capsule: the Mei Suoshuli sustained release pellet that curing finishes is poured into No. 1 Capsules to get this implementation The Mei Suoshuli spansule of example.

Then, dissolution rate test is carried out to the Mei Suoshuli spansule prepared, measuring method is surveyed with embodiment 1 Surely the dissolution results of the Mei Suoshuli spansule prepared are shown in Table g2.

Table g2

Time (hour)	Dissolution rate (%)
		0	0
1	47
		2	59
4	72
		6	76
8	83
		12	86
16	87

Embodiment g3

(1) Mei Suoshuli carries the preparation of pill core

Prescription:

Carry the composition of pill core	Parts by weight
		Mei Suoshuli	50
Low-substituted hydroxypropyl cellulose	20
		Lactose	140
Hypromellose	30

Preparation method:

(2) preparation of coating solution

1. spacer layer coating liquid

The composition of spacer layer coating liquid	Parts by weight
		PVP K30	15
Talcum powder	3
		Dehydrated alcohol	130

Preparation method: with embodiment g1.

2. slow release layer coating solution

Preparation method: with embodiment g1.

(3) carry pill core coating: method is the same as embodiment g1.

(4) it cures: Mei Suoshuli sustained release pellet obtained in step (3) is placed in 40 degrees Celsius of vacuum constant temperature drying boxes In, cure 6 hours.

Then, dissolution rate test is carried out to the Mei Suoshuli spansule prepared, measuring method is surveyed with embodiment g1 Surely the dissolution results of the Mei Suoshuli spansule prepared are shown in Table g3.

Table g3

Time (hour)	Dissolution rate (%)
		0	0
1	50
		2	57
4	72
		6	84
8	85
		12	83
16	82

Embodiment g4

(1) Mei Suoshuli carries the preparation of pill core

Prescription:

Carry the composition of pill core	Parts by weight
		Mei Suoshuli	75
Sodium carboxymethyl starch	15
		Dextrin	120
Hydroxypropyl cellulose	40

Preparation method:

It is uniformly mixed, uses by progressively increasing after Mei Suoshuli raw material ultra-fine grinding with remaining auxiliary material equivalent in above-mentioned recipe quantity As adhesive softwood is made in the above-mentioned powder mixed by 4% hydroxypropyl cellulose purification of aqueous solutions, using extrusion spheronization Load pill core is made in method.Using single screw rod, radially screen formula squeezes out extruder, hole diameter of sieve (perforated) plate 0.8mm, screw speed 40r/ min.Extrudate is rolled into Mei Suoshuli in centrifugal granulator under 500r/min revolving speed and carries pill core, and by load pill obtained Core at 40 DEG C dry to get.

(2) preparation of coating solution

1. spacer layer coating liquid

The composition of spacer layer coating liquid	Parts by weight
		PVP K30	10
Talcum powder	5.5
		Dehydrated alcohol	120

Preparation method: with embodiment g1.

2. slow release layer coating solution

Preparation method: with embodiment g1.

(3) carry pill core coating: method is the same as embodiment g1.

(4) it cures: with embodiment g1.

(5) filling capsule: with embodiment g1.

Then, dissolution rate test is carried out to the Mei Suoshuli spansule prepared, measuring method is surveyed with embodiment g1 Surely the dissolution results of the Mei Suoshuli spansule prepared are shown in Table g4, and corresponding dissolution figure is shown in attached drawing 18.

Table g4

Time (hour)	Dissolution rate (%)
		0	0
1	51
		2	65
4	78
		6	85
8	81
		12	79
16	77

Embodiment g5

(1) Mei Suoshuli carries the preparation of pill core

Prescription:

Preparation method:

It is uniformly mixed, uses by progressively increasing after Mei Suoshuli raw material ultra-fine grinding with remaining auxiliary material equivalent in above-mentioned recipe quantity As adhesive softwood is made in the above-mentioned powder mixed by 4% sodium carboxymethylcellulose purification of aqueous solutions, using extrusion spheronization Method load pill core is made.Using single screw rod, radially screen formula squeezes out extruder, hole diameter of sieve (perforated) plate 0.8mm, and screw speed is 40r/min.Extrudate is rolled into Mei Suoshuli in centrifugal granulator under 500r/min revolving speed and carries pill core, and by load obtained Pill core at 40 DEG C dry to get.

(2) preparation of coating solution

1. spacer layer coating liquid

The composition of spacer layer coating liquid	Parts by weight
		PVP K30	25
Talcum powder	2.5
		Dehydrated alcohol	100

Preparation method: with embodiment g1.

2. slow release layer coating solution

Preparation method: with embodiment g1.

(3) carry pill core coating: method is the same as embodiment g1.

(4) it cures: with embodiment g1.

(5) filling capsule: with embodiment g1.

Then, dissolution rate test is carried out to the Mei Suoshuli spansule prepared, measuring method is surveyed with embodiment g1 Surely the dissolution results of the Mei Suoshuli spansule prepared are shown in Table g5.

Table g5

Embodiment g6

(1) Mei Suoshuli carries the preparation of pill core

Prescription:

Carry the composition of pill core	Parts by weight
		Mei Suoshuli	100
Crospovidone	12
		Microcrystalline cellulose	100
Hypromellose	40

Preparation method:

(2) preparation of coating solution

1. spacer layer coating liquid

The composition of spacer layer coating liquid	Parts by weight
		PVP K30	18
Talcum powder	1.3
		Dehydrated alcohol	110

Preparation method: with embodiment g1.

2. slow release layer coating solution

Preparation method: with embodiment g1.

(3) carry pill core coating: method is the same as embodiment g1.

(4) it cures: with embodiment g1.

(5) filling capsule: with embodiment g1.

Embodiment g7

Inventor has carried out influence factor test in 10 days to Mei Suoshuli spansule is prepared in embodiment g1.Specifically It is as follows:

The Mei Suoshuli spansule (preparing according to embodiment g1 method) of 100mg specification is uncovered in culture dish, It is placed 10 days under the conditions of high temperature (60 DEG C), high humidity (RH 92.5%, 25 DEG C), Qiang Guang (4500lx ± 500lx), in the 5th, 10 day Sampling, the projects such as observation formulation aesthetics, content, dissolution rate, related substance, and compared with the inspection data for investigating preceding sample Compared with as a result such as table g6:

Table g6:

10 days influence factor test results of upper table show Mei Suoshuli spansule in high temperature, high humidity and illumination condition Under, quality be it is stable, content without be substantially reduced, related substance rises without obvious, show Mei Suoshuli dispersion of the invention The quality stability of piece is good.

The present inventor uses same method, carries out influence factor test in 10 days to embodiment g2- embodiment g6, as a result The Mei Suoshuli spansule quality stability for showing that preparation process of the present invention obtains is good.

Embodiment g8

Using the Mei Suoshuli spansule prepared in embodiment g1 as research object, conventionally, have studied Mei Suoshuli spansule is shown in Figure 19 in the intracorporal pharmacokinetics behavior of Beagle dog, pharmacokinetics test result.

As seen from Figure 19, spansule possesses very stable blood concentration, and it is existing to avoid or reduce blood medicine peak valley The appearance of elephant is conducive to improve the safety that drug uses, reduces medicining times, improve the compliance of patient.

In the description of the present invention, it is to be understood that, term " first ", " second " are used for description purposes only, and cannot It is interpreted as indication or suggestion relative importance or implicitly indicates the quantity of indicated technical characteristic.Define as a result, " the One ", the feature of " second " can explicitly or implicitly include one or more of the features.In the description of the present invention, The meaning of " plurality " is two or more, unless otherwise specifically defined.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office It can be combined in any suitable manner in one or more embodiment or examples.In addition, without conflicting with each other, the skill of this field Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples It closes and combines.

Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims

1. a kind of Mei Suoshuli Film coated tablets, which is characterized in that according to parts by weight, composed of the following components:

Mei Suoshuli 25-150 parts by weight by micronization processes；

Filler 50-200 parts by weight；

Adhesive 6-12 parts by weight；

Interior plus disintegrating agent and the total 5-20 parts by weight of additional disintegrating agent；And

Lubricant 0.8-4 parts by weight.

2. Mei Suoshuli Film coated tablets according to claim 1, which is characterized in that the filler further comprises being selected from At least one of lactose, dextrin, sucrose, starch, pregelatinized starch and mannitol, wherein the starch is cornstarch.

3. Mei Suoshuli Film coated tablets according to claim 1 or 2, which is characterized in that

The disintegrating agent is fine selected from crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and cross-linked carboxymethyl Tie up at least one of plain sodium；

Described adhesive is fine selected from PVP K30, hypromellose, methylcellulose, hydroxypropyl cellulose, carboxymethyl Tie up at least one of plain sodium, starch slurry, dextrin；

The lubricant be selected from magnesium stearate, superfine silica gel powder, sodium stearyl fumarate, lauryl sodium sulfate, silica, At least one of polyethylene glycol.

4. a kind of method for preparing the described in any item Mei Suoshuli Film coated tablets of claim 1-3 characterized by comprising

(1) Mei Suoshuli is subjected to micronization processes, and by obtained Mei Suoshuli micro powder granule and filler, disintegrating agent, At least one of adhesive, lubricant mixing, to obtain medicinal mixture；

(2) Mei Suoshuli Film coated tablets is made in the medicinal mixture.

5. according to the method described in claim 4, it is characterized in that, the partial size of the Mei Suoshuli micro powder granule is that 1-100 is micro- Rice.

6. according to the method described in claim 4, it is characterised in that it includes one of following:

(a1) Mei Suoshuli and filler are mixed, and obtained mixture is subjected to micronization processes, to obtain partial size For 5 microns to 100 microns of mixture micro powder granule, disintegrating agent, adhesive and lubricant are smashed it through into 80 meshes respectively, it is standby With；

(a2) described adhesive is mixed with purified water, the binder aqueous solution a I for being 6%~12% with obtained mass fraction is standby With；

(a3) the mixture micro powder granule is mixed with the interior disintegrating agent added, obtains mixture a II；

(a4) described adhesive aqueous solution a I is added in the mixture a II, and softwood is made in obtained mixture, it will Gained softwood crosses the sieve granulation of 18 mesh stainless steels, to obtain wet granular；

(a5) at 55 DEG C~65 DEG C, by the dry 1~4h of the wet granular, 18 mesh stainless steels is then crossed and sieve whole grain, to obtain Dry particl；

(a6) dry particl is mixed with additional disintegrating agent, then obtained mixture is mixed with magnesium stearate, so as to Obtain the medicinal mixture；

(a7) content of dispersion of the medicinal mixture is measured, and is calculated the theoretical tablet weight, then presses the medicinal mixture Piece, to obtain the Mei Suoshuli label；

(a8) coating powder is added in purified water, is configured to the Coating Solution that solid content is 20%, then utilizes the coating Solution is coated processing to the Mei Suoshuli label, to obtain Mei Suoshuli Film coated tablets.