CN115068422B - Lamotrigine wet suspension and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a lamotrigine wet suspension and a preparation method and application thereof, wherein the wet suspension comprises a lamotrigine raw material drug, a suspending agent, a wetting agent, a sweetening agent, a flavoring agent, a pH regulator, an antioxidant, a preservative and the balance of water, the lamotrigine raw material drug is selected from a mixture of a lamotrigine monohydrate crystal form A and a lamotrigine monohydrate crystal form H, and the lamotrigine monohydrate crystal form A accounts for 30-70% of the molar weight of the mixture. The lamotrigine suspension provided by the invention can realize the technical effects of reducing bitter taste and slowing down the agglomeration of particles of the raw material medicine, and is convenient to use and good in stability compared with the existing product in the prior art.
Description
Technical Field
The invention belongs to the field of suspensions, and particularly relates to a lamotrigine wet suspension as well as a preparation method and application thereof.
Background
Lamotrigine (Lamotrigine) is a phenyl triazine antiepileptic drug, can selectively inhibit depolarization and high-frequency discharge of neurons in epileptic foci while not influencing normal electrophysiological processes of the neurons, stabilize presynaptic membranes of the neurons and inhibit glutamate, thereby playing an antiepileptic role, and the action mechanism of the Lamotrigine can generate the antiepileptic role by inhibiting the release of excitatory amino acids, namely glutamic acid and aspartic acid, in the brain.
The lamotrigine has the chemical name of 3,5-diamino-6- (2,3-dichlorophenyl) -triazine and the molecular formula of C 9 H 7 N 5 Cl 2 Molecular weight is 256.09. The lamotrigine bulk drug is white to light butter powder, and the pKa of the lamotrigine bulk drug is 5.7; slightly soluble in water (0.17 mg/mL at 25 ℃), slightly soluble in 0.1M HCl (4.1 mg/mL at 25 ℃), and having the formula:
commercially available lamotrigines include 25 mg, 50 mg, 100mg and 200 mg-sized orally disintegrating tablets and 25 mg, 50 mg, 100mg, 200 mg, 250 mg and 300 mg-sized sustained release tablets, with low dose specifications typically given to pediatric patients. Many patients, particularly elderly and pediatric patients, experience difficulty in swallowing or chewing tablet dosage forms. For these patients, it is considered that the method of pulverizing the tablet to form powder and mixing the powder with the solution is administered to the patient, and such a temporary preparation is expedient because the auxiliary material and the raw material in the tablet are often agglomerated and rapidly settled in the solution after being mixed with water, resulting in inaccurate dosage, which may cause immeasurable damage to the patient. Oral solutions are a common dosage form for elderly and paediatric patients, but lamotrigine has very low solubility in water and its solution is very bitter, requiring the addition of large amounts of solubilizers, sweeteners and flavors, which also poses great difficulties for the preparation of palatable oral solutions, see in particular patent applications cna 10288845.X and CN201510350210.8.
In order to solve the technical problem, the patent ZL201611175342.2 discloses a dry suspension which can be prepared by pharmacists or parents of patients or other adults according to the requirements of the instruction and is prepared into a liquid suspension with specific concentration, preferably 10mg/ml, by using water for oral administration of patients. The volume of the medicine taken by the patient at this time is calculated according to a table of the relationship between the weight of the patient and the dosage of the medicine taken by the patient on the specification, and the suspension with the accurate volume is sucked by using a matched oral administration device and is directly administered into the mouth of the patient. The dry suspension just solves part of the problems because the patient still needs to prepare the dry suspension and water into wet suspension before using the dry suspension, and the dry suspension cannot be directly used. The raw material medicine and proper auxiliary materials are mixed to prepare the wet suspension with stable quality, so that the technical problems that the raw material medicine particles commonly existing in the conventional wet suspension are easy to agglomerate and settle, and the uniformly dispersed suspension is not easy to form again due to violent shaking after settlement are solved, and the medication compliance of patients is undoubtedly improved.
Disclosure of Invention
The invention mainly aims to provide a novel lamotrigine wet suspension, which overcomes the technical problem of low drug-loading rate of an oral solution caused by low solubility of raw material medicines, and also overcomes the technical problems of inconvenient use of a dry suspension and the technical problems of instability, easy sedimentation and agglomeration, difficult re-suspension and the like of the wet suspension in the prior art.
In order to realize the purpose, the invention adopts the technical scheme that:
provided is a lamotrigine wet suspension comprising lamotrigine drug substance, suspending agent, wetting agent, sweetener, flavoring agent, pH regulator, antioxidant, preservative and the balance of water, characterized in that the lamotrigine drug substance is selected from the mixture of lamotrigine monohydrate crystal form A and lamotrigine monohydrate crystal form H, the lamotrigine monohydrate crystal form A is 35-65% (molar ratio), preferably 40-60% (molar ratio), more preferably 50% (molar ratio) of the lamotrigine drug substance.
And the XRPD spectrum of lamotrigine monohydrate form a includes characteristic peaks at diffraction angles (2 θ) of 11.4, 13.2, 14.8, 16.3, 18.9, 22.2, 22.9, 23.2, 24.8, 25.1, 26.2, 27.6, 28.4, 29.1, 29.7, 30.2, 31.2, 33.1, 34.3, 35.5, 36.1, 39.7, and 48.9 degrees; the XRPD spectrum of lamotrigine monoethanol hydrate form H comprises characteristic peaks at diffraction angles (2 θ) of 9.6, 10.5, 12.2, 13.5, 14.7, 15.1, 16.5, 16.7, 17.0, 18.5, 19.5, 20.5, 21.8, 22.2, 24.0, 24.6, 25.7, 26.3, 27.5, 28.4, 28.9, 29.4, 30.5, 31.1, 31.8, 33.3, and 35.1 degrees; the 2 theta values of the present invention allow for a measurement error of + -0.2.
Preferably, the particle size (D90) of lamotrigine monohydrate form a and lamotrigine monoethanol hydrate form H of the present invention is from about 1 to 30 μm, preferably from 4 to 20 μm, more preferably from 8 to 12 μm.
Preferably, the suspending agent of the present invention is selected from hydrocolloids, such as xanthan gum, guar gum, locust bean gum and carrageenan; cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose and hydroxypropyl methyl cellulose; polysaccharides such as starch and pregelatinized starch; alginates, such as sodium alginate; acrylic acid copolymers, such as carbomer; and combinations thereof;
preferably, the suspending agent is selected from xanthan gum, povidone, colloidal microcrystalline cellulose, sodium alginate, and combinations thereof;
preferably, the suspending agent is selected from sodium carboxymethylcellulose; and preferably, the suspending agent is about 0.25 to 1 part by weight, preferably about 0.3 to 0.8 part by weight, preferably about 0.4 to 0.6 part by weight, and most preferably 0.5 part by weight, based on about 10 parts by weight of lamotrigine.
Preferably, the wetting agent is selected from polysorbate, preferably polysorbate-80 or polysorbate-60; the wetting agent is present in an amount of about 0.5 to 2 parts by weight, preferably 0.6 to 1.2 parts by weight, and most preferably 1 part by weight, based on about 10 parts by weight of lamotrigine.
Preferably, the sweetener is selected from one or more of sucralose, aspartame and saccharin sodium, and preferably, the sweetener is about 0.5 to 3 parts by weight, preferably 0.8 to 2 parts by weight, based on about 10 parts by weight of the lamotrigine.
Preferably, the flavoring agent is selected from one or more of strawberry flavor, banana flavor, sweet orange flavor and mint flavor, and preferably, the flavoring agent is about 0.5 to 3 parts by weight, preferably 0.8 to 2 parts by weight, based on about 10 parts by weight of lamotrigine.
Preferably, the pH regulator is one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid and sodium citrate; and preferably, the pH adjusting agent is about 2 to 5 parts by weight based on about 10 parts by weight of the lamotrigine; it is further preferred that the disodium hydrogen phosphate is 1 to 2 parts by weight and the citric acid is 2 to 3 parts by weight, based on about 10 parts by weight of the lamotrigine.
Preferably, the preservative is selected from one or more of sodium hydroxy phenyl benzoate, sodium hydroxy benzoate, sodium benzoate and potassium sorbate, and preferably, the preservative is about 1-3 parts by weight based on about 10 parts by weight of the lamotrigine.
Preferably, the antioxidant is selected from one or more of sodium citrate, sodium sulfite, sodium bisulfite, lycopene, procyanidins, ascorbic acid, vitamin E and sodium thiosulfate; and preferably, the preservative is about 0.5 to 2 parts by weight based on about 10 parts by weight of the lamotrigine.
Preferably, the wet suspension of the invention has a relative amount of lamotrigine to the wet suspension of 8-12mg/ml, preferably 10mg/ml, calculated as lamotrigine.
The invention further provides a preparation method of the lamotrigine quick-release preparation, which comprises the following steps of micronizing the lamotrigine monohydrate crystal form A and the lamotrigine monoethanol complex crystal form H; weighing lamotrigine monohydrate crystal form A and lamotrigine monoethanol hydrate crystal form H, a suspending agent, a wetting agent, a sweetening agent, a flavoring agent, a pH regulator, an antioxidant and a preservative according to a material ratio for later use; adding suspending agent, wetting agent, sweetener, correctant, pH regulator, antioxidant and antiseptic into partial water at room temperature, stirring, adding micronized lamotrigine monohydrate crystal form A and lamotrigine monoethanol hydrate crystal form H and the rest water, and stirring.
The lamotrigine monohydrate crystal form a of the present invention is prepared by referring to the method of WO2005003104A2 of the prior art, specifically, see page 13, example 3; the lamotrigine monoethanol hydrate crystal form H is prepared by a method which refers to WO2002068398A1 in the prior art, and can be specifically referred to page 27-28 as example 16.
Compared with the prior art, the invention has the following beneficial effects:
the wet suspension prepared by the invention shows satisfactory pourability, stability, resuspendability and redispersibility, and meets the technical requirements of medical supervision departments on suspension preparations;
the wet suspension prepared by the invention is an oral liquid suspension, active ingredients are only slightly dissolved in a solvent, the proportion of the dissolved bulk drugs is low, the bitterness is small, and the bitterness of the bulk drugs can be shielded by adding a small amount of sweetening agents and flavoring agents, so that the wet suspension is suitable for children and dysphagia patients; can be rapidly dissolved in digestive tract and gradually absorbed after oral administration.
The wet suspension prepared by the invention overcomes the technical problem of low drug-loading rate of oral solution, and multiple doses of suspension are convenient for a patient to use for multiple times, thereby avoiding the trouble of preparation before each administration and improving the compliance of the patient in use. Suspensions of different sizes also facilitate dispensing of the drug product by the physician, and in contrast to single dose suspensions, multiple doses of the suspension can be taken on a dose basis specifically required for each dose, thereby avoiding excessive waste. The forms a and H obtained by this method are defined.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Lamotrigine monohydrate form a is prepared by referring to the method of WO2005003104A2 of the prior art, and in particular, see page 13, example 3:
a mixture of lamotrigine (200 g), isopropanol (2.2L) and water (0.6L) was stirred at 80-85 ℃ for 4-6h to obtain a clear homogeneous solution. Activated carbon (10 g) was added and stirred at the same temperature for another 30 minutes. The mixture was filtered hot and the filtrate was cooled to 10 ℃. The obtained white crystals of lamotrigine were collected by filtration, washed with isopropyl alcohol (IPA), and dried at 50 ℃ to provide lamotrigine monohydrate of high purity.
The lamotrigine monoethanol hydrate crystal form H is prepared by a method referring to WO2002068398A1 in the prior art, and can be specifically referred to page 27-28 as example 16:
a three-necked round bottom flask equipped with a mechanical stirrer, condenser and thermometer was charged with about 200 grams of anhydrous lamotrigine and about 8 liters of ethanol. The suspension was stirred for an additional about 24 hours at about 25 ℃ and then the solid and liquid phases were separated by filtration to yield lamotrigine monoethanol complex form H.
General preparation examples of lamotrigine wet suspensions of the present invention:
micronizing said lamotrigine monohydrate form a and lamotrigine monoethanol complex form H to 12 μm (D90); weighing lamotrigine monohydrate crystal form A and lamotrigine monoethanol hydrate crystal form H, a suspending agent, a wetting agent, a sweetening agent, a flavoring agent, a pH regulator, an antioxidant and a preservative according to a material ratio for later use; adding suspending agent, wetting agent, sweetener, correctant, pH regulator, antioxidant and antiseptic into part of water (20% of total amount) at room temperature, stirring, adding micronized lamotrigine monohydrate crystal form A and lamotrigine monoethanol hydrate crystal form H and the rest water, and stirring.
Specific examples (100 mg scale, table 1)
| Material(s) | Example 1 | Example 2 | Example 3 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 |
| Lamotrigine monohydrate form a | 42.8mg | 53.5mg | 64.2mg | 107.0mg | 0mg | 107.0mg | 0mg |
| Lamotrigine monoethanol complex form H | 70.8mg | 59.0mg | 47.2mg | 0mg | 118.0mg | 0mg | 118.0mg |
| Sodium carboxymethylcellulose | 5mg | 5mg | 5mg | 5mg | 5mg | 5mg | 0mg |
| Polysorbate-80 | 10mg | 10mg | 10mg | 10mg | 10mg | 0mg | 10mg |
| Sucralose | 10 mg | 10mg | 10mg | 10 mg | 10 mg | 10 mg | 10mg |
| Orange essence | 10 mg | 10mg | 10mg | 10 mg | 10mg | 10 mg | 10mg |
| Disodium hydrogen phosphate | 15 mg | 15 mg | 15mg | 15 mg | 15mg | 15 mg | 15mg |
| Citric acid | 25 mg | 25mg | 25mg | 25mg | 25mg | 25mg | 25mg |
| Hydroxy phenylpropyl ester sodium salt | 2mg | 2mg | 2mg | 2mg | 2mg | 2mg | 2mg |
| Sodium hydroxybenzene methyl ester | 20mg | 20mg | 20mg | 20mg | 20mg | 20mg | 20mg |
| Sodium thiosulfate | 10mg | 10mg | 10mg | 10mg | 10mg | 10mg | 10mg |
| The balance of water | To 10 ml | To 10 ml | To 10 ml | To 10 ml | To 10 ml | To 10 ml | To 10 ml |
The lamotrigine monohydrate crystal form A + lamotrigine monoethanol hydrate crystal form H is reduced to 100mg lamotrigine
Test example 1: and (3) particle size distribution determination:
the lamotrigine wet suspensions obtained in examples 1 to 3 and comparative examples 1 to 4 were left for 3 months under accelerated test conditions (temperature 40 ℃. + -. 2 ℃, relative humidity 75% RH. + -.5 RH), the wet suspension was suction-filtered with a Buchner funnel, and the water-soluble deposit on the surface of the solid was washed with purified water, and the resulting solid was dried at room temperature; the particle size (D90) of the sample was measured by a laser diffraction scattering method using a Japanese Shimadzu laser diffraction type particle size distribution measuring apparatus SALD-2300, and the results are shown in Table 2:
table 2:
| type A ratio | H type ratio | 0 month | 3 months old | |
| Example 1 | 40% | 60% | 12μm | 16μm |
| Example 2 | 50% | 50% | 12μm | 14μm |
| Example 3 | 60% | 40% | 12μm | 19μm |
| Comparative example 1 | 100% | 0% | 12μm | 59μm |
| Comparative example 2 | 0% | 100% | 12μm | 73μm |
| Comparative example 3 | 100% | 0% | 12μm | 159μm |
| Comparative example 4 | 0% | 100% | 12μm | 233μm |
The above data indicate that the particle size of the combination of form a and form H increases more slowly in the wet suspension, which means that the wet suspension prepared by the present invention is more stable, because the rapid increase of the particles in the suspension will result in the increase of the sedimentation of the bulk drug and the difficulty of resuspension by means of shaking, etc.
Test example 2: stability analysis
Taking a sample obtained by the steps of suction filtration, drying and the like after the test example 1 is placed for 3 months under an accelerated condition, dissolving the sample by using methanol or acetonitrile, detecting the relative content of lamotrigine relative to the initial (0 month) time point by using an HPLC (internal standard method), and carrying out chromatographic column: YMC-Pack ODS C 18 150. X 4.6mm,5 μm, ultraviolet detector. See table 3 for results:
TABLE 3
| Example 1 | Example 2 | Example 3 | Comparative example 1 | Comparative example 1 | Comparative example 1 | Comparative example 1 | |
| Relative content | 99.96% | 99.95% | 99.97% | 99.93% | 99.97% | 99.94% | 99.92% |
The data show that the auxiliary material has good compatibility with the raw material medicine, and especially the existence of the antioxidant and the preservative can effectively protect the raw material medicine and prevent the raw material medicine from oxidative deterioration.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (14)
1. A lamotrigine wet suspension, the wet suspension comprises a lamotrigine bulk drug, a suspending agent, a wetting agent, a sweetener, a flavoring agent, a pH regulator, an antioxidant, a preservative and the balance of water, and is characterized in that the lamotrigine bulk drug is selected from a mixture of a lamotrigine monohydrate crystal form A and a lamotrigine monoethanol hydrate crystal form H, wherein the lamotrigine monohydrate crystal form A is 35-65% of the molar amount of the lamotrigine bulk drug;
and the XRPD spectrum of lamotrigine monohydrate form a includes characteristic peaks at diffraction angles (2 θ) of 11.4, 13.2, 14.8, 16.3, 18.9, 22.2, 22.9, 23.2, 24.8, 25.1, 26.2, 27.6, 28.4, 29.1, 29.7, 30.2, 31.2, 33.1, 34.3, 35.5, 36.1, 39.7, and 48.9 degrees; the XRPD spectrum of lamotrigine monoethanol hydrate form H includes characteristic peaks at diffraction angles (2 θ) of 9.6, 10.5, 12.2, 13.5, 14.7, 15.1, 16.5, 16.7, 17.0, 18.5, 19.5, 20.5, 21.8, 22.2, 24.0, 24.6, 25.7, 26.3, 27.5, 28.4, 28.9, 29.4, 30.5, 31.1, 31.8, 33.3, and 35.1 degrees.
2. Lamotrigine wet suspension according to claim 1 characterized in that the particle size D90 of lamotrigine monohydrate form a and lamotrigine monoethanol hydrate form H is from 1 to 30 μm.
3. Lamotrigine wet suspension according to claim 1, characterized in that said suspending agent is selected from the group consisting of hydrocolloids, cellulose derivatives, polysaccharides, acrylic copolymers and combinations thereof; wherein the cellulose derivatives are selected from sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose or hydroxypropyl methylcellulose.
4. Lamotrigine wet suspension according to claim 1, characterized in that said suspending agent is selected from alginates.
5. Lamotrigine wet suspension according to claim 3, characterized in that the hydrocolloid suspending agent is selected from xanthan gum, guar gum, locust bean gum or carrageenan; the polysaccharide suspending agent is selected from starch or pregelatinized starch; the acrylic acid copolymer is selected from carbomers.
6. Lamotrigine wet suspension according to claim 4, characterized in that said alginate suspending agent is selected from sodium alginate.
7. The lamotrigine wet suspension according to claim 3 wherein said suspending agent is selected from the group consisting of sodium carboxymethylcellulose, xanthan gum, povidone, colloidal microcrystalline cellulose, sodium alginate and combinations thereof.
8. Lamotrigine wet suspension according to claim 1, characterized in that the suspending agent is 0.25-1 parts by weight based on 10 parts by weight of lamotrigine.
9. Lamotrigine wet suspension according to claim 1, characterized in that said wetting agent is selected from polysorbates, in an amount of 0.5-2 parts by weight based on 10 parts by weight of lamotrigine.
10. Lamotrigine wet suspension according to claim 1, characterized in that said sweetening agent is selected from the group consisting of sucralose, aspartame, sodium saccharin in combination of one or more of 0.5 to 3 parts by weight based on 10 parts by weight of said lamotrigine.
11. Lamotrigine wet suspension according to claim 1, wherein said flavoring agent is selected from one or more of strawberry flavor, banana flavor, sweet orange flavor, mint flavor in an amount of 0.5-3 parts by weight based on 10 parts by weight of lamotrigine.
12. Lamotrigine wet suspension according to claim 1, characterized in that the pH adjusting agent is one or a combination of more of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, 2-5 parts by weight based on 10 parts by weight of lamotrigine.
13. Lamotrigine wet suspension according to claim 1, characterized in that the preservative is selected from the group consisting of sodium hydroxy-phenylpropionate, sodium hydroxy-benzoate, sodium benzoate, potassium sorbate in one or more combinations thereof, in an amount of 1 to 3 parts by weight based on 10 parts by weight of lamotrigine.
14. Lamotrigine wet suspension according to claim 1, characterized in that said antioxidant is selected from one or more of sodium citrate, sodium sulfite, sodium bisulfite, lycopene, procyanidins, ascorbic acid, vitamin E, sodium thiosulfate; the preservative is 0.5-2 parts by weight based on 10 parts by weight of lamotrigine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210997297.8A CN115068422B (en) | 2022-08-19 | 2022-08-19 | Lamotrigine wet suspension and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210997297.8A CN115068422B (en) | 2022-08-19 | 2022-08-19 | Lamotrigine wet suspension and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115068422A CN115068422A (en) | 2022-09-20 |
| CN115068422B true CN115068422B (en) | 2022-11-29 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002068398A1 (en) * | 2001-02-27 | 2002-09-06 | Teva Pharmaceutical Industries Ltd. | New crystal forms of lamotrigine and processes for their preparations |
| WO2005003104A2 (en) * | 2003-07-03 | 2005-01-13 | Jubilant Organosys Limited | Crystalline forms of lamotrigine monohydrate and anhydrous lamotrigine and a process for their preparation |
| US20090176787A1 (en) * | 2007-11-09 | 2009-07-09 | Thar Pharmaceuticals | Crystalline Forms of lamotrigine |
| CN106491539A (en) * | 2016-12-19 | 2017-03-15 | 上海奥科达生物医药科技有限公司 | A kind of lamotrigine dry suspension and preparation method thereof |
| CN113214177A (en) * | 2021-04-16 | 2021-08-06 | 上海奥科达生物医药科技有限公司 | Crystal form of lamotrigine hydrate, preparation method thereof and composition containing crystal form |
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2022
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002068398A1 (en) * | 2001-02-27 | 2002-09-06 | Teva Pharmaceutical Industries Ltd. | New crystal forms of lamotrigine and processes for their preparations |
| WO2005003104A2 (en) * | 2003-07-03 | 2005-01-13 | Jubilant Organosys Limited | Crystalline forms of lamotrigine monohydrate and anhydrous lamotrigine and a process for their preparation |
| US20090176787A1 (en) * | 2007-11-09 | 2009-07-09 | Thar Pharmaceuticals | Crystalline Forms of lamotrigine |
| CN106491539A (en) * | 2016-12-19 | 2017-03-15 | 上海奥科达生物医药科技有限公司 | A kind of lamotrigine dry suspension and preparation method thereof |
| CN113214177A (en) * | 2021-04-16 | 2021-08-06 | 上海奥科达生物医药科技有限公司 | Crystal form of lamotrigine hydrate, preparation method thereof and composition containing crystal form |
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| CN115068422A (en) | 2022-09-20 |
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Address after: No. 10, Lane 100, Banxia Road, Pudong New Area, Shanghai 200120 Patentee after: Shanghai Aokeda Pharmaceutical Technology Co.,Ltd. Address before: No. 10, Lane 100, Banxia Road, Pudong New Area, Shanghai 200120 Patentee before: SHANGHAI AUCTA PHARMACEUTICALS Co.,Ltd. |
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