CN101095942A - Formulation of the Exendin injection medicine containing stabilizing agent - Google Patents
Formulation of the Exendin injection medicine containing stabilizing agent Download PDFInfo
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- CN101095942A CN101095942A CNA2006100909058A CN200610090905A CN101095942A CN 101095942 A CN101095942 A CN 101095942A CN A2006100909058 A CNA2006100909058 A CN A2006100909058A CN 200610090905 A CN200610090905 A CN 200610090905A CN 101095942 A CN101095942 A CN 101095942A
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Abstract
The invention relates to Exendin that is extracted from lizard saliva. It is natural blood sugar reduction polypeptide substance. The invention also relates to a stable liquid formulation for Exendin, which is used to treat diabetes. It is especially related to a formulation that can improve Exendin stability distinctively, that can prolong liquid Exendin storage time, and is favorable for clinical extension.
Description
Technical field
The present invention relates to a kind of Exendin injection preparation method.Particularly, the present invention relates to a kind of Exendin injection prescription and its production and application.
Background technology
Diabetes are a kind of worldwide diseases, whole world diabetics surpasses 1.5 hundred million, increasing along with growth in the living standard and operating pressure, the onset diabetes rate presents popular situation, whole world diabetics number is estimated will double less than the time in 25 years in future and is reached 3.0 hundred million, and wherein type ii diabetes accounts for 90%.
At present, China type ii diabetes patient nearly 4,000 ten thousand, along with growth in the living standard, sickness rate will be more and more higher, and the city is more than the rural area, because patient's medication throughout one's life, market every year of medicine of therefore treating type ii diabetes is more than tens billion of RMB.
Exendin-4 (Exenatide) is a kind of specially good effect new drug for the treatment of type ii diabetes, has the extremely strong power of striving unexpectedly in similar medicine.
The peptide amide class material that Exenatide is made up of 39 amino acid residues, aminoacid sequence is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2, mean molecule quantity is 4186.6D.
Up to now clinical research result shows, compares with the medicine of other treatment type ii diabetes, and Exenatide has many remarkable advantages:
1, can improve the function of beta Cell of islet, at present clinical treatment type ii diabetes patient's commonly used sulfonylureas mainly is to stimulate the islet cells excreting insulin, but can not improve the function of islet cells, Exenatide can not only promote islet cells to produce insulin, can also promote the differentiation of islet cells, breed, improve the function of islet cells, might fundamentally reach the purpose of treatment diabetes.
2, except the effect islet cells, Exenatide can also directly act on liver and muscle cell, and the approach that does not rely on insulin suppresses the degraded of glycogen and promotes the synthetic of glycogen, reaches hypoglycemic effect.The appetite that can suppress diabetic simultaneously by the inhibition gastric emptying, thus the body weight control that can improve the patient is of value to treatment of diabetes.
3, relevant with blood sugar concentration, with sulfonylurea and biguanides treatment, it promotes the effect of pancreas excreting insulin not rely on the height of blood sugar concentration, life-time service can excessively cause pancreatic beta-cell failure because of insulin secretion, and Exenatide only just plays a role under the high situation of blood sugar concentration, and life-time service can not damage islet cells.Patient's state of an illness is alleviated or keep stable.
Lilly and peace Milin company have drawn two doses of adults one day after through secular animal experiment and clinical experimental study, the consumption of every dose 5 μ g or 10 μ g can obtain clinical effectiveness preferably, the patient carries and uses for convenience, adopt novel administering mode-written examination syringe, per injection volume 20 μ l or 40 μ l, therefore the concentration of the principal agent Exenatide of selecting is 250 μ g/ml.
Exenatide is the newtype drug of treatment type ii diabetes, but similar to insulin is necessary multiple dosing, the dosage form of most convenient should be a peroral dosage form, but because Exenatide is a polypeptide drug, in digestive system easily by enzymatic degradation, cause bioavailability lower, therapeutic effect is poor, and therefore common peroral dosage form is difficult to reach the treatment requirement.Except peroral dosage form, be conveniently injection, for the patient carries with easy to use, the dosage form that the present invention adopts is a liquid preparation, carry out packing with the cassette bottle, the administration of written examination syringe, the preparation specification is: the clinical consumption 5 μ g/dose of 600 μ g/2.4ml, 10 μ g/dose, subcutaneous injection, twice on the one.Completed stability test proof adopts its stability in use of liquid preparation of above-mentioned prescription good.
The present invention describes in detail
The object of the present invention is to provide a kind of is stabilizing agent with the glycine, and what contain antiseptic, buffer agent and other injectable liquefied composition commonly used is specifically designed to Exendin-4 injection of written examination syringe and preparation method thereof, is used for treatment of diabetes.These injection characteristics are to be to contain the glycine that is higher than main active medicine content, have good stable.
Technical scheme of the present invention is:
1) preparation of buffer
600 milliliters of preparation acetic acid/sodium acetates/mannitol/glycine buffer
Take by weighing sodium acetate trihydrate, mannitol, glycine adds 200 milliliters of injection waters.Other gets 2M HCl, and metacresol transfers with 2M HCl behind the mixing that to add the injection water behind the pH to 4.5 fixed molten to 600 milliliters, get 480 milliliters of above-mentioned buffer and add 1920 milliliters of waters for injection, behind the mixing with stand-by behind the 0.22 μ m membrane filtration.
2) preparation of preparation
Accurately the weighing Exenatide is 600 milligrams, place clean, sterilization, dried 1000 milliliters of triangle vials baking to add 600 milliliters of above-mentioned filtration buffer, after gently stirring dissolving, pour in clean, sterilization, the dried 5000 milliliters of vials baking, add 1800 milliliters of above-mentioned buffer, take out oxygen in the liquid with vacuum pump after, packing behind the reuse 0.22 μ m membrane filtration, dividing packaging container is 3 milliliters Carlsberg's flask, 2.4 milliliters of every bottle of packing, promptly.
Glycine concentration is 0.05-0.4mM in the described buffer, and acetic acid/sodium acetate concentration range is 1 5-50mM, and mannitol concentration is 0.05-0.3mM, metacresol 3-9mL.
The specific embodiment
Embodiment 1
The buffer preparation:
Preparation 0.3M acetic acid/sodium acetate, 0.75M mannitol, 600 milliliters of 0.75M glycine buffers.Take by weighing 12.24 gram sodium acetate trihydrates, 41 gram mannitol, 17 gram glycine, add 200 milliliters of injection waters, fully get 10 milliliters of 2M HCl after the dissolving, 6 milliliters of metacresols, fixed molten behind the mixing to 600 milliliters with adding the injection water behind the 2M HCl accent pH to 4.5, get 480 milliliters of above-mentioned buffer and add 1920 milliliters of waters for injection, behind the mixing with stand-by behind the 0.22 μ m membrane filtration.
Embodiment 2
Formulation preparation:
Accurately the weighing Exenatide is 600 milligrams, place clean, sterilization, dried 1000 milliliters of triangle vials baking to add 600 milliliters of above-mentioned filtration buffer, after gently stirring dissolving, pour in clean, sterilization, the dried 5000 milliliters of vials baking, add 1800 milliliters of above-mentioned buffer, take out oxygen in the liquid with vacuum pump after, behind the reuse 0.22 μ m membrane filtration, get the branch packaging container and be 3 milliliters cassette bottle, 2.4 milliliters of every bottle of packing.
Embodiment 3
The stability accelerated test
Get 3 batches in the sample of different batches, check relevant stable high spot reviews project respectively, as the preceding 0 day basic data of accelerated test, and then get three batches of same lot number, the cillin bottle that sample is housed is inserted in 25 ± 2 ℃ the water isolation type electrical equipment calorstat, respectively 1,2,3, every batch of sampling is measured during June, compares with zero sky.
Three batch samples are trimestral accelerated test result show, this product outward appearance is constant, and content is compared constant substantially with zero moon, and its related substances is constant substantially, and pH is constant substantially.
Claims (7)
1. an Exendin injection is filled a prescription, and every 1ml formulation components comprises Exendin-4, metacresol, mannitol, glycine, the aseptic buffering of acetate.It is characterized in that containing the glycine that is higher than main active medicine content, and by add buffer agent make active substance from the pH in water-bearing media in 4～5 scope.
2. according to the stable pharmaceutically active substance of claim 1, wherein glycine content is that every 1ml contains 1-10mg, is preferably 3-8mg/ml.
3. according to the stable pharmaceutically active substance of claim 1, wherein antiseptic is a metacresol, and content is 0.5-4mg/ml.
4. according to the stable pharmaceutically active substance of claim 1, it is characterized in that described active substance has the pH value in the 4-6 scope in water-bearing media.
5. according to the stable liquid pharmaceutical formulations of claim 4, its buffer component is acetic acid/sodium acetate, and concentration is at 25-60mM, preferably at 30mM.
6. according to the stable pharmaceutically active substance of claim 1, also comprise at least a composition that is selected from solubilizing agent, surfactant, osmotic pressure regulator; Randomly also comprise drug injection prescription other composition commonly used.
7. according to the stable liquid pharmaceutical formulations of claim 4, the aqueous solution that it is characterized in that described pharmaceutical formulation has and is lower than 5 pH value.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100909058A CN101095942B (en) | 2006-06-30 | 2006-06-30 | Formulation of the Exendin injection medicine containing stabilizing agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100909058A CN101095942B (en) | 2006-06-30 | 2006-06-30 | Formulation of the Exendin injection medicine containing stabilizing agent |
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| Publication Number | Publication Date |
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| CN101095942A true CN101095942A (en) | 2008-01-02 |
| CN101095942B CN101095942B (en) | 2011-11-16 |
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| CN2006100909058A Active CN101095942B (en) | 2006-06-30 | 2006-06-30 | Formulation of the Exendin injection medicine containing stabilizing agent |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009024015A1 (en) * | 2007-08-15 | 2009-02-26 | Jiangsu Hansen Pharmaceutical Co., Ltd. | A stable formulation of exenatide |
| CN102026646A (en) * | 2008-05-05 | 2011-04-20 | 奥拉姆德有限公司 | Methods and compositions for oral administration of exenatide |
| CN102100906A (en) * | 2011-02-18 | 2011-06-22 | 深圳翰宇药业股份有限公司 | Medicinal preparation of exenatide and preparation method thereof |
| CN101766812B (en) * | 2008-12-31 | 2012-08-22 | 上海医药工业研究院 | Liquid drug combination containing exenatide or analogues thereof |
| CN103705446A (en) * | 2012-10-08 | 2014-04-09 | 正大天晴药业集团股份有限公司 | Polyene phosphatidyl choline injection, and preparation method thereof |
| CN102100912B (en) * | 2009-12-16 | 2015-04-22 | 上海蓝心医药科技有限公司 | Administration composition and preparation method and using method thereof |
| US9259456B2 (en) | 2005-09-06 | 2016-02-16 | Oramed Pharmaceuticals Inc. | Methods and compositions for oral administration of proteins |
| CN108042794A (en) * | 2018-01-05 | 2018-05-18 | 北京博康健基因科技有限公司 | Stabilization formulations of Exendin-4 and preparation method thereof |
| US10058593B2 (en) | 2008-03-26 | 2018-08-28 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
| US10342764B2 (en) | 2012-02-01 | 2019-07-09 | Oramed Ltd. | Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same |
| US10398762B2 (en) | 2012-01-03 | 2019-09-03 | Oramed Ltd. | Methods and compositions for treating diabetes |
| US10967051B2 (en) | 2013-01-03 | 2021-04-06 | Oramed Ltd. | Methods and compositions for treating NAFLD, hepatic steatosis, and sequelae thereof |
-
2006
- 2006-06-30 CN CN2006100909058A patent/CN101095942B/en active Active
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9259456B2 (en) | 2005-09-06 | 2016-02-16 | Oramed Pharmaceuticals Inc. | Methods and compositions for oral administration of proteins |
| WO2009024015A1 (en) * | 2007-08-15 | 2009-02-26 | Jiangsu Hansen Pharmaceutical Co., Ltd. | A stable formulation of exenatide |
| US10058593B2 (en) | 2008-03-26 | 2018-08-28 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
| US11660327B2 (en) | 2008-03-26 | 2023-05-30 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
| US10881714B2 (en) | 2008-03-26 | 2021-01-05 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
| CN102026646A (en) * | 2008-05-05 | 2011-04-20 | 奥拉姆德有限公司 | Methods and compositions for oral administration of exenatide |
| CN105903005A (en) * | 2008-05-05 | 2016-08-31 | 奥拉姆德有限公司 | Methods And Compositions For Oral Administration Of Exenatide |
| US10350162B2 (en) | 2008-05-05 | 2019-07-16 | Oramed Ltd. | Methods and compositions for oral administration of exenatide |
| CN101766812B (en) * | 2008-12-31 | 2012-08-22 | 上海医药工业研究院 | Liquid drug combination containing exenatide or analogues thereof |
| CN102100912B (en) * | 2009-12-16 | 2015-04-22 | 上海蓝心医药科技有限公司 | Administration composition and preparation method and using method thereof |
| CN102100906A (en) * | 2011-02-18 | 2011-06-22 | 深圳翰宇药业股份有限公司 | Medicinal preparation of exenatide and preparation method thereof |
| US11395848B2 (en) | 2012-01-03 | 2022-07-26 | Oramed Ltd. | Methods and compositions for treating diabetes |
| US10398762B2 (en) | 2012-01-03 | 2019-09-03 | Oramed Ltd. | Methods and compositions for treating diabetes |
| US10342764B2 (en) | 2012-02-01 | 2019-07-09 | Oramed Ltd. | Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same |
| US10933022B2 (en) | 2012-02-01 | 2021-03-02 | Oramed Ltd. | Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same |
| CN103705446A (en) * | 2012-10-08 | 2014-04-09 | 正大天晴药业集团股份有限公司 | Polyene phosphatidyl choline injection, and preparation method thereof |
| US10967051B2 (en) | 2013-01-03 | 2021-04-06 | Oramed Ltd. | Methods and compositions for treating NAFLD, hepatic steatosis, and sequelae thereof |
| CN108042794B (en) * | 2018-01-05 | 2022-01-25 | 北京博康健基因科技有限公司 | Stable preparation of recombinant insulinotropic hormone secretagogue and preparation method thereof |
| CN108042794A (en) * | 2018-01-05 | 2018-05-18 | 北京博康健基因科技有限公司 | Stabilization formulations of Exendin-4 and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101095942B (en) | 2011-11-16 |
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Addressee: Zheng Haifa Document name: the First Notification of an Office Action |
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Address after: 100071 Beijing City, Daxing District Daxing biomedical industry base of Zhongguancun science and Technology Park Si Miao Road No. 35 Patentee after: Beijing Min Hai Bio-Scientific Inc. Address before: 100071 Beijing city Haidian District North Shimonoseki street, No. seven, 4 floor 416 Patentee before: Beijing Min Hai Bio-Scientific Inc. |