CN102100906A - Medicinal preparation of exenatide and preparation method thereof - Google Patents
Medicinal preparation of exenatide and preparation method thereof Download PDFInfo
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- CN102100906A CN102100906A CN2011100406153A CN201110040615A CN102100906A CN 102100906 A CN102100906 A CN 102100906A CN 2011100406153 A CN2011100406153 A CN 2011100406153A CN 201110040615 A CN201110040615 A CN 201110040615A CN 102100906 A CN102100906 A CN 102100906A
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Abstract
The invention provides a medicinal preparation of exenatide and a preparation method thereof. The preparation comprises a protective agent, a buffering agent, an isotonic regulator, 0.001 to 1.0 percent of preservative and 0.005 to 0.5 percent (w/v) of exenatide, and the pH value of the preparation is between 3.0 and 7.0, wherein the protective agent is one or a combination of two or more of polysorbate 80, lecithin, pluronic F68 and human serum albumin. The preparation method comprises the following steps of: (1) weighing prescription dose of preservative, isotonic regulator and buffering agent, dissolving sequentially by using water for injection and putting the mixture into a liquid preparation tank; (2) dissolving the exenatide in the solution, and diluting to the prescription concentration; and (3) filtering and sterilizing by using a filter membrane of 0.22 micrometer to obtain exenatide injection. The long-term stability of the preparation is improved obviously, and the preparation contains 0.005 to 0.5 percent (w/v) of exenatide, the protective agent, the buffering agent, the isotonic regulator and the preservative.
Description
Technical field
The present invention relates to a kind of polypeptide medicines and its preparation method, relate in particular to preparation of Exenatide and preparation method thereof.
Background technology
Exenatide is that excretory natural intestine pancreotropic hormone is intended like thing (incretin mimetic) from Southwestern United Stares Monster saliva, can simulate the effect of glucagon-like-peptide-1 (glucagon like peptide-1 GLP-1), thereby reach the effect of blood sugar control, develop jointly by U.S. Amylin and Lilly drugmaker.The Exenatide of synthetic is that the first incretin of getting permission to go on the market is intended like thing, its new drug application obtains drugs approved by FDA in April, 2005, is mainly used in to improve the glycemic control that metformin and sulfonylureas are treated unfavorable type 2 diabetes mellitus patient.Exenatide is a kind of 39 amino acid whose polypeptide that contain, and has only 53% homology with the aminoacid sequence of mammal GLP-1; Mammiferous GLP-1 is from Proglucagon (proglucagon) gene of small intestinal L cell; And Exenatide is not from deriving from the glucagon protogene, and therefore can not be called is the analog of GLP-1.But Exenatide is that (glucagon-like peptide 1 receptor, a kind of effective activator GLP-1R) have high affinity with the GLP-1 receptor to pancreas GLP-1 receptor.Therefore have the biological action similar, intend intending agonist (GLP-1R agonist) like thing (GLP-1 mimetic) or GLP-1R like thing, GLP-1 so Exenatide can be described as incretin to GLP-1.
Exenatide is as a kind of peptide medicament, and its stability can't be compared with the conventional chemical medicine, and its physics and chemistry, biological property can change because of being subjected to multiple Effect of Environmental when long term store.Have data to show that there is intermolecular interaction in Exenatide, dynamic spectral data confirms that there is the balance between monomer and the aggregation in Exenatide.The generation of the gathering of albumen or polypeptide, particularly high polymer will cause molecular weight to increase, and be prone to precipitation, and the corresponding minimizing of activated monomer form.The replacing of pH value and variation of temperature, solvent all can cause the generation of aggregation and the variation of quantity.The molecular exclusion chromatography result of study shows, contains the tetramer of 5%-25% in the Exenatide aqueous solution, and there is the phenomenon of hydrolysis in its preparation in preparation, storage and use in addition, and transportation inconvenience, placement and storage-stable are bad.
Summary of the invention
The object of the present invention is to provide a kind of stable Exenatide formulation and preparation method, cause molecular weight to increase, be prone to precipitation and make corresponding minimizing of activated monomer form and the bad problem of the hydrolysis in preparation, storage and use, placement and storage-stable with the generation that solves the Exenatide high polymer.Technical scheme of the present invention is as follows:
A kind of pharmaceutical formulation of Exenatide; the antiseptic that comprises protective agent, buffer agent, isoosmotic adjusting agent and 0.001% to 1.0%; 0.005% to 0.5%w/v Exenatide; the pH of described preparation is 3.0 to 7.0, and wherein protective agent is that polyoxyethylene sorbitan monoleate, lecithin, general youth Buddhist nun restrain a kind of or its two or more the combination arbitrarily among F68, the human albumin.
The preferred concentration of concentration of Exenatide is 0.005% to 0.05% w/v in the Exenatide injection of the present invention, and preferred concentration is 0.025% w/v, the adjustment of dosage when this concentration more helps clinical use.
The protective agent that the present invention selects for use is that polyoxyethylene sorbitan monoleate, lecithin, general youth Buddhist nun restrain a kind of or its two or more the combination arbitrarily among F68, the human albumin.Described protectant concentration is 0.2% to 2%.Test shows that adding protective agent can reduce the polymeric generation of Exenatide, thereby increases its stability; Simultaneously, the applicant finds that unexpectedly protectant adding can reduce the absorption of packaging material to Exenatide, reduces the reduction of content.The applicant also find when protectant concentration less than 0.2% the time, it reduces Exenatide polymer and produces and reduce a little less than the effect of packaging material to the absorption of Exenatide DeGrain; And when protectant concentration can be greater than 2% the time because consumption is excessive the pharmacological action of generation protective agent itself, for example excessive generation that will cause haemolysis of polyoxyethylene sorbitan monoleate consumption; And consumption not only can play the effect of protection but also can avoid producing bad pharmacological action when 0.2%-2%.
The antiseptic of selecting for use of the present invention is this area antiseptic commonly used, preferred preservative is selected from any or its arbitrarily two or more the combination in metacresol, benzyl alcohol, chlorobutanol, the thimerosal, more preferably any or its combination in chlorobutanol and the metacresol.The consumption of antiseptic of the present invention is 0.001% to 1.0%w/v, preferred 0.01% to 1.0% w/v.
The pH value of preparation of the present invention is 3.0 to 7.0, finds that unexpectedly pH value is 4.0 to 5.0, Exenatide stable best.More preferably 4.5.
Used buffer agent comprises a kind of or its two or more the combination arbitrarily in acetate buffer, citrate buffer, phosphate buffer, the tartrate buffer, preferred tartrate buffer among the present invention.
The content of selected isoosmotic adjusting agent is 0.9% to 10%w/v among the present invention, used isoosmotic adjusting agent is a kind of or its two or more the combination arbitrarily in mannitol, glucose, sodium chloride, lactose, sorbitol, sucrose, the maltose, preferred sodium chloride.
The preparation method of Exenatide injection of the present invention comprises the steps:
(1) takes by weighing antiseptic, isoosmotic adjusting agent, the buffer agent of recipe quantity, successively with the water for injection dissolving and move into Agitation Tank;
(2) with above-mentioned solution Exenatide is dissolved, and be diluted to prescription concentration;
(3), get the Exenatide injection with 0.22 μ m membrane filtration degerming.
Described step (1) takes by weighing the adjuvant of recipe quantity, and adjuvant is antiseptic, isoosmotic adjusting agent, buffer agent, successively with water for injection dissolving and immigration Agitation Tank.Described recipe quantity is meant for the antiseptic mass concentration that realizes is 0.001% to 1.0%, and the content of isoosmotic adjusting agent is 0.9% to 10%w/v, and pH value is 3.0 to 7.00. adjuvant parameter, according to production scale, determines the consumption of each adjuvant.
After described step (2) prescription concentration was meant Exenatide dissolving dissolving, it was 005% to 0.5%w/v that Exenatide is diluted to mass concentration.
The present invention has determined the stable key condition of Exenatide injection, promptly rational prescription, pH value scope, preparation technology, help the control of Exenatide injection quality, thereby the producting rule of the science of formulation makes Exenatide injection mass industrialized production become possibility.
[specific embodiment]
Embodiment one: prescription 1
Exenatide 250mg
Mannitol 40g
Chlorobutanol 5.0g
Glacial acetic acid 0.87g
Sodium acetate trihydrate 1.43g
General youth Buddhist nun restrains F68 2.0g
Water for injection adds to 1000ml
The mannitol, chlorobutanol, glacial acetic acid, sodium acetate trihydrate, the general youth Buddhist nun that take by weighing recipe quantity restrain F68, add 800ml water for injection, add the Exenatide of recipe quantity after the dissolving again, add to 1000ml with water for injection then, use the filter membrane aseptic filtration of 0.22 μ m, promptly.
Embodiment two: prescription 2
Exenatide 250mg
Sodium chloride 7.2g
Metacresol 2.2g
Glacial acetic acid 0.87g
Sodium acetate trihydrate 1.43g
Polyoxyethylene sorbitan monoleate 2g
Water for injection adds to 1000ml
Take by weighing sodium chloride, metacresol, glacial acetic acid, sodium acetate trihydrate, the polyoxyethylene sorbitan monoleate of recipe quantity, add 800ml water for injection, add the Exenatide of recipe quantity after the dissolving again, add to 1000ml with water for injection then, use the filter membrane aseptic filtration of 0.22 μ m, promptly.
Embodiment three: prescription 3
Exenatide 250mg
Mannitol 40g
Chlorobutanol 5.0g
Sodium hydrogen phosphate 6.51g
Citric acid 2.29g
Polyoxyethylene sorbitan monoleate 2g
Water for injection adds to 1000ml
Take by weighing mannitol, chlorobutanol, sodium dihydrogen phosphate, citric acid, the polyoxyethylene sorbitan monoleate of recipe quantity, add 800ml water for injection, add the Exenatide of recipe quantity after the dissolving again, add to 1000ml with water for injection then, use the filter membrane aseptic filtration of 0.22 μ m, promptly.
Embodiment four: prescription 4
Exenatide 250mg
Sodium chloride 7.2g
Chlorobutanol 5.0g
Tartaric acid 1.5g
Sodium tartrate 5.5g
Human albumin 5g
Water for injection adds to 1000ml
Take by weighing glucose, chlorobutanol, tartaric acid, sodium tartrate, the human albumin of recipe quantity, add 800ml water for injection, add the Exenatide of recipe quantity after the dissolving again, add to 1000ml with water for injection then, use the filter membrane aseptic filtration of 0.22 μ m, promptly.
Embodiment five:
The study on the stability of Exenatide injection
With embodiment 4 is a collection of preparation of prescription preparation, prepare a collection of preparation that does not contain the human albumin by identical prescription simultaneously, every batch is divided into two parts: portion is positioned under 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% condition and carries out accelerated test, respectively at 0,1,2,3, the sampling in June detects; Another part is positioned over 6 ℃ ± 2 ℃ isoperibol long term tests of temperature, respectively at 0,3,6,9, the December sampling detects.
25 ℃ of stability tests of table 1 Exenatide injection are investigated the result
6 ℃ of stability tests of table 2 Exenatide injection are investigated the result
From above-mentioned experimental result as seen, the protectant Exenatide injection stability that contains among the present invention is not significantly improved than not containing protectant preparation stability, shows that the present invention can improve the stability of Exenatide injection greatly.
Through stability experiment research, the present invention restrains F68 as protectant Exenatide pharmaceutical formulation with polyoxyethylene sorbitan monoleate, general youth Buddhist nun, and it is stable compares with the prescription that does not contain stabilizing agent, contains protectant preparation stability and is significantly improved.
Above content be in conjunction with concrete preferred implementation to further describing that the present invention did, can not assert that concrete enforcement of the present invention is confined to these explanations.For the general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, can also make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
Claims (9)
1. the pharmaceutical formulation of an Exenatide; it is characterized in that: comprise the antiseptic of protective agent, buffer agent, isoosmotic adjusting agent and 0.001% to 1.0% and 0.005% to 0.5%w/v Exenatide; the pH of described preparation is 3.0 to 7.0, and wherein protective agent is that polyoxyethylene sorbitan monoleate, lecithin, general youth Buddhist nun restrain a kind of or its two or more the combination arbitrarily among F68, the human albumin.
2. the pharmaceutical formulation of Exenatide according to claim 1, it is characterized in that: pharmaceutical formulation is an injection.
3. the pharmaceutical formulation of Exenatide according to claim 1, it is characterized in that: the concentration of described Exenatide is 0.025%.
4. the pharmaceutical formulation of Exenatide according to claim 2, it is characterized in that: the concentration of described Exenatide is 0.025%.
5. according to the pharmaceutical formulation of any described Exenatide of claim 1-4, it is characterized in that: described protectant concentration is 0.2% to 2%.
6. according to the pharmaceutical formulation of any described Exenatide of claim 1-4, it is characterized in that: the pH value of described pharmaceutical formulation is 4.0 to 5.0.
7. according to the pharmaceutical formulation of any described Exenatide of claim 1-4, it is characterized in that: described buffer agent is a kind of or its two or more the combination arbitrarily in acetate buffer, citrate buffer, phosphate buffer, the tartrate buffer.
8. according to the pharmaceutical formulation of any described Exenatide of claim 1-4, it is characterized in that: described isoosmotic adjusting agent content is 0.7% to 10%w/v, and isoosmotic adjusting agent is a kind of or its two or more the combination arbitrarily in mannitol, glucose, sodium chloride, lactose, sorbitol, sucrose, the maltose.
9. according to the preparation method of the pharmaceutical formulation of any described Exenatide of claim 1-8, it is characterized in that: pharmaceutical formulation is an injection, and comprises the steps:
(1) takes by weighing antiseptic, isoosmotic adjusting agent, the buffer agent of recipe quantity, successively with the water for injection dissolving and move into Agitation Tank;
(2) with above-mentioned solution Exenatide is dissolved, and be diluted to prescription concentration;
(3), get the Exenatide injection with 0.22 μ m membrane filtration degerming.
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| CN2011100406153A CN102100906A (en) | 2011-02-18 | 2011-02-18 | Medicinal preparation of exenatide and preparation method thereof |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9670261B2 (en) | 2012-12-21 | 2017-06-06 | Sanofi | Functionalized exendin-4 derivatives |
| US9694053B2 (en) | 2013-12-13 | 2017-07-04 | Sanofi | Dual GLP-1/glucagon receptor agonists |
| CN107106499A (en) * | 2014-11-02 | 2017-08-29 | 纳诺精密医疗有限公司 | Implantable medical devices for extending release therapeutic agent |
| US9751926B2 (en) | 2013-12-13 | 2017-09-05 | Sanofi | Dual GLP-1/GIP receptor agonists |
| US9750788B2 (en) | 2013-12-13 | 2017-09-05 | Sanofi | Non-acylated exendin-4 peptide analogues |
| US9758561B2 (en) | 2014-04-07 | 2017-09-12 | Sanofi | Dual GLP-1/glucagon receptor agonists derived from exendin-4 |
| US9771406B2 (en) | 2014-04-07 | 2017-09-26 | Sanofi | Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4 |
| US9775904B2 (en) | 2014-04-07 | 2017-10-03 | Sanofi | Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists |
| US9789165B2 (en) | 2013-12-13 | 2017-10-17 | Sanofi | Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| US9982029B2 (en) | 2015-07-10 | 2018-05-29 | Sanofi | Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists |
| US10758592B2 (en) | 2012-10-09 | 2020-09-01 | Sanofi | Exendin-4 derivatives as dual GLP1/glucagon agonists |
| US10806797B2 (en) | 2015-06-05 | 2020-10-20 | Sanofi | Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate |
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Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10758592B2 (en) | 2012-10-09 | 2020-09-01 | Sanofi | Exendin-4 derivatives as dual GLP1/glucagon agonists |
| US9670261B2 (en) | 2012-12-21 | 2017-06-06 | Sanofi | Functionalized exendin-4 derivatives |
| US9745360B2 (en) | 2012-12-21 | 2017-08-29 | Sanofi | Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists |
| US10253079B2 (en) | 2012-12-21 | 2019-04-09 | Sanofi | Functionalized Exendin-4 derivatives |
| US9751926B2 (en) | 2013-12-13 | 2017-09-05 | Sanofi | Dual GLP-1/GIP receptor agonists |
| US9750788B2 (en) | 2013-12-13 | 2017-09-05 | Sanofi | Non-acylated exendin-4 peptide analogues |
| US9694053B2 (en) | 2013-12-13 | 2017-07-04 | Sanofi | Dual GLP-1/glucagon receptor agonists |
| US9789165B2 (en) | 2013-12-13 | 2017-10-17 | Sanofi | Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists |
| US9775904B2 (en) | 2014-04-07 | 2017-10-03 | Sanofi | Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists |
| US9771406B2 (en) | 2014-04-07 | 2017-09-26 | Sanofi | Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4 |
| US9758561B2 (en) | 2014-04-07 | 2017-09-12 | Sanofi | Dual GLP-1/glucagon receptor agonists derived from exendin-4 |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| CN107106499A (en) * | 2014-11-02 | 2017-08-29 | 纳诺精密医疗有限公司 | Implantable medical devices for extending release therapeutic agent |
| US10688056B2 (en) | 2014-11-02 | 2020-06-23 | Nano Precision Medical, Inc. | Implantable medical devices for extended release of therapeutic agents |
| CN107106499B (en) * | 2014-11-02 | 2021-09-17 | 纳诺精密医疗有限公司 | Implantable medical device for extended release of therapeutic agents |
| US11478430B2 (en) | 2014-11-02 | 2022-10-25 | Nano Precision Medical, Inc. | Implantable medical devices for extended release of therapeutic agents |
| US10806797B2 (en) | 2015-06-05 | 2020-10-20 | Sanofi | Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate |
| US9982029B2 (en) | 2015-07-10 | 2018-05-29 | Sanofi | Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists |
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Application publication date: 20110622 |