CN108635332A

CN108635332A - A kind of preparation method of voglibose particle

Info

Publication number: CN108635332A
Application number: CN201810863323.1A
Authority: CN
Inventors: 黎红; 汪洋; 徐豪杰
Original assignee: Shandong Xinhua Pharmaceutical Co Ltd
Current assignee: Shandong Xinhua Pharmaceutical Co Ltd
Priority date: 2018-08-01
Filing date: 2018-08-01
Publication date: 2018-10-12

Abstract

The present invention provides a kind of preparation methods of voglibose particle, the particle is prepared by a step prilling, friability is low, roundness is good, voglibose energy Fast Stripping therein, and content uniformity is preferable, suitable for capsule, tablet (including dispersible tablet and oral disintegrating tablet), granule is further made.It is to be added to voglibose in the polar solvent of containing water-soluble adhesive, and be injected in the step comminutor containing diluent and disintegrant in such a way that top spray is granulated that it, which prepares thinking,.The preparation method is easy to operate, reduces hand labor intensity, is suitble to large-scale production.

Description

A kind of preparation method of voglibose particle

Technical field

The present invention relates to a kind of preparation methods of voglibose particle, belong to field of pharmaceutical biology.

Background technology

Diabetes are a kind of endocrine and metabolic disorders diseases, are caused by insulin secretion and Use barriers with hyperglycemia The chronic disease being characterized.It is counted according to International Diabetes Federation (IDF), ends 2015, diabetic in global range Have 4.15 hundred million (illness rate up to 8.8%), pre-diabetic has 3.18 hundred million (illness rate up to 6.7%).If being not added with intervention, arrive The year two thousand forty diabetic will be up to 6.42 hundred million, and prediabetes crowd will be up to 4.81 hundred million.Wherein, in 4.15 hundred million diabetics There is 46.5% crowd not to be diagnosed.There are 5,100,000 people to die of diabetes related diseases every year, accounts for the 8.39% of total death toll. It is predicted according to the World Health Organization (WHO), medical expenses of the whole world in 2016 for diabetes will reach 53,000,000,000 dollars, only It comes second inferior to tumour.Therefore, the research and development of diabetes medicament not only have high commercial value, more have to human health Very huge meaning.

Being continuously increased for diabetes number is mainly derived from type 2 diabetes patient, and morbidity is usually associated with a series of next It such as smokes derived from the risk factor of bad life habits, is fat, bad diet, not getting enough athletic exercise.α-glucosidase inhibitors medicine Object (the representative drug such as listed has acarbose, voglibose and Miglitol) has enteral alpha-glucosidase Inhibiting effect can delay simultaneously largely to reduce postprandial grape of the carbohydrate in enteral digestion to reduction of patient Sugared pressure.Different alpha-glucosidases in small intestine have its substrate specificity.As oligosaccharides can quilt by α-amylasehydrolysis, maltose Maltose or sucrose enzyme hydrolysis, sucrose can further hydrolyze generation glucose by sucrose enzyme hydrolysis, maltose, and sucrose can water Solution generates glucose or fructose.The digestion for blocking due to it and non-fully carbohydrate, it is normal daily can to meet patient Energy requirement.There is different alpha-glucosidases different substrate specificities, ideal hypoglycemic medicine to be while efficiently block shallow lake Powder, maltose and sucrose hydrolysis can generate the preferable purpose for reducing postprandial blood sugar at the process of glucose.

Voglibose is to be pressed down by the alpha-glucosidase of new generation that Japanese Takede Chemical Industries Ltd develops Preparation (Curr Med Chem, 2006,13 (1), 109-116), is the amino sugar analog found from unwrapping wire bacteria culture fluid. Voglibose tablet or dispersible tablet trade nameOrIt is listed for the first time in Japan within 1994,1998 in South Korea City, 1999 in Discussion on Chinese Listed, in multiple national list marketings.

Disaccharide class hydrolysis in the inhibition enteron aisle of Antagonism can be competed after oral voglibose, to delay disappearing for carbohydrate Change and absorb, to improve postprandial hyperglycemia, while the fasting blood-glucose and saccharification blood of type 2 diabetes patient can also be effectively reduced Red eggs white level (Shanghai medicine, 2013 (1):18-21).It does not stimulate insulin secretion, this point is different from sulfonylureas, and current Unlike clinical widely used biguanides：Voglibose delays rather than inhibits digesting and assimilating for carbohydrate, and therefore, it has There is unique hypoglycemic effect.

Voglibose as antidiabetic drug has stringent application method, it is necessary to could effectively being administered orally before meals Control postprandial blood glucose levels.The present invention is that voglibose is prepared into the particle with fater disintegration, Fast Stripping, should Particle can be used for further being made capsule, tablet, granule, and main purpose is to make voglibose fast quick-release in vivo Put, shorten it is oral after to playing soak time in drug effect this segment body, fast onset drug effect, to efficiently control postprandial blood Sugar.If to reach above-mentioned purpose, first, must have the feature that disintegration is fast, dissolution rate is high outside prepared granule；Its Secondary, uniformity of dosage units has to conform to quality requirements, since voglibose dosage is smaller (only 0.2 or 0.3mg), if content is equal Evenness cannot be protected, then be difficult effectively to control postprandial blood sugar.

First, voglibose is white crystalline powder, although itself is water-soluble, (solubility reaches in water very well 26.73mg/mL), according to well known to a person skilled in the art common sense, its dissolution rate of water soluble drug should be easy to solve, but right For voglibose, it appears that fail to agree with above-mentioned theory, facts proved that, for voglibose conventional tablet, the body of 30min Outer dissolution rate only has 83% or so (document CN200710129313.7), it may be possible to since raw material crystalline form is the needle-shaped of matrix arrangement Structure (document CN201010100033.5).

To solve the problems, such as the dissolution of voglibose, there is patent to propose and dispersible tablet, oral film is made in voglibose The dosage forms such as agent, oral disnitegration tablet.Also patent (such as CN201410854236.1) proposes voglibose micronization processes again Prepare piece agent.

Describing such as patent CN200710129313.7 and CN200710305247.4 and prepare voglibose dispersible tablet Method.The preparation method of patent CN200710129313.7 is first voglibose to be added in polar solvent solution is made, then Be added in the mixture containing filler and disintegrant, wet granulation, it is dry, last additional disintegrant and lubricant prepare and .Patent CN200710305247.4 is the method prepared composition discrete piece using conventional tablet.

Voigelibo is prepared as CN201010100033.5, CN201610516869.0 and EP1561458 patent propose The method of sugared film.CN201010100033.5 is that voglibose is highly dispersed at plasticizer-containing, corrigent and titanium dioxide Polyvinyl alcohol or hydroxypropylcellulose or polyoxyethylene water-soluble high-molecular material in；CN201610516869.0 is at the former On the basis of be added to increase permeability as sodium salicylate, edetate, NaTDC, oleic acid, octanoic acid, sodium salicylate, One or more penetrating agents such as lauryl sodium sulfate, polyoxyethylene lauryl base ester, azone.EP1561458 is then system Standby two film layers, one layer be supporting layer that thickness is 15 μm, the drug containing that another layer is 30 μm for the thickness containing voglibose Layer.

As CN99808969.9 discloses voglibose oral disintegrating tablet preparation method.The patent thinks to prepare the pass of oral disintegrating tablet Key technology is to prepare crucial auxiliary material, i.e., a kind of to have immediately disintegrable, intensity appropriate and the low-substituted hydroxypropyl without harsh feeling Cellulose.

Also there are document (modern medicine health, 2017,33 (14):The method that equivalent is progressively increased 2107-2109) is used directly will Raw material is mixed with auxiliary material, and the Voglibose tablet to conform to quality requirements can be made using direct compression method.

Since voglibose dosage is smaller, common method is difficult to ensure its uniformity of dosage units, granule content fluctuation compared with (such as larger than 5%) greatly.In order to make particle there is preferable uniformity, CN201210580191.4 patents to propose voigelibo first Sugar is gradually mixed with a certain proportion of starch, wet granulation, and dry, whole grain obtains, and is finally prepared to tablet, this method is different Voglibose tablet (modern medicine health, 2017,33 (14) are prepared in traditional equivalent gradually-increased:2107-2109).

Therefore, for the oral preparation of voglibose, how to solve its dissolution rate and content uniformity two large problems is Put a difficult problem in face of most of voglibose preparations producer.

Invention content

Present invention aims at a kind of preparation method of voglibose particle is provided, the purpose is to so that the particle is had soon It is instant go out, and preferable dual characteristics of content uniformity, the particle suitable for be further made capsule, tablet (including oral disintegrating tablet, Dispersible tablet), granule.

The present invention provides a kind of preparation method of voglibose particle, which is made using a step prilling, Include the following steps：

(1) water-soluble binder is dissolved in polar solvent, solution A is used as after evenly dispersed；

(2) solution A is divided into two parts, for a copy of it as A-1, the evenly dispersed rear conduct of voglibose is added in another Solution A -2；

(3) diluent and disintegrant are taken, is added in a step comminutor, mixing；Control wind turbine frequency：20Hz~30Hz；It is mixed Close the time：5~30min.

(4) solution A -1 is taken to be injected in the step comminutor described in above-mentioned (3) in such a way that top spray is granulated；Control wind 20~30Hz of unit frequency, 40~85 DEG C, 0.15~0.25Mpa of atomisation pressure, 20~80rpm of wriggling revolution speed of inlet air temperature.

(5) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤4.0%.Wind turbine 20~30Hz of frequency is controlled, into 40~85 DEG C of air temperature.

(6) solution A -2 is taken to be injected in the step comminutor described in (4) in such a way that top spray is granulated；Control wind turbine frequency 20~30Hz of rate, 40~85 DEG C, 0.15~0.25Mpa of atomisation pressure, 20~80rpm of wriggling revolution speed of inlet air temperature.

(7) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤4.0%；Wind turbine 20~30Hz of frequency is controlled, into 40~85 DEG C of air temperature.

The present invention provides a kind of preparation method of voglibose particle, water-soluble binder is povidone, hydroxypropyl fibre Dimension element, one kind in hydroxypropyl methylcellulose and its a variety of mixtures.

The present invention provides a kind of preparation method of voglibose particle, polar solvent is water, ethyl alcohol, isopropanol, third One kind in ketone and its a variety of mixtures.

The present invention provides a kind of preparation method of voglibose particle, diluent is the lactose sieved with 100 mesh sieve, sweet dew One kind in alcohol, xylitol, trehalose, microcrystalline cellulose and its a variety of mixtures.

The present invention provides a kind of preparation method of voglibose particle, disintegrant is the starch sieved with 100 mesh sieve or pre- Gelling starch.

The present invention provides a kind of preparation method of voglibose particle, the usage amount of voglibose is 1 part, water-soluble Property adhesive be 5~100 parts (weight ratios, similarly hereinafter), preferably 10~80 parts, more preferably 15~60 parts；Polar solvent is 100 ~2000 parts, preferably 200~1500 parts, more preferably 300~1000 parts；Diluent be 200~1000 parts, preferably 250 ~800 parts, more preferably 300~700 parts；Disintegrant is 10~1000 parts, preferably 25~800 parts, more preferably 50~500 Part.Solution A is divided into two parts of A-1 and A-2, and the ratio of this two parts of solution is 0:1 or 1:(0.2~5).

When the ratio of two parts of solution of A-1 and A-2 is 0:When 1, above-mentioned technological evolution is at following technique：

Include the following steps：

(1) water-soluble binder is dispersed in polar solvent, solution A is used as after mixing；

(2) voglibose is added in solution A, solution B is used as after evenly dispersed；

(3) diluent and disintegrant are taken, is added in a step comminutor, mixing.Control wind turbine frequency：20Hz~30Hz；It is mixed Close the time：5~30min.

(4) solution B is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 40~85 DEG C, 0.15~0.25Mpa of atomisation pressure, 20~80rpm of wriggling revolution speed of inlet air temperature.

(5) dry after having sprayed above-mentioned solution B, until pellet moisture≤4.0%.Control wind turbine 20~30Hz of frequency, air inlet 40~85 DEG C of temperature.

In view of polar solvent is water, ethyl alcohol, isopropanol, one kind in acetone and its a variety of mixtures, therefore, needing will be into Air temperature controls in a certain range.The composition of polar solvent is different, and the range of control also should difference.In addition, experiment is also It was found that inlet air temperature is related with temperature of charge, leaving air temp, these three temperature need to maintain a balance, under normal circumstances, object Conveniently at 28~35 DEG C, leaving air temp control is appropriate at 25~32 DEG C for the control of material temperature degree.

Furthermore, it is contemplated that intragranular disintegrant be starch or pregelatinized starch, due to disintegrant type and dosage not Together, the moisture of final material control is also answered different.Under normal circumstances, pellet moisture control obtained is in 4% range.Due to Starch or the material of the strong moisture absorption of pregelatinized starch, under the larger environmental condition of relative humidity, material moisture is larger；Simultaneously because Lactose or mannitol are all the materials for being not easy the moisture absorption, when starch or smaller pregelatinized starch dosage, pellet moisture control obtained System should tighten, if any control in 3% range, what is had should control in 2.5% range.

The present invention provides a kind of preparation methods of voglibose particle, after having sprayed A-1 solution, wait for dry materials to water A-2 solution is sprayed again after point designated value, the purpose is to：(1) if spray velocity is very fast, granular grows are also very fast, it is easy to form one A little larger particles, the bulk density of material are smaller；After having sprayed A-1 solution, for a period of time by dry materials, material is dry in boiling Due to constantly moving during dry, particle has the tendency that grain size reduction, can increase the mouthfeel of Orally disintegrating tablet, is unlikely to too thick It is rough.(2) after material first dries a period of time, the moisture evaporation inside particle is come out, will not be mingled in follow-up coating in this way Unevaporated " internal moisture ", such particle easily parches, and is conducive to subsequent operation.

The present invention provides a kind of preparation methods of voglibose particle, if being further prepared into tablet or particle, also The lubricant (such as 0.5% magnesium stearate) of obtained particle gross weight 0.3%~1.0% and/or 0.1%~2.0% help need to be added Flow agent (such as 0.2% gaseous silicon oxide).

Another object of the present invention is to provide a kind of preparation methods of Voglibose tablet：According to described one kind Lubricant (such as 0.5% stearic acid that particle gross weight 0.3%~1.0% is made is added in the preparation method of voglibose particle Magnesium) and/or 0.1%~2.0% glidant (such as 0.2% gaseous silicon oxide).

Another object of the present invention is to provide a kind of preparation methods of voglibose dispersible tablet：According to described one The preparation method of kind voglibose particle, also needs 10~200 parts additional of disintegrant；Disintegrant is typically chosen disintegration ability Stronger low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch.

Another object of the present invention is to provide a kind of preparation methods of voglibose granule：According to described one The preparation method of kind voglibose particle also needs to use cane sugar substitution filler therein, prepares blank granules, and according to certain Blank granules and medicine-containing particle are mixed and made into voglibose granule by ratio.

A kind of Voglibose tablet, a kind of voglibose dispersible tablet, a kind of voglibose granule Preparation method is：After tablet, dispersible tablet or granule is made, each preparation unit contain voglibose be 0.2mg or 0.3mg。

In order to make voglibose particle be provided simultaneously with the feature that dissolution is fast, dissolution rate is high and content uniformity is good, simultaneously A large amount of document has been made suitable for several formulations, the present inventor such as tablet (including oral disintegrating tablet, dispersible tablet), capsule or granule is made Investigation and optimization work.

Although oral disintegrating tablet, pelliculae pro cavo oris and dispersible tablet can solve the problems, such as that dissolution is fast, dissolution rate is high, this patent proposes A step comminution granulation be different from the dispersion blade technolgy that patent CN200710129313.7 is proposed.I.e. in essence, both sides The particle shape of method is different, and for the former particle shape with more spherical shape, mobility is more preferable.It is said from preparation process, after Person is first voglibose to be added in polar solvent solution is made, and is then added to the mixing containing filler and disintegrant It is dry by wet granulation in object, the techniques such as additional disintegrant and lubricant are added and are prepared.The identical point of two patents：All Voglibose is dissolved in the polar solvent containing water-soluble binder, can be transferred through effectively improving due to Fu Gelie Dissolution rate that the acicular texture of wave sugar matrix arrangement is brought is low and content homogeneity question.But this patent also has as is evident below Advantage：

(1) production technology is simplified, the production time is shortened.The method that this patent proposes does not use wet granulation technology, It is that material is completed to mixing, granulation and drying process directly on a step comminutor.According to wet granulation technology, material has needed At mixing, wet granulation, these three dry independent technological operations, these operations are all unaided, be not it is integrated, It is respectively necessary for using equipment such as mixing machine, wet granulator, vacuum feeder and boiling driers.And the preparation that this patent proposes Method is not required to carry out material transfer on various devices, therefore shortens the entire production time, can be completed more within the unit interval The preparation process of more preparations.

(2) it improves human resources utilization to lead, reduces hand labor intensity.Since the method that this patent proposes is not required to make With multiple equipments such as mixing machine, wet granulator and boiling driers, operating personnel's degeneracy of three processes is at a process Operating personnel, improve human resources utilization and lead.Since the solution containing voglibose is that gradual spray pattern is added, Rather than be directly added according to wet granulation mode, hand labor intensity substantially reduces.

(3) this patent obtains particle friability is relatively low, roundness is more preferable, is conducive to the preparation of follow-up several formulations.According to This patent propose operating method, particle be will contain the solution of voglibose slowly spray by way of made from, be not Made from fluidized drying mode, obtained particle shape is more complete, and friability is relatively low, roundness is higher.According to wet granulation In addition the combination of fluidized drying, obtained particle may be less due to the dosage of adhesive, though roundness is preferable, friability Spend higher, broad particle distribution；The dosage of adhesive is higher, though narrower particle size distribution, friability are relatively low, roundness is bad. Therefore, the method that this patent proposes can be further prepared into tablet, capsule and granule.If selecting different supplementary product kind collocation It uses, it is preferably to be prepared into oral disintegrating tablet and dispersible tablet.When such as preparing oral disintegrating tablet, mannitol and pregelatinized starch conduct are selected respectively Filler and disintegrant when one step is granulated, while the disintegrants such as additional low-substituted hydroxypropyl cellulose and magnesium. When such as preparing dispersible tablet, a filler when step is granulated selects mannitol, lactose, disintegrant to select starch or pregelatinized starch, Disintegrants and the magnesium stearate lubricant such as additional low-substituted hydroxypropyl cellulose simultaneously.

These creative advantages are all because the preparation method for the voglibose particle that this patent proposes has Prominent feature.Separate since voglibose is dispersed in polar solvent, and by water-soluble adhesive, solution second of the three ten-day periods of the hot season lattice row After wave sugar is existing for molecular forms, to be sprayed onto the fooled polar solvent volatilization of material, since the process for losing solvent is too fast, Fu Gelie Also have little time to reassemble between wave glycan molecule and just have become the minimum solid state of particle, since voglibose is with molecular state It being blocked in water-soluble binder, voglibose finally exists with molecular state or microcrystalline form in obtained particle outer layer, Voglibose dispersibility is significantly improved, dissolution rate and dissolution rate are improved.

This patent is different from the voglibose that Takede Chemical Industries Ltd proposes in CN99808969.9 patents Oral disintegrating tablet production technology.What is proposed in CN99808969.9 patent Examples 6 is also a kind of life using fluidised bed granulator Production. art, it is spray after mixing voglibose, mannitol, low-substituted hydroxypropyl cellulose, anhydrous citric acid and aspartic acid Enter water to be granulated, obtain the particle of oral disnitegration tablet, disintegration time is 27 seconds.Since the dosage of voglibose is relatively low (only 0.2mg or 0.3mg), in a large amount of material, it is difficult to be uniformly mixed, uniformity of dosage units cannot be guaranteed；Simultaneously because powder Voglibose after broken is arranged with acicular texture, there are problems that potential dissolution rate.

This patent is also differs from Athena Drug Delivery Solutions companies of India in WO2014184806 The voglibose oral disintegrating tablet production technology of proposition.The voglibose mouth proposed in WO2014184806 patent Examples 1 Disintegrating tablet production technology is first to prepare the medicine-containing particle containing voglibose.The preparation method of the medicine-containing particle is：First by Fu Gelie Wave sugar is dissolved in purified water, and sequentially adds mannitol, liquid flavoring banana essence, and the solution of formation is added to by mannitol and two In the material of silica premixing, stirring, drying.

This patent is other than proposing particle and the technique being once granulated can be used, it is also proposed that the technique that can be repeatedly granulated.It is such as right It is granulated in twice, granulation process is：The solution of containing water-soluble adhesive is first divided into two parts, Fu Gelie is added in a copy of it Wave sugar, another is then not added with.Solution without voglibose is then first injected to filler and the disintegration of a step comminutor In the mixed material of agent composition, the blank granules for being covered with water-soluble binder are made, then spray into again while containing voigelibo The solution of sugar and water-soluble binder, the particle obtained in this way has apparent three-decker, respectively by filler and disintegration The internal layer that agent is constituted, the middle layer being made of water-soluble binder, by two kinds of material structures of voglibose and water-soluble binder At outer layer.Experiment finds that its disintegration rate of the particle of this three-decker is also faster than double-layer structure, fast suitable for being prepared into It is instant go out dispersible tablet or oral disintegrating tablet.

For the voglibose that though water solubility is good but solution rate is slower, and the method applied in the present invention, complete gram It has taken above-mentioned dissolution rate, dispersibility and content uniformity etc. and has seemed the difficulty that can not possibly be solved.This is one fruitful Work.Surprisingly, it was found that first voglibose is dissolved in polar solvent appropriate, a step suitable system after being granulated The several formulations such as standby piece agent (including oral disintegrating tablet, dispersible tablet), capsule and granule, the preparation obtained using the present invention are being provided Dissolution rate in time is almost 100%, and uniformity of dosage units meets the quality requirement of Chinese Pharmacopoeia.

Description of the drawings

The stripping curve of Fig. 1 tablet and reference preparation made from embodiment 23~25

As seen from the figure, the dissolution rate of embodiment 23~25 slightly has difference, this may be due in prescription adhesive model with Caused by dosage and filler and the dosage difference of disintegrant.Homemade tablet dissolved corrosion is produced with Wu Tian companies of Japan Voglibose tablet reference preparation it is different, have the characteristics that Fast Stripping, tri- time points of 5min, 10min, 15min it is molten Out-degree is far above reference preparation, therefore tablet obtained meets the dissolution feature for not only conforming with tablet (30min dissolves out 85% or more), And it also is compliant with the dissolution feature (85% or more 15min dissolutions) of dispersible tablet.Since the tablet of embodiment 23~25 is by implementing The particle preparation of example 1~3 and obtain, therefore, the characteristics of particle in Examples 1 to 3 is likewise supplied with Fast Stripping.

The stripping curve of Fig. 2 oral disintegrating tablet and reference preparation made from embodiment 26~30

As seen from the figure, the voglibose oral disintegrating tablet reference preparation that embodiment 26~30 and Wu Tian companies of Japan produce it is molten Dissolution rate is 85% or more in 5min for out-degree, therefore tablet obtained meets dissolution feature (the 15min dissolutions 85% of oral disintegrating tablet More than).Since the oral disintegrating tablet of embodiment 26~30 is obtained by the particle preparation of embodiment 4~8, in embodiment 4~8 Particle the characteristics of being likewise supplied with Fast Stripping.

The stripping curve of Fig. 3 capsule and reference preparation made from embodiment 31~33

As seen from the figure, homemade three batches of capsules dissolution rate in 5min is attained by 50% or more, the dissolution rate in 10min 80% or more, in 15min, dissolution rate is 85% or more, therefore capsule energy Fast Stripping obtained, has fater disintegration, quickly The characteristics of dissolution.Since the capsule of embodiment 31~33 is after 0.5% magnesium stearate is added by the particle of 9~11 gained of embodiment Can filling capsule be prepared, therefore, the characteristics of particle in embodiment 9~11 is likewise supplied with Fast Stripping.

The stripping curve of Fig. 4 dispersible tablet and reference preparation made from embodiment 31~33

As seen from the figure, the dissolution rate of embodiment 34~38 and reference preparation in 5min dissolution rate 90% or more, therefore Preparation obtained meets the dissolution feature (85% or more 15min dissolutions) of dispersible tablet.Since the dispersible tablet of embodiment 34~38 is It is prepared after 0.5% magnesium stearate is added by the particle of 12~16 gained of embodiment, therefore, the particle in embodiment 12~16 The characteristics of being likewise supplied with Fast Stripping.

The stripping curve of Fig. 5 granules made from embodiment 39~42

As seen from the figure, dissolution rate is 90% or more in 5min for the dissolution rate of embodiment 39~42, therefore particle obtained Agent has the characteristics of Fast Stripping, and particle of the granule of embodiment 39~42 from 17~20 gained of embodiment, therefore implements The characteristics of particle in example 17~20 is likewise supplied with Fast Stripping.

Specific implementation mode

The present invention described further below, but the practical range of the present invention is not limited.

The preparation of 1 voglibose particle of embodiment

Prescription：

Technique：

(1) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, LXF models) and it is dissolved in purified water (certainly System, similarly hereinafter) in, it is used as solution A after evenly dispersed；

(2) take solution A, be added recipe quantity voglibose (Shanghai Tianwei Biological Pharmaceutical Corp., pharmaceutical grade, under Together), evenly dispersed rear as solution B；

(3) lactose (Foremost Farms USA companies of the U.S., pharmaceutical grade, 312 models, with preceding mistake 100 of recipe quantity are taken Mesh sieves, similarly hereinafter) and starch (Weifang Shengtai Medicine Co., Ltd., pharmaceutical grade, 200 mesh, similarly hereinafter), a step comminutor (Chongqing is added Rising sun pharmaceutical machine device fabrication Co., Ltd of section, LBL-30 type fluidized bed granulation seed-coating machines, similarly hereinafter) in, mix 30min, control Wind turbine frequency：20Hz~30Hz.

(4) solution B is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 45~85 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 25rpm of inlet air temperature.

(5) dry after having sprayed above-mentioned solution B, until pellet moisture≤2.5% (moisture teller, Ohaus companies, M1345 models, determination condition：105 DEG C of 10min, similarly hereinafter).Control wind turbine 20~30Hz of frequency, 40~80 DEG C of inlet air temperature.

The preparation of 2 voglibose particle of embodiment

Prescription：

Technique：

(1) ethyl alcohol (Xuzhou Xiang Pei Wine Co., Ltd, pharmaceutical grade, a concentration of 95%, V/V, similarly hereinafter) 2.0kg is taken, is added Purified water 18.0kg is configured to 10% ethanol (W/W).

(2) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, EXF models) and it is dissolved in 10% ethyl alcohol In liquid (W/W), solution A is used as after evenly dispersed；

(3) solution A is taken, the voglibose of recipe quantity is added, solution B is used as after evenly dispersed；

(4) the newborn sugar and starch of recipe quantity is taken, is added in a step comminutor, 25min is mixed, controls wind turbine frequency：20Hz ~30Hz.

(5) solution B is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, inlet air temperature set 55~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 50rpm.

(6) dry after having sprayed above-mentioned solution B, until pellet moisture≤4.0%.Control wind turbine 20~30Hz of frequency, air inlet 65 DEG C of temperature.

The preparation of 3 voglibose particle of embodiment

Prescription：

Technique：

(1) ethyl alcohol 8.0kg is taken, purified water 12.0kg is added, is configured to 40% ethanol (W/W).

(2) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, ELF models) and it is dissolved in 40% ethyl alcohol In liquid (W/W), solution A is used as after evenly dispersed；

(4) the newborn sugar and starch of recipe quantity is taken, is added in a step comminutor, 15min is mixed, controls wind turbine frequency：20Hz ~30Hz.

(5) solution B is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 40~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 80rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution B, until pellet moisture≤3.5%.Control wind turbine 20~30Hz of frequency, air inlet 40~80 DEG C of temperature.

The preparation of 4 voglibose particle of embodiment

Prescription：

Technique：

(1) ethyl alcohol 4.5kg is taken, purified water 10.5kg is added, is configured to 30% ethanol (W/W).

(2) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, EF models) and it is dissolved in 30% ethanol (W/W) in, solution A is used as after evenly dispersed；

(4) take recipe quantity mannitol (French Roquette companies,25C models, with before sieving with 100 mesh sieve, Similarly hereinafter) and pregelatinized starch (Huzhou Zhanwang Pharmaceutical Co., Ltd., ZW-Y3 models, with before sieving with 100 mesh sieve, similarly hereinafter), a step is added In comminutor, 25min is mixed, controls wind turbine frequency：20Hz~30Hz.

(5) solution B is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 50~85 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 55rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution B, until pellet moisture≤2.5%.Control wind turbine 20~30Hz of frequency, air inlet 50~85 DEG C of temperature.

The preparation of 5 voglibose particle of embodiment

Prescription：

Technique：

(1) taking acetone, (Sinopharm Chemical Reagent Co., Ltd. analyzes pure, purity：>=99.5%, similarly hereinafter) 7.5kg, add Enter purified water 7.5kg, is configured to 50% acetone solution (W/W).

(1) by the hydroxypropyl methylcellulose of recipe quantity (Ashland companies of the U.S., Benecel^TM, K100LV PH PRM models) It is dissolved in 50% acetone solution (W/W), solution A is used as after evenly dispersed；

(2) solution A is taken, the voglibose of recipe quantity is added, solution B is used as after evenly dispersed；

(3) take the mannitol of recipe quantity, microcrystalline cellulose (Huzhou Linghu Xinwang Chemical Co., Ltd., PH101 models, Similarly hereinafter) and pregelatinized starch, it is added in a step comminutor, mixes 20min, control wind turbine frequency：20Hz~30Hz.

(4) solution B is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 40~55 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 70rpm of inlet air temperature.

(5) dry after having sprayed above-mentioned solution B, until pellet moisture≤3.5%.Control wind turbine 20~30Hz of frequency, air inlet 40~55 DEG C of temperature.

The preparation of 6 voglibose particle of embodiment

Prescription：

Technique：

(1) ethyl alcohol 0.6kg is taken, purified water 2.4kg is added, is configured to 20% ethanol (W/W).

(2) by the povidone of recipe quantity (Ashland companies of the U.S., Plasdone^TM, K-17 models) and it is dissolved in 20% ethanol (W/W) in, solution A is used as after evenly dispersed；

(4) mannitol, trehalose (the Japanese Asahi Chemical Industry companies, with preceding mistake 100 of recipe quantity are taken Mesh sieves, similarly hereinafter) and pregelatinized starch, it is added in a step comminutor, mixes 15min, control wind turbine frequency：20Hz~30Hz.

(5) solution B is taken to be injected to the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz, 50~70 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 40rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution B, until pellet moisture≤3.5%.Control wind turbine 20~30Hz of frequency, air inlet 50~70 DEG C of temperature.

The preparation of 7 voglibose particle of embodiment

Prescription：

Technique：

(1) isopropanol (Sinopharm Chemical Reagent Co., Ltd., analysis is pure, >=99.7%, similarly hereinafter) 0.9kg is taken, is added Purified water 2.1kg is configured to 30% isopropyl alcohol liquid (W/W).

(2) by the hydroxypropyl methylcellulose of recipe quantity (Lotte Fine Chemical companies of South Korea, AnyCoat-C^TM, AN6 Model) it is dissolved in 30% isopropyl alcohol liquid (W/W), it is used as solution A after evenly dispersed；

(4) take the mannitol of recipe quantity, xylitol (Futaste Co., Ltd., with before sieving with 100 mesh sieve, under Together) and pregelatinized starch, it is added in a step comminutor, mixes 20min, control wind turbine frequency：20Hz~30Hz.

(5) solution B is taken to be injected to the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz, 50~70 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 30rpm of inlet air temperature.

The preparation of 8 voglibose particle of embodiment

Prescription：

Technique：

(1) ethyl alcohol 2.0kg is taken, purified water 18.0kg is added, is configured to 10% ethanol (W/W).

(2) by the hydroxypropyl methylcellulose of recipe quantity (Lotte Fine Chemical companies of South Korea, AnyCoat-C^TM, AN4 Model) it is dissolved in 10% ethanol (W/W), it is used as solution A after evenly dispersed；

(4) mannitol of recipe quantity, newborn sugar and starch are taken, is added in a step comminutor, 20min, control wind turbine frequency are mixed Rate：20Hz~30Hz.

(5) solution B is taken to be injected to the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz, 50~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 40rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution B, until pellet moisture≤2.5%.Control wind turbine 20~30Hz of frequency, air inlet 50~80 DEG C of temperature.

The preparation of 9 voglibose particle of embodiment

Prescription：

Technique：

(1) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, LXF models) and it is dissolved in purified water, Solution A is used as after evenly dispersed；Solution is divided into 1:1 two parts, it is respectively labeled as A-0 and A-1.

(2) voglibose of recipe quantity is added in solution A -0, (is noted as solution A -2 after evenly dispersed：Solution A -0 Difference with A-2 is that the former is free of voglibose, and the latter contains voglibose, similarly hereinafter)；

(3) the newborn sugar and starch of recipe quantity is taken, is added in a step comminutor, 30min is mixed, controls wind turbine frequency：20Hz ~30Hz.

(4) solution A -1 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, 45~85 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 20rpm of inlet air temperature.

(5) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤2.5%.Wind turbine 20~30Hz of frequency is controlled, into 40~80 DEG C of air temperature.

(6) solution A -2 is taken to be injected to the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 40~85 DEG C, 0.15~0.25Mpa of atomisation pressure, 20~80rpm of wriggling revolution speed of inlet air temperature.

(7) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤4.0%.Wind turbine 20~30Hz of frequency is controlled, into 40~85 DEG C of air temperature.

The preparation of 10 voglibose particle of embodiment

Prescription：

Technique：

(2) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, EXF models) and it is dissolved in 10% ethyl alcohol In liquid (W/W), solution A is used as after evenly dispersed；Solution is divided into 2:1 two parts, it is respectively labeled as A-0 and A-1.

(3) voglibose that recipe quantity is added in solution A -0 is evenly dispersed rear as solution A -2；

(5) solution A -1 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, inlet air temperature set 55~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 50rpm.

(6) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤4.0%.Wind turbine 20~30Hz of frequency is controlled, into 65 DEG C of air temperature.

(7) solution A -2 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, inlet air temperature set 55~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 50rpm.

(8) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤4.0%.Wind turbine 20~30Hz of frequency is controlled, into 65 DEG C of air temperature.

The preparation of 11 voglibose particle of embodiment

Prescription：

Technique：

(2) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, ELF models, similarly hereinafter) it is dissolved in 40% In ethanol (W/W), solution A is used as after evenly dispersed；Solution is divided into 1:2 two parts, it is respectively labeled as A-0 and A-1.

(3) voglibose of recipe quantity is added in solution A -0, solution A -2 is used as after evenly dispersed；

(5) solution A -1 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, 40~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 80rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤3.5%.Wind turbine 20~30Hz of frequency is controlled, into 40~80 DEG C of air temperature.

(7) solution A -2 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, 40~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 80rpm of inlet air temperature.

(8) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤3.5%.Wind turbine 20~30Hz of frequency is controlled, into 40~80 DEG C of air temperature.

The preparation of 12 voglibose particle of embodiment

Prescription：

Technique：

(2) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, EF models) and it is dissolved in 30% ethanol (W/W) in, solution A is used as after evenly dispersed；Solution is divided into 3:1 two parts, it is respectively labeled as A-0 and A-1.

(4) mannitol and pregelatinized starch of recipe quantity are taken, is added in a step comminutor, 25min, control wind turbine frequency are mixed Rate：20Hz~30Hz.

(5) solution A -1 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, 50~85 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 55rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤2.5%.Wind turbine 20~30Hz of frequency is controlled, into 50~85 DEG C of air temperature.

(7) solution A -2 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, 50~85 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 55rpm of inlet air temperature.

(8) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤2.5%.Wind turbine 20~30Hz of frequency is controlled, into 50~85 DEG C of air temperature.

The preparation of 13 voglibose particle of embodiment

Prescription：

Technique：

(1) acetone 7.5kg is taken, purified water 7.5kg is added, is configured to 50% acetone solution (W/W).

(2) by the hydroxypropyl methylcellulose of recipe quantity (Ashland companies of the U.S., Benecel^TM, K100LV PH PRM models) It is dissolved in 50% acetone solution (W/W), solution A is used as after evenly dispersed；Solution is divided into 1:3 two parts, it is respectively labeled as A-0 and A- 1。

(4) take the mannitol of recipe quantity, microcrystalline cellulose (Huzhou Linghu Xinwang Chemical Co., Ltd., PH101 models, Similarly hereinafter) and pregelatinized starch, it is added in a step comminutor, mixes 20min, control wind turbine frequency：20Hz~30Hz.

(5) solution A -1 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, 40~55 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 70rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤3.5%.Wind turbine 20~30Hz of frequency is controlled, into 40~60 DEG C of air temperature.

(7) solution A -2 is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine 20~30Hz of frequency, 40~55 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 70rpm of inlet air temperature.

(8) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤3.5%.Wind turbine 20~30Hz of frequency is controlled, into 40~60 DEG C of air temperature.

The preparation of 14 voglibose particle of embodiment

Prescription：

Technique：

(2) by the povidone of recipe quantity (Ashland companies of the U.S., Plasdone^TM, K-17 models) and it is dissolved in 20% ethanol (W/W) in, solution A is used as after evenly dispersed；Solution is divided into 5:1 two parts, it is respectively labeled as A-0 and A-1.

(5) solution A -1 is taken to be injected to the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 50~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 40rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤3.5%.Wind turbine 20~30Hz of frequency is controlled, into 50~80 DEG C of air temperature.

(7) solution A -2 is taken to be injected to the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 50~80 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 40rpm of inlet air temperature.

(8) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤3.5%.Wind turbine 20~30Hz of frequency is controlled, into 50~80 DEG C of air temperature.

The preparation of 15 voglibose particle of embodiment

Prescription：

Technique：

(1) isopropanol 0.9kg is taken, purified water 2.1kg is added, is configured to 30% isopropyl alcohol liquid (W/W).

(2) by the hydroxypropyl methylcellulose of recipe quantity (Lotte Fine Chemical companies of South Korea, AnyCoat-C^TM, AN6 Model) it is dissolved in 30% isopropyl alcohol liquid (W/W), it is used as solution A after evenly dispersed；Solution is divided into 1:It 5 two parts, is respectively labeled as A-0 and A-1.

(4) mannitol, xylitol and pregelatinized starch of recipe quantity are taken, is added in a step comminutor, 20min, control are mixed Wind turbine frequency processed：20Hz~30Hz.

(5) solution A -1 is taken to be injected to the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 50~70 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 30rpm of inlet air temperature.

(6) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤3.5%.Wind turbine 20~30Hz of frequency is controlled, into 50~70 DEG C of air temperature.

(7) solution A -2 is taken to be injected to the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 50~70 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 30rpm of inlet air temperature.

(8) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤3.5%.Wind turbine 20~30Hz of frequency is controlled, into 50~70 DEG C of air temperature.

The preparation of 16 voglibose particle of embodiment

Prescription：

Technique：

(2) by the hydroxypropyl methylcellulose of recipe quantity (Lotte Fine Chemical companies of South Korea, AnyCoat-C^TM, AN4 Model) it is dissolved in 10% ethanol (W/W), it is used as solution A after evenly dispersed；Solution is divided into 1:2 two parts, it is respectively labeled as A- 0 and A-1.

(6) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤2.5%.Wind turbine 20~30Hz of frequency is controlled, into 50~80 DEG C of air temperature.

(8) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤2.5%.Wind turbine 20~30Hz of frequency is controlled, into 50~80 DEG C of air temperature.

The preparation of 17 voglibose particle of embodiment

Prescription：

Technique：

(1) by the hydroxypropylcellulose of recipe quantity (Ashland companies of the U.S., Klucel^TM, EF models) and it is dissolved in purified water, Solution A is used as after evenly dispersed；

(2) voglibose of recipe quantity is added in solution A, solution B is used as after evenly dispersed；

(3) the newborn sugar and starch of recipe quantity is taken, is added in a step comminutor, 20min is mixed, controls wind turbine frequency：20Hz ~30Hz.

(4) solution B is taken to be injected in the step comminutor containing above-mentioned material in such a way that top spray is granulated.Control wind turbine frequency 20~30Hz of rate, 65~85 DEG C, 0.15~0.25Mpa of atomisation pressure, wriggling revolution speed 26rpm of inlet air temperature.

(5) dry after having sprayed above-mentioned solution B, until pellet moisture≤2.5%.Control wind turbine 20~30Hz of frequency, air inlet 65~80 DEG C of temperature.

The preparation of 18 voglibose particle of embodiment

Prescription：

Technique：

(1) by the hydroxypropyl methylcellulose of recipe quantity (Lotte Fine Chemical companies of South Korea, AnyCoat-C^TM, AN3 Model) it is dissolved in purified water, it is used as solution A after evenly dispersed；

(3) mannitol and pregelatinized starch of recipe quantity are taken, is added in a step comminutor, 30min, control wind turbine frequency are mixed Rate：20Hz~30Hz.

(5) dry after having sprayed above-mentioned solution B, until pellet moisture≤4.0%.Control wind turbine 20~30Hz of frequency, air inlet 40~80 DEG C of temperature.

The preparation of 19 voglibose particle of embodiment

Prescription：

Technique：

(1) by the povidone of recipe quantity (Ashland companies of the U.S., Plasdone^TM, K-12 models) and it is dissolved in purified water, Solution A is used as after evenly dispersed；

(3) mannitol and starch of recipe quantity are taken, is added in a step comminutor, 20min is mixed, controls wind turbine frequency： 20Hz~30Hz.

(5) dry after having sprayed above-mentioned solution B, until pellet moisture≤4.0%.Control wind turbine 20~30Hz of frequency, air inlet 45~80 DEG C of temperature.

The preparation of 20 voglibose particle of embodiment

Prescription：

Technique：

(1) by the hydroxypropyl methylcellulose of recipe quantity (Lotte Fine Chemical companies of South Korea, AnyCoat-C^TM, AN15 Model) it is dissolved in purified water, it is used as solution A after evenly dispersed；

(3) mannitol and pregelatinized starch of recipe quantity are taken, is added in a step comminutor, 15min, control wind turbine frequency are mixed Rate：20Hz~30Hz.

The measurement of the 21 granule content uniformity of embodiment

When the bottom pot for after drying, taking out a step comminutor, for the particle in this patent Examples 1 to 20, respectively According to the method for uniformity of dosage units sampling, 10 samples are taken.

All granule contents are measured using following method：

Chromatographic condition shines high performance liquid chromatography (Chinese Pharmacopoeia four general rules of version in 2015 with system suitability 0512) it measures.With polyamino bonding polyvinyl alcohol be filler (Shodex Asahipak NH2P-50 4E, 250 × 4.6mm, 5 μm or the comparable chromatographic column of performance)；35 DEG C of column temperature；With phosphate buffer (sodium dihydrogen phosphate 1.56g is taken, water 500mL is added to make Dissolving, with disodium hydrogen phosphate 3.58g, adds water 500mL to make dissolving, takes sodium dihydrogen phosphate 500mL, use disodium phosphate soln PH value is adjusted to 6.5)-acetonitrile (37:63) it is mobile phase；With fluorescence detector, a length of 350nm of excitation light wave, wavelength of transmitted light For 430nm；Taurine 6.25g and sodium metaperiodate 2.56g are taken, be dissolved in water and is diluted to 1000mL, is shaken up, as fluorescence reaction Reagent；Post-column derivation；React about 100 DEG C of bath temperature, polytetrafluoroethylene (PTFE) reaction tube length 20m (internal diameter 0.5mm)；Cooling bath temperature is about It it is 15 DEG C, polytetrafluoroethylene (PTFE) cools down pipe range 2m (internal diameter 0.3mm)；Flow velocity is 1mL per minute, the flow velocity of mobile phase and fluorescent reagent It is identical.Number of theoretical plate is calculated by voglibose peak should be not less than 3000, the separating degree between voglibose peak and auxiliary material peak It should meet the requirements, the relative standard deviation of reference substance solution replication 6 times, peak area should be not more than 3.0%.

Measuring method

Take this product appropriate, it is finely ground, it weighs appropriate (being approximately equivalent to voglibose 2mg), it is accurately weighed, set 50mL measuring bottles In, add flowing to make an appointment 40mL, shake well 30 minutes makes voglibose dissolve, is diluted to scale with mobile phase, shakes up, put It sets, takes supernatant to be filtered through 0.45 μm of filter membrane, take subsequent filtrate as test solution；Separately take voglibose reference substance about 22mg, it is accurately weighed, it sets in 50mL measuring bottles, adds flowing phased soln and be diluted to scale, shake up, precision measures 5mL, sets 50mL amounts In bottle, it is diluted to scale with mobile phase, is shaken up, as a contrast product solution.Precision measures reference substance solution and test solution is each 50 μ L are injected separately into liquid chromatograph, record chromatogram.By external standard method with calculated by peak area granule content (mg/g).

Calculation formula：

In formula：

A_SampleThe peak area at main composition peak in → test solution；

A_{It is right}The average value of the main peak area of → contrast solution；

W_{It is right}→ prepare weighing (mg) for voglibose reference substance used in contrast solution；

W_Sample→ the sample for preparing test solution is weighed (mg)；

P → reference substance content；

F → reference substance solution extension rate.

Calculate after granule content obtained by Examples 1 to 20, the granule content of the value divided by theory obtains each The percentage composition of grain, the granule content uniformity the results are shown in Table 1.

1 Determination of Content Uniformity result (n=10) of table

By table as it can be seen that in all embodiments voglibose particle content RSD≤0.50%；According to Chinese Pharmacopoeia 2015 The requirement of four 0941 Content uniformity tests of version calculates A+2.2S, and result is much smaller than 15, illustrates according to 1~20 institute of embodiment The granule content uniformity obtained is preferable.

The measurement of 22 particle friability of embodiment

According to document (Drug Dev Ind Pharm.1987,13:1-14) method introduced is measured.

When the bottom pot for after drying, taking out a step comminutor, for the particle in this patent Examples 1 to 20, respectively According to the method for uniformity of dosage units sampling, 10 samples are taken, the sample measured as friability after mixing.

Assay method：Particle in Example 1~20 is appropriate, crosses 35 mesh and 60 mesh medicines sieve, takes 35~60 mesh particle (grains Diameter is about 250~500 μm) 10.0g, it is accurately weighed, it is placed in friability somascope (FT-2000AE models, the extremely big Tian Fa sections in Tianjin Skill Development Co., Ltd) in, additional average diameter is the bead about 200, rotational time 10min of 4mm, and rotating speed is 25rpm after rotation, removes bead, crosses 60 mesh sieve, weighs the quality of remainder particulate, calculates friability.

It is comparative example 1 according to the particle that patent CN200710129313.7 voglibose dispersible tablets are prepared.

Particle friability in Examples 1 to 20 and comparative example 1 the results are shown in Table 2.

2 friability measurement result of table

	Friability
		Unit	%
Embodiment 1	28.51
		Embodiment 2	26.72
Embodiment 3	16.42
		Embodiment 4	13.25
Embodiment 5	28.28
		Embodiment 6	27.48
Embodiment 7	12.33
		Embodiment 8	15.57
Embodiment 9	27.84
		Embodiment 10	26.16
Embodiment 11	15.64
		Embodiment 12	12.59
Embodiment 13	27.76
		Embodiment 14	25.66
Embodiment 15	11.39
		Embodiment 16	24.44
Embodiment 17	26.36
		Embodiment 18	10.54
Embodiment 19	12.25
		Embodiment 20	21.68
Comparative example 1	65.69

As seen from the above table, the friability of voglibose particle is respectively less than 30% in all embodiments, and comparative example 1 Friability be more than 60%, it is seen that using a step be granulated method made from particle friability it is smaller.In addition, from the crisp of pelleting Broken degree is related with the water-soluble binder dosage and model that are added, and water-soluble binder molecular weight is higher, and content is bigger, obtained Particle has the tendency that friability is smaller.

The preparation of 23~25 Voglibose tablet of embodiment

Voglibose particle obtained in this patent Examples 1 to 3 is taken respectively, and in pelletizing machine, (YK160 types are swing On granulator, Kuibao Group Co., Ltd., Jiangsu, similarly hereinafter) 40 mesh sieve, in mixing machine, (the quasi- mixing machine in the type sides HZD-150L is breathed out 10min is mixed on your shore nano medication chemistry equipment Co., Ltd, similarly hereinafter), the stearic acid of particle gross weight 0.5% is added later Magnesium remixes 5min.Using high speed tablet press (GZP-26 type tablet press machines, Beijing Hanlin Hangyu Science And Technology Development Co., Ltd, under Together), scrobicula round diameter is impressed mold tabletting among 7.0mm, and the pressure for controlling tabletting is 4~6KN, forces charging speed Degree is 10rpm, and the tablet of hardness >=2KN is made, and the sample of embodiment 23~25 is made respectively.

Since rate of dissolution may be variant in different media for voglibose, when doing Dissolution experiments, Voglibose tablet dissolved corrosion in different medium is inconsistent.Have document (Liaoning chemical industry, 2017, (3):211-213) Report：The Voglibose tablet stripping curve that different manufacturers produce in pH5.8 buffer solutions has larger difference, therefore, with pH5.8 Distinction medium of the buffer solution as Voglibose tablet.

Using the Voglibose tablet of Japanese Takede Chemical Industries Ltd production as the reference preparation of embodiment 23~25.

The stripping curve of Voglibose tablet and reference preparation made from embodiment 23~25 is carried out according to following measuring method Experiment：

Chromatographic condition shines high performance liquid chromatography (Chinese Pharmacopoeia four general rules of version in 2015 with system suitability 0512) it measures.It is filler (Shodex Asahipak NH with polyamino bonding polyvinyl alcohol₂P-50 4E, 250 × 4.6mm, 5 μm or the comparable chromatographic column of performance)；35 DEG C of column temperature；With phosphate buffer (sodium dihydrogen phosphate 1.56g is taken, water 500mL is added to make Dissolving, with disodium hydrogen phosphate 3.58g, adds water 500mL to make dissolving, takes sodium dihydrogen phosphate 500mL, use disodium phosphate soln PH value is adjusted to 6.5)-acetonitrile (37:63) it is mobile phase；With fluorescence detector, a length of 350nm of excitation light wave, wavelength of transmitted light For 430nm；Taurine 6.25g and sodium metaperiodate 2.56g are taken, be dissolved in water and is diluted to 1000mL, is shaken up, as fluorescence reaction Reagent；Post-column derivation；React about 100 DEG C of bath temperature, polytetrafluoroethylene (PTFE) reaction tube length 20m (internal diameter 0.5mm)；Cooling bath temperature is about It it is 15 DEG C, polytetrafluoroethylene (PTFE) cools down pipe range 2m (internal diameter 0.3mm)；Flow velocity is 1mL per minute, the flow velocity of mobile phase and fluorescent reagent It is identical.Number of theoretical plate is calculated by voglibose peak should be not less than 3000, the separating degree between voglibose peak and auxiliary material peak It should meet the requirements, the relative standard deviation of reference substance solution replication 6 times, peak area should be not more than 3.0%.

Measuring method takes this product, according to dissolution method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 second method), with PH5.8 phosphate buffers 900mL is dissolution medium, and rotating speed is 50 turns per minute, is operated in accordance with the law, through 5,10,15,20 and 30 minutes When, it takes solution appropriate, is filtered through 0.45 μm of filter membrane, take subsequent filtrate as test solution；Separately take voglibose reference substance about 22mg, it is accurately weighed, it sets in 50mL measuring bottles, adds flowing phased soln and be diluted to scale, shake up, precision measures 5mL, sets 50mL amounts In bottle, it is diluted to scale with mobile phase, is shaken up, then accurate measurement 1mL, set in 200mL measuring bottles, solubilization goes out medium to quarter Degree, shakes up, then accurate measurement 3mL, sets in 10mL measuring bottles, with dilution in acetonitrile to scale, shakes up, as a contrast product solution.It is accurate Reference substance solution and each 100 μ L of test solution are measured, liquid chromatograph is injected separately into, records chromatogram.By external standard method with peak The stripping quantity of areal calculation every.

The dissolution results of Voglibose tablet and reference preparation made from this patent embodiment 23~25 are shown in Table 3 and Fig. 1.

The dissolution results of 3 embodiment of table 23~25 Voglibose tablet and reference preparation

	Embodiment 23	Embodiment 24	Embodiment 25	Reference preparation
					Corresponding embodiment	Embodiment 1	Embodiment 2	Embodiment 3	——
Unit	%	%	%	%
					5min	70.25	64.25	56.70	32.75
10min	99.42	95.77	90.26	65.29
					15min	99.24	99.52	99.14	82.28
20min	99.62	99.23	98.38	94.21
					30min	99.38	99.24	98.96	99.23

The preparation of 26~30 voglibose oral disintegrating tablet of embodiment

Voglibose particle obtained in this patent embodiment 4~8 is taken respectively, and 40 mesh sieve is crossed on pelletizing machine, 10min is mixed on mixing machine, is sequentially added disintegrant in table 4 (numerical value is the multiple of voglibose batch dosage), is being mixed 10min is mixed on machine, adds the magnesium stearate mixing 5min of the 0.5% of particle weight.Scrobicula is used on high speed tablet press Round diameter is impressed mold tabletting among 7.0mm, and the pressure for controlling tabletting is 4~6KN, and pressure charging rate is The tablet of hardness >=2KN is made in 10rpm.

The disintegrant and its disintegrating method result being added in 4 embodiment 26~30 of table

	Embodiment 26	Embodiment 27	Embodiment 28	Embodiment 29	Embodiment 30
						Corresponding embodiment	Embodiment 4	Embodiment 5	Embodiment 6	Embodiment 7	Embodiment 8
Low-substituted hydroxypropyl cellulose	10	50	——	——	——
						Crospovidone	——	——	100	——	——
Croscarmellose sodium	——	——	——	150	——
						Sodium carboxymethyl starch	——	——	——	——	200
The intraoral disintegration time	40 seconds	36 seconds	18 seconds	26 seconds	24 seconds

Note：The amount that each disintegrant is added is the multiple of voigelibo sugar weight.Such as embodiment 26, Example 4 is made Particle, voglibose dosage is 0.02kg in the embodiment, then additional low-substituted hydroxypropyl cellulose is 0.2kg.Firmly Fatty acid magnesium dosage is the 0.5% of particle gross weight, and such as embodiment 26, particle gross weight is 17.02kg, then magnesium stearate is added 0.851kg.Disintegrant and magnesium stearate is added using identical method in other embodiment.

Low-substituted hydroxypropyl cellulose selects the low substitution of the LH-32 models (20 μm of average grain diameter) of Shinetsu companies of Japan Hydroxypropylcellulose (similarly hereinafter)；

Crospovidone selects BASF Corp. of GermanyCL-SF (10~30 μm) model Crospovidone (under Together).

Croscarmellose sodium selects DEF companies of HollandCroscarmellose sodium (under Together).

JRS companies of sodium carboxymethyl starch GermanySodium carboxymethyl starch (similarly hereinafter).

Select voglibose oral disnitegration tablet (the ベイス Application OD Ingot of Japanese Takede Chemical Industries Ltd's production 0.2) reference preparation as embodiment 26~30.

According to the method for dissolution rate in embodiment 23~25, with citrate phosphate buffer (dilute McIlvaine buffer solutions, pH 5.0) it is dissolution medium, voglibose oral disintegrating tablet and reference preparation made from embodiment 26~30 is measured, as a result seen Fig. 2.

From Figure 2 it can be seen that all formulations dissolution rate in 5min is attained by 90% or more, in 10min, dissolution rate exists 95% or more, the characteristics of meeting oral disintegrating tablet Fast Stripping.

The preparation of 31~33 voglibose capsule of embodiment

Voglibose particle obtained in this patent embodiment 9~11 is taken respectively, and 40 mesh sieve is crossed on pelletizing machine, 10min is mixed on mixing machine, and 0.5% magnesium stearate of particle weight is added later, 5min is remixed, using fully-automatic capsule Filling machine (Zhejiang Feiyun Technology Co., Ltd., NJP7500 types) fills capsule, and the sample of embodiment 31~33 is made respectively.

According to the method for dissolution rate in embodiment 23~25, with citrate phosphate buffer (dilute McIlvaine buffer solutions, pH 5.0) be dissolution medium, to voglibose capsule made from embodiment 31~33 and reference preparation (Voglibose tablet, 0.2mg, Japanese Takede Chemical Industries Ltd) it is measured.As a result see Fig. 3.As seen from Figure 3, all formulations are in 5min Dissolution rate is attained by 50% or more, and in 10min, dissolution rate is 80% or more, and in 15min, dissolution rate is made 85% or more The capsule energy Fast Stripping obtained.

The preparation of 34~38 voglibose dispersible tablet of embodiment

Voglibose particle obtained in this patent embodiment 12~16 is taken respectively, and 40 mesh sieve is crossed on pelletizing machine, 10min is mixed on mixing machine, sequentially adds the disintegrant (numerical value is the multiple of voglibose batch dosage) in table 5, 10min is mixed on mixing machine, adds the magnesium stearate mixing 5min of the 0.5% of particle weight.It is used on high speed tablet press Scrobicula round diameter is impressed mold tabletting among 7.0mm, and the pressure for controlling tabletting is 4~6KN, and pressure charging rate is The tablet of hardness >=2KN is made in 10rpm.

The sample of embodiment 34~38 is carried out using disintegration tester (Tianjin Tianda Tianfa Science and Technology Co. Ltd., ZB-1E types) Disintegrating property measures (37 DEG C ± 0.5 DEG C, 800mL purified waters), the results are shown in Table 5.

The disintegrant and its disintegrating method result being added in 5 embodiment 34~38 of table

Upper table shows that dispersible tablet made from embodiment 34~38 meets requirement (3min of the dispersible tablet generally to disintegration time limited Within).Since the dispersible tablet of embodiment 34~38 is obtained by the particle preparation of embodiment 12~16, embodiment 12~ 16 particle has the characteristics of fater disintegration.

Select voglibose oral disnitegration tablet (the ベイス Application OD Ingot of Japanese Takede Chemical Industries Ltd's production 0.2mg) the reference preparation as 34~38 dispersible tablet of embodiment.

According to the method for dissolution rate in embodiment 23~25, with citrate phosphate buffer (dilute McIlvaine buffer solutions, pH 5.0) it is dissolution medium, voglibose dispersible tablet and reference preparation made from embodiment 34~38 is measured.As a result see Fig. 4.From fig. 4, it can be seen that all formulations dissolution rate in 5min is attained by 90% or more, in 10min dissolution rate 95% with On, the characteristics of meeting dispersible tablet Fast Stripping.Since the dispersible tablet of embodiment 34~38 is by of 12~16 gained of embodiment Grain is prepared after 0.5% magnesium stearate is added, and therefore, the particle in embodiment 12~16 is likewise supplied with the spy of Fast Stripping Point.

The preparation of 39~42 voglibose granule of embodiment

The method according to above-described embodiment 17~20 prepares blank granules respectively, and lactose in prescription or mannitol are substituted for Sucrose (Zhang Fu sugar industries Co., Ltd of Zhangzhou City with preceding crushing and sieves with 100 mesh sieve).It takes and contains according to prepared by embodiment 17~20 respectively Medicine particle and blank granules, the ratio by two kinds of particles according to following table 6 mix 10min, 39~42 voigelibo of embodiment are made Sugared granule (every bag of 1.0g).

The preparation of 6 voglibose granule of table

	Embodiment 39	Embodiment 40	Embodiment 41	Embodiment 42
					The preparation method of particle	Embodiment 17	Embodiment 18	Embodiment 19	Embodiment 20
Medicine-containing particle	157.2	194.9	212.9	166.5
					Blank granules	842.8	805.1	787.1	833.5
Voigelibo sugared content	0.3mg/ bags	0.3mg/ bags	0.3mg/ bags	0.3mg/ bags

According to the method for dissolution rate in embodiment 23~25, with citrate phosphate buffer (dilute McIlvaine buffer solutions, pH 5.0) it is dissolution medium, voglibose granule made from embodiment 39~42 is measured.As a result see Fig. 5.It can by Fig. 5 See, all formulations dissolution rate in 5min is attained by 90% or more, and in 10min, dissolution rate meets particle 95% or more The characteristics of agent Fast Stripping.

Claims

1. a kind of preparation method of voglibose particle is prepared by step granulation, it is characterized in that：Including following step Suddenly：

(2) solution A is divided into two parts, as A-1, another is added voglibose, is used as after evenly dispersed molten a copy of it Liquid A-2；

(3) diluent and disintegrant are taken, is added in a step comminutor, mixing；Control wind turbine frequency：20Hz~30Hz；When mixing Between：5~30min.

(4) solution A -1 is taken to be injected in the step comminutor described in (3) in such a way that top spray is granulated；Control wind turbine frequency 20 ~30Hz, 40~85 DEG C, 0.15~0.25Mpa of atomisation pressure, 20~80rpm of wriggling revolution speed of inlet air temperature.

(5) dry after having sprayed above-mentioned solution A -1, until pellet moisture≤4.0%；Wind turbine 20~30Hz of frequency is controlled, into wind-warm syndrome 40~85 DEG C of degree.

(6) solution A -2 is taken to be injected in the step comminutor described in (4) in such a way that top spray is granulated；Control wind turbine frequency 20 ~30Hz, 40~85 DEG C, 0.15~0.25Mpa of atomisation pressure, 20~80rpm of wriggling revolution speed of inlet air temperature.

(7) dry after having sprayed above-mentioned solution A -2, until pellet moisture≤4.0%；Wind turbine 20~30Hz of frequency is controlled, into wind-warm syndrome 40~85 DEG C of degree.

2. a kind of preparation method of voglibose particle according to claim 1, it is characterized in that：Solution A be divided into A-1 and The weight ratio of two parts of A-2, this two parts of solution are 0:1 or 1:(0.2~5).

3. a kind of preparation method of voglibose particle according to claim 1, it is characterized in that：Water-soluble binder is One kind in povidone, hydroxypropylcellulose, hydroxypropyl methylcellulose and its a variety of mixtures；Polar solvent is water, ethyl alcohol, isopropyl One kind in alcohol, acetone and its a variety of mixtures；Diluent is the lactose sieved with 100 mesh sieve, mannitol, xylitol, trehalose, micro- One kind in crystalline cellulose and its a variety of mixtures；Disintegrant is the starch or pregelatinized starch sieved with 100 mesh sieve.

4. a kind of preparation method of voglibose particle according to claim 1, it is characterized in that：Voglibose makes Dosage is 1 part, and water-soluble binder is 5~100 parts (weight ratios, similarly hereinafter)；Polar solvent is 100~2000 parts；Diluent is 200~1000 parts；Disintegrant is 10~1000 parts.

5. a kind of preparation method of voglibose particle according to claim 1, it is characterized in that：Voglibose makes Dosage is 1 part, and water-soluble binder is 10~80 parts (weight ratios, similarly hereinafter)；Polar solvent is 200~1600 parts；Diluent is 250~800 parts；Disintegrant is 25~800 parts.

6. a kind of preparation method of voglibose particle according to claim 1, it is characterized in that：Voglibose makes Dosage is 1 part, and water-soluble binder is 15~60 parts (weight ratios, similarly hereinafter)；Polar solvent is 300~1500 parts；Diluent is 300~700 parts；Disintegrant is 50~500 parts.

7. a kind of preparation method of Voglibose tablet, it is characterized in that：A kind of voglibose described in accordance with the claim 1 The preparation method of particle, be added the lubricant (such as 0.5% magnesium stearate) that particle gross weight 0.3%~1.0% is made and/or 0.1%~2.0% glidant (such as 0.2% gaseous silicon oxide).

8. a kind of preparation method of voglibose dispersible tablet, it is characterized in that：A kind of voigelibo described in accordance with the claim 1 The preparation method of sugared particle also needs 10~200 parts additional of disintegrant；Disintegrant is typically chosen that disintegration ability is stronger low to be taken For hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch.

9. a kind of preparation method of voglibose granule, it is characterized in that：A kind of voigelibo described in accordance with the claim 1 The preparation method of sugared particle also needs to use cane sugar substitution filler therein, prepares blank granules, and shines certain proportion by blank Particle and medicine-containing particle are mixed and made into voglibose granule.

10. preparation method or a kind of voglibose of a kind of Voglibose tablet according to claim 7 or 8 or 9 The preparation method of dispersible tablet or a kind of preparation method of voglibose granule, it is characterized in that：Be made tablet, dispersible tablet or After granula, it is 0.2mg or 0.3mg that each preparation unit, which contains voglibose,.