CN102198103B - Stable exenatide sustained-release microsphere preparation and preparation method thereof - Google Patents
Stable exenatide sustained-release microsphere preparation and preparation method thereof Download PDFInfo
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- CN102198103B CN102198103B CN201110142532.5A CN201110142532A CN102198103B CN 102198103 B CN102198103 B CN 102198103B CN 201110142532 A CN201110142532 A CN 201110142532A CN 102198103 B CN102198103 B CN 102198103B
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Abstract
The invention provides a stable exenatide sustained-release microsphere preparation and a preparation method thereof. The preparation contains 0.1 to 12.5 mass percent of exenatide and 77.5 to 99 percent of glycolide and lactide copolymer. The preparation method comprises the following steps: (a) dissolves glycolide and lactide copolymer in an organic solvent to form an oil phase, wherein the organic solvent may be one or the combination of dichloromethane and ethyl acetate; (b) dissolving exenatide, a protective agent and a suspending aid in water to form an internal water phase; (c) mixing the internal water phase and the oil phase to form emulsion; and (d) after the organic solvent violates, obtaining exenatide-containing sustained-release microspheres. As the formula composition of the stable exenatide sustained-release microsphere preparation is reasonable, the stable exenatide sustained-release microsphere preparation is prepared by common sustained-release microsphere technique, and the sustained-release period of the sustained-release microspheres is as long as 7 to 35 days. The technical effect is better when the exenatide sustained-release microspheres are prepared by a multiple emulsion (water-oil-water) method.
Description
Technical field
The present invention relates to the field of pharmaceutical preparations of sustained-release micro-spheres, relate in particular to Exenatide release microsphere preparation and preparation method thereof.
Background technology
Exenatide is the natural incretin mimetic of secreting from Southwestern United Stares Monster saliva, can simulate the effect of glucagon-like-peptide-1 (glucagon like peptide-1 is GLP-1), thereby reach the effect of controlling blood glucose, by U.S. Amylin and Lilly drugmaker joint development.The Exenatide of synthetic is the first incretin mimetic of getting permission listing, its new drug application obtains U.S. FDA approval in April, 2005, is mainly used in improving the glycemic control that metformin and sulfonylureas are treated undesirable type 2 diabetes mellitus patient.Exenatide is a kind of 39 amino acid whose polypeptide that contain, and only has 53% homology with the aminoacid sequence of mammal GLP-1; Mammiferous GLP-1 is from the glucagon protogene of small intestinal L cell; And Exenatide is not from deriving from glucagon protogene, therefore can not be called is the analog of GLP-1.But Exenatide is a kind of effective activator of pancreas GLP-1 receptor, has high affinity with GLP-1 receptor.Therefore Exenatide there is the biological action similar to GLP-1, therefore can be described as incretin mimetic, GLP-1 intends the agonist like thing or GLP-1R.
Exenatide injection is approved listing by U.S. FDA in April, 2005, and commodity are called Byetta.Said preparation be proved improve glycemic control and lose weight aspect there is good result.But because the half-life of Exenatide is only 2.4 hours, be steadily to control blood glucose, need every day subcutaneous injection to be administered twice, injection makes patient's compliance poor frequently.
Summary of the invention
The invention provides a kind of can effectively extend Exenatide Exenatide release microsphere preparation of action time in vivo, reduced the administration frequency of Exenatide." microsphere " of the present invention comprises the spheroidal microcapsule of class or the small microcapsule of granule in galenic pharmacy.The Exenatide release microsphere preparation of the present invention slow release cycle in vitro can reach 7-35 days.
The present invention also provides a kind of preparation method of Exenatide release microsphere preparation.
Exenatide release microsphere preparation of the present invention, comprises Exenatide, Vicryl Rapide, and its mass percent is respectively: Exenatide 0.1%-12.5%, Vicryl Rapide 77.5%-99%.
Vicryl Rapide [poly(lactide-co-glycolide) be PLGA] be to have Acetic acid, hydroxy-, bimol. cyclic ester and lactide a kind of macromolecular material that block copolymerization forms in varing proportions, have good biocompatibility and degradability, its final catabolite is carbon dioxide and water.Vicryl Rapide described in the present invention is Acetic acid, hydroxy-, bimol. cyclic ester: the copolymer that lactide is 25:75 ~ 75:25, and its molecular weight is 2000 ~ 25000 dalton, intrinsic viscosity is 0.1 ~ 0.5dL/g.
In order to realize Exenatide release microsphere, have desirable drug loading, it is applied clinically becomes a kind of possibility.Inventor studies the physicochemical property of Exenatide and formulation factors, found that, adopt Exenatide 0.1%-12.5%, the formula preparation of Vicryl Rapide 77.5%-99% becomes sustained-release micro-spheres, can realize the Exenatide release microsphere that drug loading is 0.5%-9.8%, in writing out a prescription by change, the consumption of Vicryl Rapide can regulate the drug loading of microsphere, facilitates clinical application.
Exenatide release microsphere preparation of the present invention also comprises the protective agent that mass percent is 0.1-10.0%, and this protective agent is selected from a kind of or two or more the combination arbitrarily in human serum albumin, gelatin, trehalose, sucrose, ammonium sulfate or mannitol.Because Exenatide is 39 peptides, change or the degraded of meeting occurred conformation in preparation process, existing bibliographical information Exenatide can form the tetramer, adds above-mentioned protective agent in preparation process, can improve the stability of Exenatide; Meanwhile, owing to adding protective agent, reduce the chemical interaction between other the contained components in polypeptide and this sustained release microsphere agents, thereby loss of activity is reduced to minimum; And, owing to adding protective agent to make sustained release microsphere agents keep good slow release characteristic.Applicant's discovery, when protectant concentration is less than 0.1%, a little less than it improves the effect of Exenatide stability, DeGrain; And can cause because consumption is excessive when protectant concentration is greater than 10.0% density and the viscosity of interior water increase, the particle diameter of prepared colostrum can increase, and further causes the particle diameter of the sustained-release micro-spheres that finally obtains to become large, is unfavorable for the control release of medicine; Concentration is excessive in addition also can cause separating out of Exenatide on the contrary.
Inventor finds in research process, and protectant concentration is when 0.1-10.0%, owing to adding protective agent can improve the stability of Exenatide; Unexpected discovery, when protectant mass percent is 0.1-10.0%, can increase the drug loading of sustained-release micro-spheres.
Exenatide release microsphere preparation of the present invention also comprises that mass percent is the suspending agent of 0.01%-10.0%, and this suspending agent is selected from a kind of or two or more the combination arbitrarily in tragakanta, arabic gum, sodium alginate, gelatin, pectin, chitosan, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, polyvidone, polyvinyl alcohol.When if the present invention adopts multi-emulsion method (W/O/W) to prepare Exenatide release microsphere, because Exenatide is soluble in water, meeting in preparation process is because because Exenatide causes envelop rate very low from the outside water migration of interior water, and the drug loading of the sustained release microsphere agents finally obtaining is very low; And in preparation process, add above-mentioned suspending agent can increase the viscosity of interior water and then hindered the migration of Exenatide, thereby increased the drug loading of envelop rate and sustained-release micro-spheres, inventor finds in research process, when suspending agent concentration is less than 0.01%, its effect of drug loading that has increased envelop rate and sustained-release micro-spheres is not obvious, and can preparation excessive due to viscosity and microsphere bring difficulty when its concentration is greater than 10.0%.
Because the present invention writes out a prescription, form rationally, can prepare by common sustained-release micro-spheres technology, the slow release cycle of this sustained-release micro-spheres can be realized and be reached 7-35 days.Adopt multi-emulsion method (W/O/W) to prepare Exenatide release microsphere and have better technique effect.
In completing process of the present invention, applicant finds that following preparation method can make above-mentioned sustained release microsphere agents obtain better effect, and this preparation method comprises the following steps:
(a) Vicryl Rapide is dissolved in to organic solvent, forms oil phase, wherein organic solvent is a kind of or its combination in dichloromethane, ethyl acetate;
(b) Exenatide, protective agent, suspending agent is water-soluble, water in forming;
(c) interior water and described oil phase are mixed to form to colostrum, and this colostrum is joined in the outer water that contains surfactant and forms emulsion.Described surfactant is selected from a kind of or two or more the combination arbitrarily in polyvinyl alcohol, poloxamer, enuatrol, sodium stearate, tween or span.
(d), after organic solvent volatilization, obtain being enclosed with the sustained-release micro-spheres of Exenatide.
The preparation method of sustained-release micro-spheres of the present invention (a) step and (b) step its objective is and prepares the required semi-finished product of colostrum, thus preparation method (a) step and (b) step can carry out simultaneously, the carrying out of order in no particular order.
Above-mentioned preparation method preferably includes following steps:
Vicryl Rapide is dissolved in to organic solvent, and making described Vicryl Rapide concentration is 10%-40%(W/V) oil phase, wherein organic solvent is a kind of or its compositions in dichloromethane, ethyl acetate.
Exenatide, protective agent, suspending agent is water-soluble, and forming Exenatide concentration is 5%-50%(W/V) interior water.
Interior water and described oil phase are mixed to form to colostrum, and this colostrum is joined in the outer water that contains surfactant and forms emulsion.Described surfactant is selected from a kind of or two or more the combination arbitrarily in polyvinyl alcohol, poloxamer, enuatrol, sodium stearate, tween or span.Preferred surfactant is polyvinyl alcohol, and its concentration is 0.1%-5%(W/V).
After organic solvent volatilization, obtain being enclosed with the sustained-release micro-spheres of Exenatide.
In in the present invention, the volume ratio of water and the volume ratio of oil phase, outer water and colostrum all can have influence on the release of particle diameter, drug loading and the medicine of final sustained release microsphere agents.Although inventor finds can improve when the volume ratio of interior water and oil phase is greater than 1:5 the drug loading of microsphere in research process, the envelop rate of medicine can decline, and causes the waste of medicine; When being less than 1:100, its volume ratio can cause the decline of drug loading.When the volume ratio of outer water and colostrum is less than 20:1, can too smallly due to the volume of outer water cause solidifying of microsphere slow, extend hardening time, and a large amount of medicines can enter in water, causes drug loading to decline; When its volume ratio is greater than 2000:1, can make microsphere curing rate too fast because outer water is excessive, affect sphericity and the outward appearance of microsphere.Therefore the interior water described in the present invention and the volume ratio of oil phase are 1:5-1:100, the volume ratio 20:1-2000:1 of outer water and colostrum.
Colostrum in the present invention can adopt the modes such as high-speed stirred, high pressure homogenize or ultrasonication to prepare, as long as can guarantee that the particle diameter of colostrum meets the requirements.Prepared colostrum will leave in 20 ℃ of following environment to increase the stability of colostrum.
accompanying drawing explanation:
The cumulative in vitro release profiles of the Exenatide release microsphere preparation that Fig. 1: embodiment 1 is prepared.
The cumulative in vitro release profiles of the Exenatide release microsphere preparation that Fig. 2: embodiment 2 is prepared.
The cumulative in vitro release profiles of the Exenatide release microsphere preparation that Fig. 3: embodiment 3 is prepared.
Embodiment
Embodiment mono-:
Take 800mg Exenatide and 300mg gelatin and be dissolved in 1ml water for injection, as interior water; Take in the dichloromethane that 6g Vicryl Rapide is dissolved in 15ml as oil phase; Oil phase is joined in interior water, adopt high-speed stirred (23000rpm) 15 seconds, obtain colostrum, leave in 20 ℃ of following environment; This colostrum is joined to 6000 milliliters of 0.5%(W/V under the state stirring) poly-vinyl alcohol solution obtain emulsion, this emulsion is continued to stir and within 3 hours, flings to dichloromethane, centrifugal, washing is collected and is obtained microsphere, microspherulite diameter is less than 100 microns.Drug loading is 9.8%, and envelop rate is 87.0%.
Embodiment bis-:
Take 200mg Exenatide, 300mg sodium carboxymethyl cellulose and 100mg sucrose and be dissolved in 1ml water for injection, as interior water; Take in the dichloromethane that 12.5g Vicryl Rapide is dissolved in 50ml as oil phase; Oil phase is joined in interior water, adopt high-speed stirred (23000rpm) 15 seconds, obtain colostrum, leave in 20 ℃ of following environment; This colostrum is joined to 6000 milliliters of 0.5%(W/V under the state stirring) poly-vinyl alcohol solution obtain emulsion, this emulsion is continued to stir and within 3 hours, flings to dichloromethane, centrifugal, washing is collected and is obtained microsphere, microspherulite diameter is less than 100 microns.Drug loading is 0.5%, envelop rate 32.7%.
Embodiment tri-:
Take 500mg Exenatide, 300mg gelatin and 100mg mannitol and be dissolved in 2ml water for injection, as interior water; Take in the dichloromethane that 8g Vicryl Rapide is dissolved in 80ml as oil phase; Oil phase is joined in interior water, adopt ultrasonic cell disruption instrument (Branson S-250D) to carry out ultrasonic 30 seconds, obtain colostrum, leave in 20 ℃ of following environment; This colostrum is joined to 10000 milliliters of 1.0%(W/V under the state stirring) poly-vinyl alcohol solution obtain emulsion, this emulsion is continued to stir and within 3 hours, flings to dichloromethane, centrifugal, washing is collected and is obtained microsphere, microspherulite diameter is less than 50 microns.Drug loading is 4.2%.Envelop rate is 74.7%
Embodiment tetra-:
The mensuration of Exenatide release microsphere release in vitro
Exenatide release microsphere preparation prepared by above-described embodiment carries out the mensuration of release in vitro, assay method is: precision takes medicine-containing microsphere 50mg and is placed in 10ml tool plug test tube, the phosphate buffer that the pH of usining is 7.4 (contains 0.02% Hydrazoic acid,sodium salt as antibacterial, 0.05% Tween 80 is wetting agent) 10ml is release medium, be placed in water bath with thermostatic control shaking table, under hunting speed 100rpm, 37 ℃ ± 0.5 ℃ condition of temperature, carry out the vitro release of microsphere and measure.At 1d, 2d, 4d, 7d, 14d, 21d, 28d, respectively get 0.5ml release medium for the content of high effective liquid chromatography for measuring Exenatide respectively, and supplement fresh release medium.Fig. 1,2,3 is respectively the cumulative in vitro release profiles of the prepared Exenatide release microsphere preparation of embodiment 1,2,3.By Fig. 1～3, can be found out, the prepared Exenatide release microsphere preparation of the present invention has good slow release effect, and prominent the releasing in 1 day is all less than 25%.Its slow release cycle can be one week, can be also one month.
Above content is in conjunction with concrete preferred implementation further description made for the present invention, can not assert that specific embodiment of the invention is confined to these explanations.For 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 (2)
1. an Exenatide release microsphere preparation, is characterized in that: take 800mg Exenatide and 300mg gelatin and be dissolved in 1ml water for injection, as interior water; Take in the dichloromethane that 6g Vicryl Rapide is dissolved in 15ml as oil phase; Oil phase is joined in interior water, adopt high-speed stirred (23000rpm) 15 seconds, obtain colostrum, leave in 20 ℃ of following environment; This colostrum is joined to 6000 milliliters of 0.5%(W/V under the state stirring) poly-vinyl alcohol solution obtain emulsion, this emulsion is continued to stir and within 3 hours, fling to dichloromethane, centrifugal, washing is collected and is obtained microsphere, and microspherulite diameter is less than 100 microns, drug loading is 9.8%, and envelop rate is 87.0%.
2. an Exenatide release microsphere preparation, is characterized in that: take 500mg Exenatide, 300mg gelatin and 100mg mannitol and be dissolved in 2ml water for injection, as interior water; Take in the dichloromethane that 8g Vicryl Rapide is dissolved in 80ml as oil phase; Oil phase is joined in interior water, adopt ultrasonic cell disruption instrument (Branson S-250D) to carry out ultrasonic 30 seconds, obtain colostrum, leave in 20 ℃ of following environment; This colostrum is joined to 10000 milliliters of 1.0%(W/V under the state stirring) poly-vinyl alcohol solution obtain emulsion, this emulsion is continued to stir and within 3 hours, fling to dichloromethane, centrifugal, washing is collected and is obtained microsphere, and microspherulite diameter is less than 50 microns, drug loading is 4.2%, and envelop rate is 74.7%.
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| CN102552169B (en) * | 2012-02-17 | 2015-07-29 | 深圳市健元医药科技有限公司 | A kind of Aviptadil acetate sustained-release microsphere preparation and preparation method thereof |
| CN103142490B (en) * | 2012-11-28 | 2014-08-06 | 深圳市健元医药科技有限公司 | Nesiritide acetate sustained-release microsphere preparation and preparation method thereof |
| CN103142475B (en) * | 2012-11-28 | 2014-08-06 | 深圳市健元医药科技有限公司 | Exenatideacetate sustained-release microsphere preparation and preparation method thereof |
| CN103142489B (en) * | 2012-11-28 | 2014-08-06 | 深圳市健元医药科技有限公司 | Human alpha-atrial natriuretic peptide sustained release microsphere preparation and preparation method thereof |
| CN104107165B (en) * | 2013-04-17 | 2018-11-30 | 长春百益制药有限责任公司 | A kind of Exenatide microball preparation, preparation method and its application |
| CN104248628B (en) * | 2013-06-25 | 2017-08-29 | 深圳翰宇药业股份有限公司 | A kind of lixisenatide sustained-release micro-spheres and preparation method thereof |
| CN104922660A (en) * | 2014-03-19 | 2015-09-23 | 陕西天森药物研究开发有限公司 | Application in treating diabetes and preparation method of exenatide long-acting sustain-released agent |
| WO2015158270A1 (en) * | 2014-04-16 | 2015-10-22 | 山东绿叶制药有限公司 | Exenatide-containing composition and preparation method therefor |
| CN103932993B (en) * | 2014-04-16 | 2016-02-03 | 山东绿叶制药有限公司 | A kind of compositions containing Exenatide or its salt |
| CN103932992B (en) * | 2014-04-16 | 2015-11-04 | 山东绿叶制药有限公司 | A kind of compositions containing Exenatide |
| CN103990114B (en) * | 2014-05-06 | 2016-05-18 | 浙江圣兆药物科技股份有限公司 | A kind of Exenatide release microsphere composition |
| WO2017107906A1 (en) * | 2015-12-22 | 2017-06-29 | 四川科伦药物研究院有限公司 | Exenatide microsphere preparation and preparation method thereof |
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