CN102000325A - Pramlintide buccal tablets and preparation method thereof - Google Patents
Pramlintide buccal tablets and preparation method thereof Download PDFInfo
- Publication number
- CN102000325A CN102000325A CN 201010539878 CN201010539878A CN102000325A CN 102000325 A CN102000325 A CN 102000325A CN 201010539878 CN201010539878 CN 201010539878 CN 201010539878 A CN201010539878 A CN 201010539878A CN 102000325 A CN102000325 A CN 102000325A
- Authority
- CN
- China
- Prior art keywords
- pramlintide
- parts
- agent
- sodium
- buccal tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000011229 interlayer Substances 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009955 starching Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides pramlintide buccal tablets and a preparation method thereof. The pramlintide buccal tablets are mainly prepared from the following raw materials in part by weight: 0.1 to 20 parts of pramlintide, 40 to 99.8 parts of filler, 0.1 to 30 parts of stabilizer, 0.1 to 5 parts of lubricant, 0 to 30 parts of absorbefacient, 0 to 20 parts of taste modifier and 0.01 to 20 parts of PH buffer. The invention has the advantage of providing the pramlintide buccal tablets and the preparation method thereof; and the pramlintide buccal tablets have the good effect of treating type I diabetes mellitus, type II diabetes mellitus and obesity, and are good in the stability of active ingredients, convenient to take, and easy to be absorbed by the buccal mucous membrane.
Description
(1) technical field
The present invention relates to a kind of Pramlintide buccal tablet and preparation method thereof.
(2) background technology
Pramlintide (Pramlintide) is the peptide drug of treatment diabetes and obesity.Developed the injection dosage form by California, USA Santiago Amylin drugmaker at present, gone on the market by drugs approved by FDA, treated a type and type-II diabetes, and the curative effect of obvious treatment obesity has been arranged simultaneously.Pramlintide (Pramlintide) is 37 amino acid polypeptides, and its aminoacid sequence is as follows:
Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr-NH
2
This injection dosage form and insulin are with using, or it is private, to control a type and type-II diabetes patient's blood sugar level, its main mechanism is: (1) has delayed gastric emptying (for example food is discharged into the speed of small intestinal from stomach), does not but change all nutraceutical absorptions; (2) secretion of glucagon suppression, thus suppressed from the generation of the next endogenous blood glucose of liver; (3) the pancreas opsonin can also be regulated the picked-up of controlling food by the stomach maincenter.
This medicine needs the patient to take all the life, and every day 2～3 times, the Pramlintide of using clinically all is injections at present, and patient's life-time service is very inconvenient, and costs an arm and a leg.And peroral dosage form has following obstacle technically: the pepsin Pramlintide of easily degrading; The intestinal protease Pramlintide of under alkali condition, also will degrading; Pramlintide has the intestinal absorption obstacle.
Chinese invention patent application number 200810010894.7 discloses a kind of technology of preparing of novel oral capsule preparation of Pramlintide, though solved the above-mentioned obstacle of peroral dosage form, exists the preparation process more complicated, the cost problem of higher.
(3) summary of the invention
The purpose of this invention is to provide a kind of pharmaceutical preparation that comprises Pramlintide that absorbs by buccal, it can well keep the active component of Pramlintide and reach the effect of treatment I type, type ii diabetes and obesity by the absorption of oral mucosa, the similar therapeutical effect of its injection dosage form is not only arranged, also have easy to use, easily accepted by the patient and advantage such as low price.
The technical solution used in the present invention is:
A kind of Pramlintide buccal tablet is that primary raw material is made with quality component composed as follows:
0.1～20 part of Pramlintide
40～99.8 parts of filleies
0.1～30 part of stabilizing agent
0.1～5 part of lubricant
0～30 part of absorption enhancer
0.1～10 part of disintegrating agent
0～20 part of taste modifying agent
0.01～20 part of pH buffer agent;
Above-mentioned raw materials is the primary raw material of preparation Pramlintide buccal tablet, does not comprise the water equal solvent of using in the preparation process.
The effect of filler is dilution and absorbs Pramlintide, is convenient to bind compression molding and is easy to melt in the oral cavity, can be one of following or wherein two or more mixing: mannitol, Icing Sugar, microcrystalline Cellulose, gelatin, soluble starch, sodium carboxymethyl cellulose;
Function of stabilizer is to be used for protecting Pramlintide stable existence and to avoid it to reduce active in the medicine storage life, can be one of following or wherein two or more mixing: lysine, arginine, glycine, hetastarch, hydroxymethyl starch, sorbitol, glucosan;
The effect of lubricant is the adjuvant that reduces frictional force between granule and die wall, makes the tabletting difficulty to prevent that frictional force is big, can be one of following or wherein two or more mixing: stearic acid, magnesium stearate, Pulvis Talci, leucine;
The effect of absorption enhancer is to promote the absorption of Pramlintide in oral mucosa, suppress the oral mucosa endoenzyme, prevent Pramlintide by enzyme hydrolysis in the oral mucosa, can be one of following or wherein two or more mixing: sodium laurylsulfate, sodium deoxycholate, aprotinin, propylene glycol, azone, menthol, NaGC, sodium salicylate; When being 0, content represents not contain in the raw material this composition.
The effect of disintegrating agent is to promote the release of Pramlintide in the oral cavity, can be one of following or wherein two or more mixing: sodium carboxymethyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose;
The effect of taste modifying agent is to improve the taste of pharmaceutical preparation when containing so that the patient is happy accepts and use, and can be one of following or wherein two or more mixing: menthol, Borneolum Syntheticum, cyclamate, glycyrrhizin, citric acid; When being 0, content represents not contain in the raw material this composition.
The purpose of pH buffer agent is that the pH after regulating buccal tablet and dissolve in the oral cavity changes, is convenient to the happy acceptance of patient, can be one of following or wherein two or more mixing: acetate, phosphate, hydrochlorate (being chloride), citrate or acetic acid etc.;
The present invention makes buccal tablet with Pramlintide, makes it be easy under the effect of saliva of buccal cavity dissolving and discharges Pramlintide and absorb by oral mucosa.
Preferably, described Pramlintide buccal tablet is that primary raw material is made with quality component composed as follows:
0.3～5 part of Pramlintide
50～70 parts of filleies
0.3～3 part of stabilizing agent
0.3～1 part of lubricant
1～10 part of absorption enhancer
0.5～5 part of disintegrating agent
0.1～5 part of taste modifying agent
0.03～10 part of pH buffer agent.
Preferably, described Pramlintide buccal tablet is that primary raw material is made with quality component composed as follows:
0.3～5 part of Pramlintide
10～30 parts in mannitol
10～20 parts of soluble starches
5～15 parts in gelatin
0.2～0.5 part of glucosan
0.5～1 part of leucine
2～3 parts of carboxymethyl starch sodium
0.05～0.1 part of sodium acetate
0.05～2 part of acetic acid
0.01～0.05 part in sodium chloride.
More preferred, described Pramlintide buccal tablet is that primary raw material is made with quality component composed as follows:
0.5 part of Pramlintide
20 parts in mannitol (filler)
17.5 parts of soluble starches (filler)
9.5 parts in gelatin (filler)
0.25 part of glucosan (stabilizing agent)
1 part of leucine (lubricant)
2.5 parts of carboxymethyl starch sodium (disintegrating agent)
0.09 part of sodium acetate (pH buffer agent).
0.1 part of acetic acid (pH buffer agent)
0.045 part in sodium chloride (pH buffer agent).
Should be noted that absorption enhancer in the Pramlintide troche of the present invention and taste modifying agent can exist simultaneously or not be present in the composition of raw materials of buccal tablet, also can be that wherein more than one are present in the composition of raw materials of buccal tablet.
Should also be noted that simultaneously as the Pramlintide in the troche of the present invention not only to comprise the Pramlintide of producing, also comprise the chemical modification body of acceptable Pramlintide on the medicine by biological extraction or genetic engineering.
The invention still further relates to a kind of preparation method of Pramlintide buccal tablet, the primary raw material for preparing described Pramlintide buccal tablet is composed as follows: 0.1～20 part of Pramlintide, 40～99.8 parts of filleies, 0.1～30 part of stabilizing agent, 0.1～5 part of lubricant, 0～30 part of absorption enhancer, 0～20 part of taste modifying agent, 0.1～10 part of disintegrating agent, 0.01～20 part of pH buffer agent; Described method comprises:
(1) filler, absorption enhancer, taste modifying agent, disintegrating agent are pulverized, sieve, powder standby (absorption enhancer or taste modifying agent are 0 o'clock then do not comprise this component in the aforesaid operations);
(2) pH buffer agent, stabilizing agent are mixed with buffer solution with water for injection, described water for injection quality is 5～20% (being generally about 10%) of filler, absorption enhancer, taste modifying agent quality;
(3) with the sterilization of step (3) buffer solution, add the Pramlintide of formula ratio, fully stir evenly, obtain the pelletize slurry;
(4) take by weighing step (1) powder by prescription and add in the comminutor, and the pelletize of adding step (3) is carried out pelletize with slurry;
(5) step (4) gained granule is carried out granulate, and the adding mix lubricant is even, tabletting promptly gets described Pramlintide buccal tablet.
Preferably, described step (4) pelletize is carried out under 50～55 ℃.
Beneficial effect of the present invention is mainly reflected in: a kind of Pramlintide buccal tablet and preparation method thereof is provided, not only aspect treatment one type, type-II diabetes and the obesity good curative effect is being arranged, and the good stability of its effective ingredient, it is easy to use to suck absorption, is easy to oral mucosa and absorbs.
(4) specific embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1:
The Pramlintide buccal tablet, by 50000, the preparation process that the 1mg/100mg/ sheet feeds intake:
Pulverize adjuvant: mannitol, soluble starch, gelatin, sodium carboxymethyl cellulose are pulverized with pulverizer respectively, crossed 80 mesh sieves, stand-by.
Adjuvant is weighed:
Mannitol 2.00kg
Soluble starch 1.75kg
Gelatin 0.95kg
Carboxymethyl starch sodium 0.25kg
The preparation pelletize is with starching: sodium acetate 9.0g
Acetic acid 9.8ml
Sodium chloride 4.5g
Glucosan 25g
Water for injection 500ml
To treat that solution cooling back feeds intake by every 1mg Pramlintide according to above-mentioned pelletize with the solution autoclaving that the slurry proportioning raw materials prepares, and add Pramlintide raw material 50g altogether, be Pramlintide pelletize serosity behind the mixing fully.
(1) the adjuvant gelatin that weighs up is placed the integrated vacuum drying comminutor, heating makes temperature of charge reach 50～55 ℃; Keep this temperature, add mannitol, soluble starch, sodium carboxymethyl cellulose, rotate stirring paddle, make the abundant mixing of material;
(2) when starting stirring paddle, Pramlintide pelletize serosity is tangentially slowly added in the material, simultaneously stirring paddle does not stop to stir and makes material granulating, the sample tap granulating situation of taking a sample to check, and confirms that granulating carries out particle drying after good;
(3) drying: setting pot wall interlayer temperature is 40 ℃, and product temperature is 35 ℃.Start vacuum pump to Pramlintide granule evacuation in the pot, start stirring paddle simultaneously, rotated rotating speed 3 seconds every 300 seconds: 500 rev/mins, the pot body is constantly done 180 ° of rotations simultaneously.
(4) drop to 35 ℃ when product temperature, show that the Pramlintide particle drying finishes, moisture reaches 2～6% requirement.Feed cold water, make the product cooling, when temperature is less than or equal to cold water temperature, take out the Pramlintide granule.
(5) granulate: qualified Pramlintide granule is crossed 16 mesh sieve granulate, add the 0.1kg leucine, place the mixer mix homogeneously.
(6) tabletting: circular punch die diameter 6.5mm, the thick 2～2.5mm of sheet, 12～18 rev/mins of rotating speeds, pressure 4～6kg, tabletting.
(7) aluminum-plastic packaged: on heat 135 ℃, 135 ℃ of following heating, 200 ℃ of heat-sealing temperatures, air pressure 0.6Mpa is with the mode inner packing of Pramlintide buccal tablet with plastic-aluminum cover bubble.
(8) finished product output:＞48000.
Embodiment 2:
Pulverize adjuvant:
Mannitol 2.10kg, soluble starch 1.67kg, gelatin 0.95kg, carboxymethyl starch sodium 0.18kg;
Pelletize is prepared burden with slurry:
Sodium acetate 9.0g, acetic acid 9.8ml, sodium chloride 4.5g, glucosan 25g, carboxymethyl starch sodium 0.07g, water for injection 500ml.
Preparation method is with embodiment 1.
Embodiment 3:
Pulverize adjuvant:
Mannitol 2.10kg, microcrystalline Cellulose 1.62kg, gelatin 0.95kg, carboxymethyl starch sodium 0.18kg;
Pelletize is prepared burden with slurry:
Sodium chloride 4.5g, glucosan 25g, carboxymethyl starch sodium 0.07g, water for injection 500ml.
Preparation method is with embodiment 1.
Embodiment 4:
Pulverize adjuvant:
Mannitol 2.20kg, Icing Sugar 1.50kg, gelatin 0.95kg, carboxymethyl starch sodium 0.25kg;
Pelletize is prepared burden with slurry:
Sodium acetate 9.0g, acetic acid 9.8ml, sodium chloride 4.5g, glucosan 25g, water for injection 500ml.
When granulate, add leucine 80g, citric acid 25g.
Preparation method is with embodiment 1.
Embodiment 5: the buccal tablet long-term stable experiment
Method: get Pramlintide buccal tablet (lot number 20090301) and pramlintide acetate injection (lot number 20090423) according to the preparation of embodiment 1 method, by simulation listing fractional pack, place 6 ℃ ± 2 ℃ refrigerators of temperature to place, respectively at sampling in 3,6,9,12,18 months, measure every index, the results are shown in Table 1, table 2.
Table 1: pramlintide acetate buccal tablet long-term test results (lot number: 20090301)
| The investigation project | 0 month | March | June | JIUYUE | December | 18 months |
| Character | White tablets | White tablets | White tablets | White tablets | White tablets | White tablets |
| Dissolution | 99.5％ | 99.8％ | 99.5％ | 98.9％ | 99.2％ | 98.6％ |
| Total impurities (%) | 0.48 | 0.48 | 0.56 | 0.58 | 0.65 | 0.79 |
| Single impurity (%) | 0.20 | 0.26 | 0.25 | 0.28 | 0.34 | 0.35 |
| Acetic acid content (%) | 5.44 | 5.54 | 5.56 | 5.82 | 5.72 | 5.60 |
| Content (%) | 100.7 | 100.2 | 99.9 | 99.8 | 99.8 | 99.5 |
Table 2 pramlintide acetate injection long-term test results (lot number: 20090423)
The result shows that the Pramlintide buccal tablet for preparing by the inventive method has dissolution and stability preferably, and stability is significantly better than the Pramlintide injection.
Claims (6)
1. Pramlintide buccal tablet is that primary raw material is made with quality component composed as follows:
0.1～20 part of Pramlintide
40～99.8 parts of filleies
0.1～30 part of stabilizing agent
0.1～5 part of lubricant
0～30 part of absorption enhancer
0.1～10 part of disintegrating agent
0～20 part of taste modifying agent
0.01～20 part of pH buffer agent;
Described filler is one of following or wherein two or more mixing: mannitol, Icing Sugar, microcrystalline Cellulose, gelatin, soluble starch;
Described stabilizing agent is one of following or wherein two or more mixing: lysine, arginine, glycine, hetastarch, hydroxymethyl starch, sorbitol, glucosan;
Described lubricant is one of following or wherein two or more mixing: stearic acid, magnesium stearate, Pulvis Talci, leucine;
Described absorption enhancer is one of following or wherein two or more mixing: sodium laurylsulfate, sodium deoxycholate, aprotinin, propylene glycol, azone, menthol, NaGC, sodium salicylate;
Described disintegrating agent is one of following or wherein two or more mixing: sodium carboxymethyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose;
Described taste modifying agent is one of following or wherein two or more mixing: menthol, Borneolum Syntheticum, cyclamate, glycyrrhizin, citric acid;
Described pH buffer agent is one of following or wherein two or more mixing: sodium acetate, glacial acetic acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, citric acid.
2. Pramlintide buccal tablet as claimed in claim 1 is characterized in that described Pramlintide buccal tablet is that primary raw material is made with quality component composed as follows:
0.3～5 part of Pramlintide
50～70 parts of filleies
0.2～3 part of stabilizing agent
0.3～1 part of lubricant
1～10 part of absorption enhancer
0.5～5 part of disintegrating agent
0.1～5 part of taste modifying agent
0.03～10 part of pH buffer agent.
3. Pramlintide buccal tablet as claimed in claim 1 is characterized in that described Pramlintide buccal tablet is that primary raw material is made with quality component composed as follows:
0.3～5 part of Pramlintide
10～30 parts in mannitol
10～20 parts of soluble starches
5～15 parts in gelatin
0.2～0.5 part of glucosan
0.5～1 part of leucine
2～3 parts of carboxymethyl starch sodium
0.05～0.1 part of sodium acetate
0.05～2 part of acetic acid
0.01～0.05 part in sodium chloride.
4. Pramlintide buccal tablet as claimed in claim 3 is characterized in that described Pramlintide buccal tablet is that primary raw material is made with quality component composed as follows:
0.5 part of Pramlintide
20 parts in mannitol
17.5 parts of soluble starches
9.5 parts in gelatin
0.25 part of glucosan
1 part of leucine
2.5 parts of carboxymethyl starch sodium
0.09 part of sodium acetate
0.1 part of acetic acid
0.045 part in sodium chloride.
5. the preparation method of a Pramlintide buccal tablet, the primary raw material for preparing described Pramlintide buccal tablet is composed as follows: 0.1～20 part of Pramlintide, 40～99.8 parts of filleies, 0.1～30 part of stabilizing agent, 0.1～5 part of lubricant, 0～30 part of absorption enhancer, 0～20 part of taste modifying agent, 0.1～10 part of disintegrating agent, 0.01～20 part of pH buffer agent; Described method comprises:
(1) filler, absorption enhancer, taste modifying agent, disintegrating agent are pulverized, and sieve, and it is standby to get powder;
(2) pH buffer agent, stabilizing agent are mixed with buffer solution with water for injection, described water for injection quality is 5～20% of filler, absorption enhancer, a taste modifying agent quality;
(3) with the sterilization of step (3) buffer solution, add the Pramlintide of formula ratio, fully stir evenly, obtain the pelletize slurry;
(4) take by weighing step (1) powder by prescription and add in the comminutor, and the pelletize of adding step (3) is carried out pelletize with slurry;
(5) step (4) gained granule is carried out granulate, and the adding mix lubricant is even, tabletting promptly gets described Pramlintide buccal tablet.
6. method as claimed in claim 5 is characterized in that described step (4) pelletize carries out under 50～55 ℃.
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| CN112057619A (en) * | 2019-06-10 | 2020-12-11 | 苏州兰鼎生物制药有限公司 | A pharmaceutical composition with blood sugar lowering effect |
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|---|---|---|---|---|
| CN101822822A (en) * | 2009-03-04 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Drug composition of pramlintide and preparation method thereof |
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| CN101822822A (en) * | 2009-03-04 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Drug composition of pramlintide and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《生物药剂学与药物动力学》 20030731 梁文权 《生物药剂学与药物动力学》 第一章、第三章第二节 权1-6 , * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112057619A (en) * | 2019-06-10 | 2020-12-11 | 苏州兰鼎生物制药有限公司 | A pharmaceutical composition with blood sugar lowering effect |
| US12097245B2 (en) | 2019-06-10 | 2024-09-24 | Jing Zhang | Hypoglycemic pharmaceutical composition |
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