CN102440966A - Preparation process research of exenatide slow-release preparation - Google Patents
Preparation process research of exenatide slow-release preparation Download PDFInfo
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- CN102440966A CN102440966A CN2010105071541A CN201010507154A CN102440966A CN 102440966 A CN102440966 A CN 102440966A CN 2010105071541 A CN2010105071541 A CN 2010105071541A CN 201010507154 A CN201010507154 A CN 201010507154A CN 102440966 A CN102440966 A CN 102440966A
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- exenatide
- release preparation
- injection
- sustained release
- preparation
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Abstract
The invention provides preparation process research of an exenatide slow-release preparation, which comprises the following steps of: mixing a drug with PLGA (polymer acid-glycollic acid) copolymers with different models and different viscosity by a hot-melting extruding, freezing and grinding method, and carrying out hot-melting mixing, extruding and grinding in an equidirectional double-screw hot-melting extruder; and screening, cleaning a burst released solvent, freezing and drying. The exenatide is a drug for treating diabetes mellitus. A patient needs to be frequently injected with the drug. According to the invention, the PLGA copolymers are mixed to be prepared into the slow-release preparation, the drug can be slowly released in vivo, the released drug is the range of a therapeutic window, the release period can reach one week, two weeks, three weeks or four weeks, in this way, the compliance of the drug use is increased, and the quality of the life of the patient can be improved.
Description
Technical field
The preparation of Exenatide release preparation relates to the research of Exenatide pharmaceutical preparation, especially the research of Exenatide release preparation.
Background technology
Exenatide (Exenatide) is the synthetic material of Exendin-4, and Exendin-4 is the Monster of Southwestern United Stares a kind of 39 amino acid whose polypeptide, the molecular formula C of containing in the secreted saliva on the feed the time
184H
282N
50O
60S, molecular weight 4186.57.
Its aminoacid consists of:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH
2
Exendin-4 is glucagon-like-peptide-1 (GLP-1) analog; Has 53% homology with mammiferous GLP-1 aminoacid sequence; It is effective GLP-1 receptor stimulating agent; Have glucose dependent form blood sugar control concentration, stimulate insulin secretion, the glucagon suppression secretion, suppress the B cell apoptosis, slow down gastric emptying, reduce physiologically active such as appetite, be suitable for the treatment of type ii diabetes.These physiologically actives of Exendin-4 are similar with GLP-1; But GLP-1 is degraded by DPP IV (DPP-IV) in vivo rapidly, and the half-life has only 1-2 minute, can be eliminated very soon; And Exendin-4 is difficult for being degraded by DPP-IV; Removing to DPP-IV has certain resistant function, in vivo the circulation half-life longer, can reach 60-90 minute.
At present; It is more and more that Exenatide is used to treat the research of type ii diabetes; And its new drug application (NDA) obtains drugs approved by FDA in April, 2005, is used to improve the glycemic control of using metformin and the unfavorable type ii diabetes patient of sulfonylureas.Clinical effectiveness shows that it is obvious that Exenatide is used for the treating diabetes effect, and side reaction is less, but every day, twice subcutaneous administration brought a lot of inconvenience to patient, and its slow releasing preparation then can significantly improve compliance of patients.
Summary of the invention
The objective of the invention is in order to solve the deficiency of the frequent drug administration by injection of Exenatide, provide a kind of can a week, two weeks, three weeks or the Exenatide release preparation that is administered once all around.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
A kind of Injectable sustained release preparation, the active component of its medicine is an Exenatide, the adjuvant of medicine comprises: PLGA, protein polypeptide stabilizing agent.Through the hot melt extruding technology, its preparation is become the strip medicine, cutting is then pulverized, and washes prominent releasing, and lyophilization is processed.Other attaches solvent for injection.
A kind of Injectable sustained release preparation, its active component are Exenatide, and Exenatide content is 0mg-10mg in every injection.
A kind of Injectable sustained release preparation; Polylactic acid-glycolic guanidine-acetic acid [poly (lactide-co-glycolide); PLGA] be by lactic acid (LA) and hydroxyacetic acid (GA) a kind of macromolecular material of forming of block copolymerization in varing proportions; Have excellent biological compatibility and degradability, its end product is carbon dioxide and water.PLGA of the present invention is LA: GA=25: 75～85: 15, and viscosity is 0.15～1.8.When carrying out melt compounding, PLGA and the Exenatide mass ratio that feeds intake is 0～100.
A kind of Injectable sustained release preparation, protein polypeptide stabilizing agent comprise one or more the mixture in mannitol, sodium carboxymethyl cellulose, polyvidone (PVA), polysorbate 20, the polyoxyethylene sorbitan monoleate.The protein polypeptide stabilizing agent can prepare the stability in the process at slow releasing preparation by the protected protein polypeptide.Every contained protectant amount of slow releasing preparation is 0g～2g.
A kind of Injectable sustained release preparation, its solvent for injection can make pharmaceutical suspension, thereby makes administration evenly, smoothly.Comprise a kind of or its mixture in sodium carboxymethyl cellulose, the mannitol in the solvent for injection.The amount that every solvent for injection contains sodium carboxymethyl cellulose or mannitol is 0g～1g.
A kind of Injectable sustained release preparation adopts hot melt to extrude appearance and carries out hot melt and extrude, and it is parallel dual-screw hot melt extruder that the hot melt of employing is extruded appearance, and medicine can multidigit point administration in the hot melt extruder, the mixing of multidigit point.Its melt compounding temperature is different in different sites.Each zone temperatures scope can be set at: Die district, 45～90 ℃; The 10-4 district, 45～90 ℃; 3,2 districts, 45～80 ℃.The setting of each zone temperatures can be decided according to pharmaceutical properties.When carrying out melt compounding, the twin screw rotating speed can be set at 0～500rpm.
A kind of Injectable sustained release preparation when conducting powder is broken, adopts ball mill or pulverizer, and can medicine be crushed to particle diameter is 0～150 μ m.
A kind of Injectable sustained release preparation, when pulverizing, microparticle surfaces has the free drug of certain mass, causes the Exenatide prominent phenomenon of releasing in vivo after the administration.Event need be washed prominent releasing to the medicine after pulverizing.Washing the prominent solvent of releasing is water for injection.
Exenatide is used to treat diabetes, and administration is frequent, and its preparation is become slow releasing preparation, can make things convenient for the patient to use, and is simple, improves the compliance of patient's medication, improved patient's quality of life.
The specific embodiment
For overcoming the shortcoming that the Exenatide half-life is short, administration is frequent, the spy has developed the Exenatide release preparation.
Mode through embodiment further specifies the present invention below, among the scope of embodiments under therefore not limiting the present invention to.
Embodiment 1: Exenatide and PLGA (50/50, viscosity 0.55) are carried out melt compounding with 1: 30 mass ratio, and the twin screw rotating speed is 160rpm, and each zone temperatures is set at: Die district, 70 ℃; The 10-4 district, 70 ℃; 3,2 districts, 65 ℃.After the medicine hot melt extruded, put in the 2-8 ℃ of refrigerator and solidify.Be cut into the bar of 1cm size.Place ball mill, in liquid nitrogen, carry out freezing and pulverizing.The standard screen cloth of medicine through 150 μ m apertures after pulverizing sieved, be used in the water for injection centrifuge washing of placing in the 2-8 ℃ of refrigerator then, abandon supernatant, add the lyophilizing excipient, carry out lyophilization.
Other attaches solvent for injection, and it consists of: every water for injection 2ml that contains the mannitol of 20mg.
Embodiment 2: Exenatide and PLGA (75/25, viscosity 0.55) are carried out melt compounding with 1: 40 mass ratio, and the twin screw rotating speed is 160rpm, and each zone temperatures is set at: Die district, 70 ℃; The 10-4 district, 70 ℃; 3,2 districts, 65 ℃.After the medicine hot melt extruded, put in the 2-8 ℃ of refrigerator and solidify.Be cut into the bar of 1cm size.Place ball mill, in liquid nitrogen, carry out freezing and pulverizing.The standard screen cloth of medicine through 150 μ m apertures after pulverizing sieved, be used in the water for injection centrifuge washing of placing in the 2-8 ℃ of refrigerator then, abandon supernatant, add the lyophilizing excipient, carry out lyophilization.
Other attaches solvent for injection, and it consists of: every contains the mannitol of 10mg and the water for injection 2ml of 10mg sodium carboxymethyl cellulose.
Embodiment 3: Exenatide and PLGA (75/25, viscosity 0.55) are carried out melt compounding with 1: 10 mass ratio, and the twin screw rotating speed is 160rpm, and each zone temperatures is set at: Die district, 80 ℃; The 10-4 district, 80 ℃; 3,2 districts, 75 ℃.After the medicine hot melt extruded, put in the 2-8 ℃ of refrigerator and solidify.Be cut into the bar of 1cm size.Place ball mill, in liquid nitrogen, carry out freezing and pulverizing.The standard screen cloth of medicine through 150 μ m apertures after pulverizing sieved, be used in the water for injection centrifuge washing of placing in the 2-8 ℃ of refrigerator then, abandon supernatant, add the lyophilizing excipient, carry out lyophilization.
Other attaches solvent for injection, and it consists of: every contains the mannitol of 10mg and the water for injection 2ml of 10mg sodium carboxymethyl cellulose.
Embodiment 4: Exenatide and PLGA (50/50, viscosity 0.75) are carried out melt compounding with 1: 40 mass ratio, and the twin screw rotating speed is 160rpm, and each zone temperatures is set at: Die district, 70 ℃; The 10-4 district, 70 ℃; 3,2 districts, 65 ℃.After the medicine hot melt extruded, put in the 2-8 ℃ of refrigerator and solidify.Be cut into the bar of 1cm size.Place ball mill, in liquid nitrogen, carry out freezing and pulverizing.The standard screen cloth of medicine through 150 μ m apertures after pulverizing sieved, be used in the water for injection centrifuge washing of placing in the 2-8 ℃ of refrigerator then, abandon supernatant, add the lyophilizing excipient, carry out lyophilization.
Other attaches solvent for injection, and it consists of: every water for injection 2ml that contains the mannitol of 15mg.
Embodiment 5: Exenatide and PLGA (75/25, viscosity 0.25) are carried out melt compounding with 1: 10 mass ratio, and the twin screw rotating speed is 160rpm, and each zone temperatures is set at: Die district, 80 ℃; The 10-4 district, 80 ℃; 3,2 districts, 75 ℃.After the medicine hot melt extruded, put in the 2-8 ℃ of refrigerator and solidify.Be cut into the bar of 1cm size.Place ball mill, in liquid nitrogen, carry out freezing and pulverizing.The standard screen cloth of medicine through 150 μ m apertures after pulverizing sieved, be used in the water for injection centrifuge washing of placing in the 2-8 ℃ of refrigerator then, abandon supernatant, add the lyophilizing excipient, carry out lyophilization.
Other attaches solvent for injection, and it consists of: every contains the mannitol of 10mg and the water for injection 2ml of 10mg sodium carboxymethyl cellulose.
Claims (8)
1. Injectable sustained release preparation, the active component of its medicine is an Exenatide, the adjuvant of medicine comprises: PLGA, protein polypeptide stabilizing agent.Through the hot melt extruding technology, its preparation is become the strip medicine, cutting is then pulverized, and washes prominent releasing, and lyophilization is processed.Other attaches solvent for injection.
2. Injectable sustained release preparation, its active component is an Exenatide, Exenatide content is 0mg～10mg in every injection.
3. Injectable sustained release preparation; Polylactic acid-glycolic guanidine-acetic acid [poly (lactide-co-glycolide); PLGA] be by lactic acid (LA) and hydroxyacetic acid (GA) a kind of macromolecular material of forming of block copolymerization in varing proportions; Have excellent biological compatibility and degradability, its end product is carbon dioxide and water.PLGA of the present invention is LA: GA=25: 75～85: 15, and viscosity is 0.15～1.8.When carrying out melt compounding, PLGA and the Exenatide mass ratio that feeds intake is 0～100.
4. Injectable sustained release preparation, protein polypeptide stabilizing agent comprise one or more the mixture in mannitol, sodium carboxymethyl cellulose, polyvidone (PVA), polysorbate 20, the polyoxyethylene sorbitan monoleate.The protein polypeptide stabilizing agent can prepare the stability in the process at slow releasing preparation by the protected protein polypeptide.Every contained protectant amount of slow releasing preparation is 0g～2g.
5. Injectable sustained release preparation, its solvent for injection can make pharmaceutical suspension, thereby makes administration evenly, smoothly.Comprise a kind of or its mixture in sodium carboxymethyl cellulose, the mannitol in the solvent for injection.The amount that every solvent for injection contains sodium carboxymethyl cellulose or mannitol is 0g～1g.
6. Injectable sustained release preparation adopts the hot melt extruder to carry out hot melt and extrudes, and the hot melt extruder of employing is a parallel dual-screw hot melt extruder, and medicine can multidigit point administration in the hot melt extruder, the mixing of multidigit point.Its melt compounding temperature is different in different sites.Each zone temperatures scope can be set at: Die district, 45～90 ℃; The 10-4 district, 45～90 ℃; 3,2 districts, 45～80 ℃.The setting of each zone temperatures can be decided according to pharmaceutical properties.When carrying out melt compounding, the twin screw rotating speed can be set at 0～500rpm.
7. an Injectable sustained release preparation when conducting powder is broken, adopts ball mill or pulverizer, and can medicine be crushed to particle diameter is 0～150 μ m.
8. Injectable sustained release preparation, when pulverizing, microparticle surfaces has the free drug of certain mass, causes the Exenatide prominent phenomenon of releasing in vivo after the administration.Event need be washed prominent releasing to the medicine after pulverizing.Washing the prominent solvent of releasing is water for injection.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010105071541A CN102440966A (en) | 2010-10-06 | 2010-10-06 | Preparation process research of exenatide slow-release preparation |
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| CN2010105071541A CN102440966A (en) | 2010-10-06 | 2010-10-06 | Preparation process research of exenatide slow-release preparation |
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| CN102440966A true CN102440966A (en) | 2012-05-09 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432570A (en) * | 2013-09-09 | 2013-12-11 | 深圳翰宇药业股份有限公司 | Thymalfasin sustained-release microspheres and preparation method thereof |
| CN110582268A (en) * | 2017-03-22 | 2019-12-17 | Amw公司 | extruded depot dosage forms for sustained release of active ingredients |
| CN111065378A (en) * | 2017-07-25 | 2020-04-24 | Pk医疗公司 | Method of making a drug delivery composition |
| CN113797154A (en) * | 2020-06-17 | 2021-12-17 | 江南大学 | Preparation method and application of sustained-release material for reducing blood sugar |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101065116A (en) * | 2004-04-15 | 2007-10-31 | 安米林药品公司 | Poly (lactide-co-glycolide)-based sustained release microcapsules comprising a polypeptide and a sugar |
-
2010
- 2010-10-06 CN CN2010105071541A patent/CN102440966A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101065116A (en) * | 2004-04-15 | 2007-10-31 | 安米林药品公司 | Poly (lactide-co-glycolide)-based sustained release microcapsules comprising a polypeptide and a sugar |
Non-Patent Citations (1)
| Title |
|---|
| 杨睿等: "热熔挤出技术及其在药物传递系统中的应用", 《中国新药杂志》, vol. 16, no. 4, 31 December 2007 (2007-12-31), pages 279 - 284 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432570A (en) * | 2013-09-09 | 2013-12-11 | 深圳翰宇药业股份有限公司 | Thymalfasin sustained-release microspheres and preparation method thereof |
| CN110582268A (en) * | 2017-03-22 | 2019-12-17 | Amw公司 | extruded depot dosage forms for sustained release of active ingredients |
| CN111065378A (en) * | 2017-07-25 | 2020-04-24 | Pk医疗公司 | Method of making a drug delivery composition |
| CN113797154A (en) * | 2020-06-17 | 2021-12-17 | 江南大学 | Preparation method and application of sustained-release material for reducing blood sugar |
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Application publication date: 20120509 |