CN103610646B - Composition containing everolimus and preparation method thereof, and pharmaceutical preparation containing composition - Google Patents
Composition containing everolimus and preparation method thereof, and pharmaceutical preparation containing composition Download PDFInfo
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- CN103610646B CN103610646B CN201310642757.6A CN201310642757A CN103610646B CN 103610646 B CN103610646 B CN 103610646B CN 201310642757 A CN201310642757 A CN 201310642757A CN 103610646 B CN103610646 B CN 103610646B
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Abstract
The invention relates to a preparation method of a solid dispersion containing everolimus. The method comprises the following steps: dissolving everolimus and a high-polymer carrier hydroxy propyl methyl cellulose (HPMC) into an organic solvent, and then centrifugally atomizing and drying, so as to prepare the solid dispersion. The solid dispersion disclosed by the invention is small in particle size, even in distribution, low in preparation temperature, and free of effect on everolimus stability, and rapid dissolution is facilitated. The preparation process is quick and simple, and convenient to operate, so that the prepared product can be mixed with an auxiliary material, can be used for preparing tablets, capsules and granules, and is applicable to large-scale industrial production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, in particular to a kind of composition and method of making the same containing everolimus and application of solid dispersion form, more specifically relate to a kind of composition and method of making the same containing everolimus and the pharmaceutical preparation containing this compositions.
Background technology
Everolimus is the derivant of rapamycin, and commodity are called Afinitor or Certican, goes on the market in Europe.Afinitor goes through (EMEA/H/C/001038) on March 8th, 2009, is used for the treatment of the advanced renal cell carcinoma (RCC) in the treatment of VEGF targeted therapies or after treatment.In addition, everolimus is also sold with Certican in European Union.Certican in 2003 is approved for the adult patients being accepted allogeneic kidney or heart transplantation, low or moderate immune risk by mutual approved programme, prevention organ rejection.
Everolimus is one optionally mTOR inhibitors, specifically for mTOR signal transduction complex (mTORC1).Forms of rapamycin analogs has height lipotropy, can pass blood-brain barrier.MTOR kinases is activated mainly through phosphatidylinositols 3-kinases (PI3K) approach.
Everolimus be a kind of white to yellowish amorphous powder, carry out stability protection with the antioxidant BHT (BHT) of 0.2%, instability at higher than the temperature of 25 DEG C, to photaesthesia.
Everolimus itself is water-soluble hardly, therefore oral administration biaavailability is very low.In order to increase dissolubility and bioavailability, medicine is prepared into solid dispersion together with hydrophilic polymer HPMC.When after solid dispersion contact water, polymer quick dissolution, makes the surface area of medicine greatly increase, thus more soluble in water.
CN1195289A discloses everolimus and adopts solvent method to prepare through drying under reduced pressure, then through pulverization process, obtains the solid dispersion that can be used for preparation.The method is long for drying time in preparation process, and dissolvent residual is high, and after dry, material is hard, adopt high rotating speed pulverizer to pulverize and easily cause material high temperature degradation, and pulverizing loss is larger.
Lactose is employed in everolimus solid dispersion preparation process disclosed in prior art CN1195289A.The increase that those of ordinary skill in the art know supplementary product kind in pharmacy procedure not only can increase production cost, more can reduce the quality controllability of product.The present invention, when repeating everolimus solid dispersion preparation method in CN1195289A, when not adding lactose, finds that obtained solid dispersion quality is more tough and tensile, is unfavorable for pulverizing, and needs increase crush strength and/or extend grinding time; Make everolimus solid dispersion produce more high temperature degradation, reduce the quality of product.The present inventor finds, the compositions containing everolimus of the solid dispersion form prepared by method disclosed by the invention, compared to existing technology, when not using adjuvant lactose, can obtain good form.By reducing the supplementary product kind preparing everolimus solid dispersion, make the everolimus solid dispersion of preparation safer, quality controllable.
The preparation method of composition containing everolimus of solid dispersion form provided by the invention, operating process is simple, fast, avoids the long-time degradation of medicine.The composition grain particle diameter containing everolimus of simultaneously obtained solid dispersion form is little, is evenly distributed, without the need to grinding and processing, can be directly used in mixed pressuring plate or capsule-filling; There is good hydrophilic property, the advantage of Fast Stripping in the body being conducive to everolimus.
Summary of the invention
In view of the deficiencies in the prior art, the present invention verifies through experimental study, provides a kind of preparation method of the solid dispersion containing everolimus newly.
The invention provides a kind of compositions containing everolimus, be made up of everolimus and HPMC, described everolimus compositions is dissolved in organic solvent by everolimus and HPMC to form through centrifugal spray drying.The described compositions containing everolimus is solid dispersion form.
Preferably the mass ratio of everolimus and HPMC is 1:1 ~ 1:20; Be more preferably 1:5 ~ 1:20; Be further preferably 1:10 ~ 1:20.
Commercially available HPMC has the specification of different viscosity, and HPMC of the present invention preferably 2% aqueous solution is the HPMC of 2 ~ 7mPas at the apparent viscosity of 20 DEG C, is more preferably 2 ~ 6 mPas, is further preferably 2 ~ 4mPas, is most preferably 2.4 ~ 3.6mPas.
Preferably described organic solvent is selected from one or more in dehydrated alcohol, acetone, methanol, acetonitrile, chloroform.Being more preferably ethanol and/or acetone, is further preferably the mixed solvent of ethanol or ethanol and acetone.
Preferably the mass ratio of everolimus and organic solvent is 1:50 ~ 1:200; Be more preferably 1:100.
Meanwhile, in order to obtain the compositions containing everolimus being suitable for the solid dispersion form that pharmaceuticals industry uses, we further disclose following centrifugal spray drying condition:
The feeding temperature of described centrifugal spray drying is preferably 30 ~ 50 DEG C, is more preferably 30 ~ 40 DEG C.
The nebulizer rotating speed of described centrifugal spray drying is 7000 ~ 10000rpm, is more preferably 8000 ~ 10000rpm.
The hothouse inlet temperature of described centrifugal spray drying is 80 ~ 150 DEG C, is more preferably 100 ~ 110 DEG C.
The hothouse inlet temperature of described centrifugal spray drying is outlet temperature is 30 ~ 60 DEG C, is more preferably 40 ~ 50 DEG C.
Present invention also offers a kind of method preparing the above-mentioned compositions containing everolimus, everolimus be dissolved in organic solvent and obtain intermediate solution A, add in solution A HPMC swelling intermediate solution B; Intermediate solution B is heated, obtains the compositions containing everolimus through centrifugal spray drying.
Here centrifugal spray drying condition selects aforesaid centrifugal spray drying condition equally, that is:
The feeding temperature of described centrifugal spray drying is preferably 30 ~ 50 DEG C, is more preferably 30 ~ 40 DEG C.
The nebulizer rotating speed of described centrifugal spray drying is 7000 ~ 10000rpm, is more preferably 8000 ~ 10000rpm.
The hothouse inlet temperature of described centrifugal spray drying is 80 ~ 150 DEG C, is more preferably 100 ~ 110 DEG C.
The hothouse inlet temperature of described centrifugal spray drying is outlet temperature is 30 ~ 60 DEG C, is more preferably 40 ~ 50 DEG C.
Present invention also offers a kind of pharmaceutical preparation obtained by the above-mentioned compositions containing everolimus; Preferably described preparation is granule, tablet or capsule, is more preferably tablet.Described tablet by the described compositions containing everolimus being mixed homogeneously with filler lactose, disintegrating agent polyvinylpolypyrrolidone, magnesium stearate lubricant, can be pressed into tablet through tablet machine.
HPMC of the present invention represents hypromellose, is water soluble carrier material.343rd ~ 347 pages " pharmaceutic adjuvant handbook " (the 4th edition, Chemical Industry Press, 2005.01) have introduction.Above content is quoted into this description as a part for description of the present invention.HPMC is colourless or milky is fibrous or particulate powder; Dissolve in cold water, form viscolloid solution; Almost insoluble in chloroform, ethanol (95%) and ether.
Detailed description of the invention
Set forth implementation process of the present invention further by the following examples, need it is noted that these embodiments are not limiting the scope of the invention.One skilled in the art will understand that the equivalent replacement that content of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Need it is noted that, " part " unless otherwise indicated in the embodiment of the present invention refers to be mass parts.
comparative example 1
Everolimus 1 part
Dehydrated alcohol 50 parts
50 parts, acetone
HPMC 9 parts
Lactis Anhydrous 1 part
Preparation technology: everolimus is dissolved in dehydrated alcohol/acetone, it is swelling to add HPMC, adds lactose and stirs.According to Chinese Pharmacopoeia viscosimetry second method, measuring suspension viscosity is 25-30mPa.s.
In the present embodiment and following embodiment, unless otherwise indicated, U.S. that the HPMC used is DOW Chemical many shows (METHOCEL) E3.
comparative example 2
Solvent evaporated method: kept stirring by suspension in embodiment 1, vacuum drying, temperature is 30 ~ 50 DEG C, keeps about 48 hours, removing organic solvent; Residual solids is ground into granularity about 80 object granule through impact grinder after taking out.
Pressure atomization seasoning: by suspension in embodiment 1 through pressure spray dryer, atomisation pressure 1.2-1.5MPa, inlet temperature 150 DEG C, outlet temperature 60 DEG C.
Centrifugal spray drying method: suspension in embodiment 1 is heated to 40 DEG C, obtains dried particles through centrifugal spray drying, nebulizer rotating speed is at 8500rpm, and hothouse inlet temperature is at 100 DEG C, and outlet temperature is at 45 DEG C.
comparative example 3
The performance of the compositions containing everolimus of the solid dispersion form 3 methods in comparative example 2 obtained compares, detect its dissolvent residual, particle size distribution, content, related substance and the dissolution in 1000ml purified water respectively, result is as following table:
embodiment 1
Everolimus 1 part
Dehydrated alcohol 100 parts
HPMC 10 parts
Preparation technology: everolimus is dissolved in dehydrated alcohol, it is swelling to add HPMC, and be heated to 40 DEG C, obtain dried particles through centrifugal spray drying, nebulizer rotating speed is at 8500rpm, and hothouse inlet temperature is at 100 DEG C, and outlet temperature is at 45 DEG C.
embodiment 2
Everolimus 1 part
50 parts, acetone
HPMC 10 parts
Preparation technology: everolimus is dissolved in acetone, it is swelling to add HPMC, and be heated to 30 DEG C, obtain dried particles through centrifugal spray drying, nebulizer rotating speed is at 8000rpm, and hothouse inlet temperature is at 105 DEG C, and outlet temperature is at 45 DEG C.
embodiment 3
Everolimus 1 part
Dehydrated alcohol 200 parts
HPMC 20 parts
Preparation technology: everolimus is dissolved in dehydrated alcohol, it is swelling to add HPMC, and be heated to 40 DEG C, obtain dried particles through centrifugal spray drying, nebulizer rotating speed is at 9000rpm, and hothouse inlet temperature is at 110 DEG C, and outlet temperature is at 50 DEG C.
embodiment 4
Everolimus 1 part
Dehydrated alcohol 50 parts
50 parts, acetone
HPMC 10 parts
Preparation technology: everolimus is dissolved in dehydrated alcohol and acetone, it is swelling to add HPMC, and be heated to 40 DEG C, obtain dried particles through centrifugal spray drying, nebulizer rotating speed is at 10000rpm, and hothouse inlet temperature is at 100 DEG C, and outlet temperature is at 40 DEG C.
embodiment 5 dissolution determination
The product obtained by solvent evaporated method in comparative example 2 and the compositions containing everolimus of solid dispersion form that obtains according to the technical scheme in embodiment 1 ~ 4 are carried out dissolution contrast test:
Sample thief appropriate (containing everolimus 2.5mg), according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC second methods), with purified water 1000ml for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, through 10,20,30, when 45 minutes, get solution appropriate, filter, get subsequent filtrate and survey content, calculate stripping percentage composition.
Solid dispersion dissolution results prepared by each embodiment of table 1
| Sample point | 10min | 20min | 30min | 45min |
| Comparative example 2 | 42% | 54% | 66% | 75% |
| Embodiment 1 | 40% | 55% | 63% | 74% |
| Embodiment 2 | 45% | 58% | 68% | 79% |
| Embodiment 3 | 43% | 58% | 68% | 74% |
| Embodiment 4 | 46% | 52% | 61% | 79% |
Table 2 40 DEG C of 75%RH accelerate 6 months, the dissolution results of solid dispersion prepared by each embodiment
| Sample point | 10min | 20min | 30min | 45min |
| Comparative example 2 | 38% | 54% | 62% | 71% |
| Embodiment 1 | 41% | 51% | 61% | 78% |
| Embodiment 2 | 40% | 59% | 67% | 75% |
| Embodiment 3 | 45% | 55% | 62% | 76% |
| Embodiment 4 | 43% | 57% | 65% | 73% |
embodiment 6 particle size distribution
The product obtained by solvent evaporated method in comparative example 2 and the compositions containing everolimus of solid dispersion form that obtains according to the technical scheme in embodiment 1 ~ 4 are carried out particle size distribution.Test method is carried out with reference to the operation of the particle size distribution of rider point-score working sample in Chinese Pharmacopoeia 2010 editions two annex IX E.Experimental result is as table 3.
Solid dispersion particle size distribution result (weight ratio %) prepared by each embodiment of table 3
| Sieve mesh | More than 40 orders | 40-80 order | 80-120 order | Below 120 orders |
| Comparative example 2 | 5.4% | 8.6% | 66.8% | 19.2% |
| Embodiment 1 | 2.5% | 4.9% | 70.6% | 22.0% |
| Embodiment 2 | 5.1% | 12.5% | 65.0% | 17.4% |
| Embodiment 3 | 8.3% | 17.7% | 59.4% | 14.6% |
| Embodiment 4 | 3.9% | 5.2% | 60.1% | 30.8% |
embodiment 7 determination of related substances
The product obtained by solvent evaporated method in comparative example 2 and the compositions containing everolimus of solid dispersion form that obtains according to the technical scheme in embodiment 1 ~ 4 are carried out the mensuration of related substance.Product 0 day and 40 DEG C of 75%RH accelerate 6 each months related substance testing results in table 4.
As can be seen from Table 1, the drug-eluting speed obtained by embodiment 1-4 is suitable with solvent evaporated method in comparative example 2;
As can be seen from Table 2, the medicine solid dispersion particle size distribution obtained by embodiment 1-4 is even, suitable with mixed accessories particle size distribution, can ensure mixing homogeneity, meet large manufacturing technique requirent;
After solvent evaporated method in comparative example 2 prepares solid dispersion, need through mechanical activation comminution process, loss is larger; The particle size distribution range of pressure atomization seasoning is wider, easily causes uniformity of dosage units, dissolution difference excessive with adjuvant after mixing;
The related substance of solid dispersion prepared by the pressure atomization seasoning in comparative example 2 is relatively high, and embodiment 1-4 solid dispersion particles related substance is relatively little, and steady quality is suitable with the solvent evaporated method in comparative example 2;
Find out from embodiment and the every testing result of comparative example, the constant product quality that preparation technology of the present invention obtains, dissolution meets the requirements, simultaneously without the need to mechanical crushing process, the particle size distribution of preparation is even, is applicable to follow-up direct mixture manufacturing tablet or capsule.
embodiment 8
Solid dispersion appropriate (being equivalent to principal agent 1 part)
Lactose 30 parts
Polyvinylpolypyrrolidone 5 parts
Magnesium stearate 0.5 part
By the product obtained by solvent evaporated method in comparative example 2 and the product of solid dispersion form that obtained by technical scheme disclosed in embodiment 1-4 by film-making proportion requirement respectively with filler lactose, disintegrating agent polyvinylpolypyrrolidone, magnesium stearate lubricant is mix homogeneously in three-dimensional motion mixer, and mixed powder is pressed into tablet through rotary tablet machine.
embodiment 9
The agent of square piece everywhere in embodiment 8 is measured uniformity of dosage units, dissolution and friability, the results are shown in Table 5:
After each embodiment of table 5 is pressed into tablet, indices testing result
。
Claims (7)
1. containing a compositions for everolimus, be made up of everolimus and HPMC, it is characterized in that the described compositions containing everolimus is dissolved in organic solvent by everolimus and HPMC to form through centrifugal spray drying;
The mass ratio of everolimus and HPMC is 1:1 ~ 1:20;
The mass ratio of everolimus and organic solvent is 1:50 ~ 1:200;
The feeding temperature of described centrifugal spray drying is 30 ~ 50 DEG C, and nebulizer rotating speed is 7000 ~ 10000rpm, and hothouse inlet temperature is 80 ~ 150 DEG C, and outlet temperature is 30 ~ 60 DEG C.
2. the compositions containing everolimus according to claim 1, is characterized in that described compositions is solid dispersion.
3. the compositions containing everolimus according to claim 1, is characterized in that 2% aqueous solution of described HPMC is 2 ~ 7mPas at the apparent viscosity of 20 DEG C.
4. the compositions containing everolimus according to claim 1, it is characterized in that described organic solvent is selected from dehydrated alcohol, acetone, methanol, acetonitrile, chloroform one or more.
5. the compositions containing everolimus according to claim 1, is characterized in that the conditional sampling of centrifugal spray drying is selected from following condition one or more:
Feeding temperature is 30 ~ 40 DEG C,
Nebulizer rotating speed is 8000 ~ 10000rpm,
Hothouse inlet temperature is 100 ~ 110 DEG C,
Outlet temperature is 40 ~ 50 DEG C.
6. prepare the method for compositions containing everolimus according to any one of claim 1 ~ 5, it is characterized in that everolimus is dissolved in organic solvent obtains intermediate solution A, add in intermediate solution A HPMC swelling intermediate solution B; Intermediate solution B is heated, obtains the compositions containing everolimus through centrifugal spray drying.
7. according to any one of claim 1 ~ 5, contain the pharmaceutical preparation that the compositions of everolimus is obtained, described preparation is granule, tablet or capsule.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016135740A1 (en) * | 2015-02-23 | 2016-09-01 | Natco Pharma Limited | Process for preparing stable oral compositions of everolimus |
| CN106377507A (en) * | 2016-08-31 | 2017-02-08 | 佛山市弘泰药物研发有限公司 | Everolimus solid dispersion preparation and preparation method thereof |
| CN106265525A (en) * | 2016-09-14 | 2017-01-04 | 常州兰陵制药有限公司 | The preparation method of everolimus solid dispersion |
| CN106692067B (en) * | 2017-01-16 | 2021-03-16 | 广州新济药业科技有限公司 | Dipyridamole solid dispersion, orally disintegrating tablet and preparation method thereof |
| CN114557966B (en) * | 2022-03-09 | 2023-07-04 | 上海方予健康医药科技有限公司 | Method for producing everolimus solid dispersion through vacuum crawler-type oven |
| CN117982495B (en) * | 2024-04-07 | 2024-06-25 | 国药集团川抗制药有限公司 | Everolimus solid dispersion, preparation method thereof and everolimus tablet |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1195289A (en) * | 1995-07-14 | 1998-10-07 | 诺瓦蒂斯有限公司 | Pharmaceutical compositions |
| CN1951390A (en) * | 2001-09-28 | 2007-04-25 | 诺瓦提斯公司 | Pharmaceutical compositions comprising colloidal silicon dioxide |
| CN102138903A (en) * | 2011-03-17 | 2011-08-03 | 苏州特瑞药业有限公司 | Everolimus solid oral medicinal composition |
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2013
- 2013-12-05 CN CN201310642757.6A patent/CN103610646B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1195289A (en) * | 1995-07-14 | 1998-10-07 | 诺瓦蒂斯有限公司 | Pharmaceutical compositions |
| CN1951390A (en) * | 2001-09-28 | 2007-04-25 | 诺瓦提斯公司 | Pharmaceutical compositions comprising colloidal silicon dioxide |
| CN102138903A (en) * | 2011-03-17 | 2011-08-03 | 苏州特瑞药业有限公司 | Everolimus solid oral medicinal composition |
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Address after: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699 Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699 Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |