CN105878202A - Tofacitinib citrate tablet and preparation method thereof - Google Patents
Tofacitinib citrate tablet and preparation method thereof Download PDFInfo
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- CN105878202A CN105878202A CN201610364039.0A CN201610364039A CN105878202A CN 105878202 A CN105878202 A CN 105878202A CN 201610364039 A CN201610364039 A CN 201610364039A CN 105878202 A CN105878202 A CN 105878202A
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- tofacitinib citrate
- tablet
- microcrystalline cellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Abstract
The invention discloses tofacitinib citrate tablets, which consist of tofacitinib citrate and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise a filler, a disintegrant, a flow aid and a coating agent, the filler is a microcrystalline cellulose lactose premix with the type Celactose80, and the weight ratio of the tofacitinib citrate to the microcrystalline cellulose lactose premix with the type Celactose80 is 1: 5-25. The invention has the advantages of high content uniformity, high dissolution speed, stable chemical property and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to tofacitinib citrate tablets and a preparation method thereof.
Background
Tofacitinib citrate is a novel oral JAK pathway inhibitor developed by the company pfeiffe, and is approved by FDA in 2012 to treat patients with adult active period and moderate-to-severe rheumatoid arthritis with poor response to methotrexate. The product can be used alone or in combination with other methotrexate or antirheumatic drugs.
Most of tofacitinib citrate tablets reported in the literature at present adopt a process of mixing a raw material medicament and an auxiliary material, then performing wet granulation, and then performing tabletting, wherein the adopted auxiliary material mainly comprises lactose, microcrystalline cellulose, starch and the like. Although wet granulation is beneficial to improving the flowability and compressibility of granules, the actual production finds that tofacitinib citrate is a high-solubility compound, migration is easy to occur in the granulation drying process, so that the content of the product is not uniform, and the problems of low dissolution speed, poor stability and the like exist.
Disclosure of Invention
The invention aims to overcome the defects and provide the tofacitinib citrate tablet with high content uniformity, high dissolution speed and stable chemical property and the preparation method thereof.
The tofacitinib citrate tablet provided by the invention consists of tofacitinib citrate and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise a filling agent, a disintegrating agent, a flow aid and a coating agent, and the tofacitinib citrate tablet is characterized in that: the filler is a microcrystalline cellulose lactose premix with the type Celactose80, and the weight ratio of the tofacitinib citrate to the microcrystalline cellulose lactose premix with the type Celactose80 is 1: 5-25.
Preferably, the weight ratio of the tofacitinib citrate to the microcrystalline cellulose lactose premix with the type Celactose80 is 1: 10-20.
Preferably, the disintegrating agent is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, and accounts for 2.5-5% of the weight of the tablet. Most preferred is low substituted hydroxypropylcellulose.
Preferably, the glidant is one or more of calcium stearate, magnesium stearate, silicon dioxide and talcum powder, and the glidant accounts for 0.5-2% of the weight of the tablet. Magnesium stearate is most preferred.
Preferably, the coating agent is a film coating agent, and the film coating agent accounts for 2-5% of the weight of the tablet.
The preparation method provided by the invention comprises the following steps:
1) crushing tofacitinib citrate to a particle size of 10-100 microns;
2) mixing tofacitinib citrate and microcrystalline cellulose lactose premix of Celactose80, adding disintegrating agent, and mixing; finally adding the glidant and mixing uniformly;
3) tabletting;
4) dissolving the coating agent by using 50-80% ethanol, and then coating the film coating by using a spraying method.
Preferably, in the step 1), tofacitinib citrate is crushed to a particle size of 40-60 μm.
Preferably, in the step 3), the environmental temperature is controlled to be 10-20 ℃, the humidity is less than or equal to 60% and the pressure of the tablet press is 25-30 KN during tabletting.
According to the invention, various auxiliary materials in the tablet are screened, the preparation process is improved, the dry method is adopted for direct tabletting, and the process conditions in each step are strictly controlled, so that the finally prepared tofacitinib citrate tablet not only has higher content uniformity, but also has the advantages of high dissolution speed, stable chemical property and the like.
Drawings
FIG. 1 is a dissolution curve diagram of tofacitinib citrate tablet in 0.1mol/L hydrochloric acid solution.
FIG. 2 is a graph showing the dissolution profile of tofacitinib citrate tablets in pure water.
FIG. 3 is a graph showing the dissolution profile of tofacitinib citrate tablets in acetate buffer at pH 4.5.
FIG. 4 is a graph showing the dissolution profile of tofacitinib citrate tablets in phosphate buffer at pH 6.8.
Detailed Description
The present invention will be described in detail below with reference to specific examples.
In all examples, the microcrystalline cellulose lactose premix type Celactose80 was prepared by mixing 75% lactose and 25% microcrystalline cellulose by spray drying, available from DeMus pharmaceutical excipients; the gastric-soluble film coating premix is purchased from Shanghai Carlekang coating technology Co.
Example 1
Table 1 formulation of example 1
| Species of | Name (R) | ％(w/w) |
| Raw material medicine | Tofacitinib citrate | 13.0 |
| Filler | Celactose80 | 78.1 |
| Disintegrating agent | Croscarmellose sodium | 4.9 |
| Glidants | Silicon dioxide | 1.0 |
| Coating agent | Gastric-soluble film coating premix | 3.0 |
The preparation method comprises the following steps:
1) weighing raw material medicines and auxiliary materials according to a proportion, and crushing tofacitinib citrate to obtain particles with the particle size of 10-30 mu m;
2) mixing tofacitinib citrate powder with microcrystalline cellulose lactose premix of Celactose80, adding croscarmellose sodium, and mixing; finally, adding silicon dioxide and mixing uniformly;
3) tabletting: controlling the environment temperature to be 15 ℃ and the humidity to be 60% during tabletting, and controlling the pressure of the tabletting machine to be 25 KN;
4) dissolving the gastric-soluble film coating premix with 60% ethanol, and coating the film coating by a spraying method.
Example 2
Table 2 formulation of example 2
| Species of | Name (R) | ％(w/w) |
| Raw material medicine | Tofacitinib citrate | 8.5 |
| Filler | Celactose80 | 81.3 |
| Disintegrating agent | Low-substituted hydroxypropyl cellulose | 4.3 |
| Glidants | Magnesium stearate | 1.9 |
| Coating agent | Gastric-soluble film coating premix | 4 |
The preparation method comprises the following steps:
1) weighing raw material medicines and auxiliary materials according to a proportion, and crushing tofacitinib citrate to obtain particles with the particle size of 40-60 mu m;
2) mixing tofacitinib citrate powder with microcrystalline cellulose lactose premix of Celactose80, adding low-substituted hydroxypropyl cellulose, and mixing; finally adding magnesium stearate and mixing uniformly;
3) tabletting: during tabletting, the environment temperature is controlled to be 20 ℃, the humidity is controlled to be 40%, and the pressure of the tabletting machine is 30 KN;
4) dissolving the gastric-soluble film coating premix with 50% ethanol, and coating the film coating by a spraying method.
Example 3
Table 3 formulation of example 3
| Species of | Name (R) | ％(w/w) |
| Raw material medicine | Tofacitinib citrate | 4.4 |
| Filler | Celactose80 | 87.2 |
| Disintegrating agent | Crosslinked polyvinylpyrrolidone | 2.8 |
| Glidants | Talcum powder | 1.1 |
| Coating agent | Gastric-soluble film coating premix | 4.5 |
The preparation method comprises the following steps:
1) weighing raw material medicines and auxiliary materials according to a proportion, and crushing tofacitinib citrate to obtain particles with the particle size of 70-90 mu m;
2) mixing tofacitinib citrate powder with microcrystalline cellulose lactose premix of Celactose80, adding cross-linked polyvinylpyrrolidone, and mixing; finally adding talcum powder and mixing uniformly;
3) tabletting: controlling the environment temperature to be 10 ℃, the humidity to be 50% and the pressure of the tablet press to be 28KN during tabletting;
4) dissolving the gastric-soluble film coating premix with 80% ethanol, and coating the film coating by a spraying method.
Example 4
Table 4 formulation of example 4
| Species of | Name (R) | ％(w/w) |
| Raw material medicine | Tofacitinib citrate | 3.7 |
| Filler | Celactose80 | 88.7 |
| Disintegrating agent | Sodium carboxymethyl starch | 4.6 |
| Glidants | Magnesium stearate | 0.5 |
| Coating agent | Gastric-soluble film coating premix | 2.5 |
The preparation method comprises the following steps:
1) weighing raw material medicines and auxiliary materials according to a proportion, and crushing tofacitinib citrate to obtain particles with the particle size of 40-60 mu m;
2) mixing tofacitinib citrate powder with microcrystalline cellulose lactose premix of Celactose80, adding sodium carboxymethyl starch, and mixing; finally adding magnesium stearate and mixing uniformly;
3) tabletting: during tabletting, the environment temperature is controlled to be 20 ℃, the humidity is controlled to be 60%, and the pressure of the tabletting machine is 26 KN;
4) dissolving the gastric-soluble film coating premix with 80% ethanol, and coating the film coating by a spraying method.
Comparative example 1
TABLE 5 recipe for comparative example 1
The preparation method comprises the following steps:
1) pulverizing tofacitinib citrate into fine powder, and sieving with 60 mesh sieve;
2) uniformly mixing tofacitinib citrate, microcrystalline cellulose, lactose and croscarmellose sodium;
3) adding a proper amount of purified water into hydroxypropyl cellulose to prepare a hydroxypropyl cellulose solution with the concentration of 5%, adding the hydroxypropyl cellulose solution into the mixture obtained in the step 2), preparing a soft material, granulating by using a 20-mesh sieve, drying at 60 ℃, grading by using the 20-mesh sieve, measuring the moisture by using a rapid moisture meter, and controlling the moisture to be below 3.0%;
4) adding magnesium stearate into the dried granules, and uniformly mixing;
5) tabletting;
6) dissolving the gastric-soluble water-type film coating premix with 80% ethanol, and then coating the film coating by adopting a spraying method.
Test example 1 dissolution comparative test
The test method comprises the following steps: dissolution determination method (Chinese pharmacopoeia 2010 edition two-part appendix XC second method)
The test conditions are as follows: dissolution medium: 0.1mol/L hydrochloric acid solution, purified water, pH4.5 acetate buffer solution, pH6.8 phosphate buffer solution
Dissolution volume: 500mL
Temperature: 37 deg.C
Rotating speed: 50rpm
The tablets obtained in examples 1 to 4 and the tablet obtained in comparative example 1 were subjected to dissolution comparison, as shown in FIGS. 1 to 4.
Test results show that the dissolution rate of the tablet of the invention reaches more than 90 percent within 5 minutes, and the dissolution rate is obviously higher than that of the comparative example 1.
Test example 2 content uniformity test
The determination method comprises the steps of taking 1 tofacitinib citrate tablet, placing the tofacitinib citrate tablet in a 50mL volumetric flask, adding an appropriate amount of acetonitrile-water (1:1), carrying out ultrasonic treatment for 15 minutes, shaking to dissolve the tofacitinib tablet, diluting the tofacitinib tablet to a scale with the solvent, and shaking up; precisely transferring 5mL of the solution into a 50mL volumetric flask, adding the solvent to dilute the solution to a scale, shaking the solution uniformly, and filtering the solution to obtain a test solution. Taking a proper amount of reference substances, precisely weighing, respectively measuring absorbance at 288nm wavelength according to a spectrophotometer method (appendix IV A of the second part of the 2010 edition of Chinese pharmacopoeia), and calculating the content of each tablet.
The content of tofacitinib citrate tablets obtained in example 1 and comparative example 1 was measured in 10 tablets each, and the results are shown in the following table.
Table 6 results for content uniformity of tablets obtained in example 1
TABLE 7 results for content uniformity of tablets obtained in comparative example 1
The above results show that the content uniformity of the tablet of example 1 is significantly better than that of comparative example 1. The content uniformity of the examples 2-4 is obviously better than that of the comparative example 1.
Test example 3 stability test
And (3) detection of related substances: the HPLC method is adopted for determination, and the measurement conditions are as follows: a chromatographic column: synergi 4 μ polar-RP80A, 250 × 4.6mm, mobile phase: phase A: 0.5% ammonium acetate solution, item B: acetonitrile; column temperature: 40 ℃; detection wavelength: 288 nm; flow rate: 1.0 mL/min; sample introduction amount: 20 μ L.
The tablets obtained in examples 1 to 4 and comparative example 1 were subjected to stability studies, and the data on the substances were compared as follows:
TABLE 8 comparison of the substances (day 0)
"/" indicates no detection
TABLE 9 comparison of the substances (10 days)
"/" indicates no detection
The above results show that the tablets obtained in examples 1 to 4 have lower contents of related substances than comparative example 1, and that the related substances are not significantly increased under the conditions of high temperature of 60 ℃, high humidity of 92.5% RH, high humidity of 75% RH and light irradiation, and the chemical properties are more stable than comparative example 1.
Regarding the crystal form of tofacitinib citrate, the X-ray powder diffraction method is specified in appendix IX F of the second part of the 2010 edition of Chinese pharmacopoeia, and the test conditions are as follows: the method comprises the following steps of copper target, graphite monochromator, tube voltage of 40kv, tube current of 100mA, divergence slit and anti-divergence slit which are all 1 ℃, acceptance slit of 0.3mm, scanning speed of 5 ℃/min and scanning range of 2-40 ℃.
The results of comparing the XRPD (2 theta value with peak relative intensity of more than 15%) of tofacitinib citrate tablets in examples 1-4 of the invention with that in comparative example 1 are shown in the table below.
TABLE 10XRPD comparison results
| Sample name | 2 theta value |
| Tofacitinib citrate | 13.6808,13.8552,15.5572,15.7503,17.1458,18.3393,25.7739,25.8823 |
| Example 1 | 13.6808,13.8552,15.5572,15.7503,17.1458,18.3393,25.7739,25.8823 |
| Example 2 | 13.6808,13.8552,15.5572,15.7503,17.1458,18.3393,25.7739,25.8823 |
| Example 3 | 13.6808,13.8552,15.5572,15.7503,17.1458,18.3393,25.7739,25.8823 |
| Example 4 | 13.6808,13.8552,15.5572,15.7503,17.1458,18.3393,25.7739,25.8823 |
| Comparative example 1 | 13.6808,15.5572,15.7503,17.1458,18.3393,25.7739,25.8823 |
XRPD comparison results show that the crystal forms of the main components in the tablets obtained in examples 1-4 are consistent with those of the bulk drugs.
Claims (8)
1. The tofacitinib citrate tablet consists of tofacitinib citrate and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise a filling agent, a disintegrating agent, a flow aid and a coating agent, and the tofacitinib citrate tablet is characterized in that: the filler is a microcrystalline cellulose lactose premix with the type Celactose80, and the weight ratio of the tofacitinib citrate to the microcrystalline cellulose lactose premix with the type Celactose80 is 1: 5-25.
2. The tofacitinib citrate tablet according to claim 1, wherein: the weight ratio of the tofacitinib citrate to the microcrystalline cellulose lactose premix with the type Celactose80 is 1: 10-20.
3. The tofacitinib citrate tablet according to claim 1, wherein: the disintegrating agent is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, and accounts for 2.5-5% of the weight of the tablet.
4. The tofacitinib citrate tablet according to claim 1, wherein: the glidant is one or more of calcium stearate, magnesium stearate, silicon dioxide and talcum powder, and accounts for 0.5-2% of the weight of the tablet.
5. The tofacitinib citrate tablet according to claim 1, wherein: the coating agent is a film coating agent, and the film coating agent accounts for 2-5% of the weight of the tablet.
6. A method for preparing tofacitinib citrate tablets as claimed in any one of claims 1 to 5, characterized by comprising the following steps:
1) crushing tofacitinib citrate to a particle size of 10-100 microns;
2) mixing tofacitinib citrate and microcrystalline cellulose lactose premix of Celactose80, adding disintegrating agent, and mixing; finally adding the glidant and mixing uniformly;
3) tabletting;
4) dissolving the coating agent by using 50-80% ethanol, and then coating the film coating by using a spraying method.
7. The method of claim 6, wherein: in the step 1), tofacitinib citrate is crushed to a particle size of 40-60 microns.
8. The method of claim 6, wherein: in the step 3), the environmental temperature is controlled to be 10-20 ℃, the humidity is less than or equal to 60% and the pressure of the tablet press is 25-30 KN during tabletting.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106370757A (en) * | 2016-11-16 | 2017-02-01 | 杭州朱养心药业有限公司 | Tofacitinib citrate tablet pharmaceutical composition and quality control method |
| CN106389371A (en) * | 2016-11-16 | 2017-02-15 | 杭州朱养心药业有限公司 | Tofacitinib citrate pharmaceutical composition |
| CN106420648A (en) * | 2016-11-22 | 2017-02-22 | 山东淄博新达制药有限公司 | Tofacitinib citrate tablet and preparation method thereof |
| CN107441054A (en) * | 2017-08-24 | 2017-12-08 | 福建省微生物研究所 | A kind of tropsch imatinib tablet and preparation method thereof |
| CN110946834A (en) * | 2018-09-27 | 2020-04-03 | 四川科伦药物研究院有限公司 | Tofacitinib citrate tablet and preparation process thereof |
| CN111358795A (en) * | 2018-12-26 | 2020-07-03 | 浙江万晟药业有限公司 | Tofacitinib citrate preparation and preparation method thereof |
| CN112007004A (en) * | 2020-09-17 | 2020-12-01 | 山东鲁抗医药股份有限公司 | Tofacitinib citrate tablet and preparation method thereof |
| WO2021129735A1 (en) | 2019-12-25 | 2021-07-01 | 上海宣泰医药科技股份有限公司 | Solid preparation, and preparation method therefor and use thereof |
| CN113081992A (en) * | 2020-01-09 | 2021-07-09 | 南京正大天晴制药有限公司 | JAK kinase inhibitor tablet and preparation method thereof |
| CN116650414A (en) * | 2023-07-26 | 2023-08-29 | 北京凯莱天成医药科技有限公司 | Tofacitinib citrate oral solution and preparation method thereof |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106370757A (en) * | 2016-11-16 | 2017-02-01 | 杭州朱养心药业有限公司 | Tofacitinib citrate tablet pharmaceutical composition and quality control method |
| CN106389371A (en) * | 2016-11-16 | 2017-02-15 | 杭州朱养心药业有限公司 | Tofacitinib citrate pharmaceutical composition |
| CN106389371B (en) * | 2016-11-16 | 2019-03-15 | 杭州朱养心药业有限公司 | tofacitinib citrate pharmaceutical composition |
| CN106420648A (en) * | 2016-11-22 | 2017-02-22 | 山东淄博新达制药有限公司 | Tofacitinib citrate tablet and preparation method thereof |
| CN107441054A (en) * | 2017-08-24 | 2017-12-08 | 福建省微生物研究所 | A kind of tropsch imatinib tablet and preparation method thereof |
| CN110946834A (en) * | 2018-09-27 | 2020-04-03 | 四川科伦药物研究院有限公司 | Tofacitinib citrate tablet and preparation process thereof |
| CN111358795A (en) * | 2018-12-26 | 2020-07-03 | 浙江万晟药业有限公司 | Tofacitinib citrate preparation and preparation method thereof |
| WO2021129735A1 (en) | 2019-12-25 | 2021-07-01 | 上海宣泰医药科技股份有限公司 | Solid preparation, and preparation method therefor and use thereof |
| CN113081992A (en) * | 2020-01-09 | 2021-07-09 | 南京正大天晴制药有限公司 | JAK kinase inhibitor tablet and preparation method thereof |
| CN113081992B (en) * | 2020-01-09 | 2022-10-18 | 南京正大天晴制药有限公司 | JAK kinase inhibitor tablet and preparation method thereof |
| CN112007004A (en) * | 2020-09-17 | 2020-12-01 | 山东鲁抗医药股份有限公司 | Tofacitinib citrate tablet and preparation method thereof |
| CN116650414A (en) * | 2023-07-26 | 2023-08-29 | 北京凯莱天成医药科技有限公司 | Tofacitinib citrate oral solution and preparation method thereof |
| CN116650414B (en) * | 2023-07-26 | 2023-11-03 | 北京凯莱天成医药科技有限公司 | Tofacitinib citrate oral solution and preparation method thereof |
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Effective date of registration: 20170320 Address after: 430205 East Lake New Technology Development Zone, Wuhan Province, the south of the Yellow Dragon Road, No. section of the benefits of Industrial Park, No. 8 Applicant after: Hubei Liyi Medicine Sci-Tech Co., Ltd. Applicant after: Hubei Keyi Pharmaceutic Co., Ltd. Address before: 430205 East Lake New Technology Development Zone, Wuhan Province, the south of the Yellow Dragon Road, No. section of the benefits of Industrial Park, No. 8 Applicant before: Hubei Liyi Medicine Sci-Tech Co., Ltd. |
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Application publication date: 20160824 |