CN102198103A - 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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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 that excretory natural intestine pancreotropic hormone is intended like thing 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 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 the glucagon protogene 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 a kind of effective activator of pancreas GLP-1 receptor, has high affinity with the GLP-1 receptor.Therefore have the biological action similar, intend intending agonist like thing or GLP-1R like thing, GLP-1 so Exenatide can be described as incretin to GLP-1.
The Exenatide injection obtains the drugs approved by FDA listing in April, 2005, and commodity are called Byetta.Said preparation be proved improve glycemic control and lose weight aspect have good result.But because the half-life of Exenatide only is 2.4 hours, be steady blood sugar control, need subcutaneous injection every day is administered twice, and frequent injection makes patient's compliance relatively poor.
Summary of the invention
The invention provides a kind of can effectively prolong Exenatide Exenatide release microsphere preparation of action time in vivo, reduced the administration frequency of Exenatide." microsphere " of the present invention comprises spheroidal microcapsule of class or the small microcapsule of granule in the galenic pharmacy.Exenatide release microsphere preparation of the present invention can reach 7-35 days in the external slow release cycle.
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] is that Acetic acid, hydroxy-, bimol. cyclic ester and lactide a kind of macromolecular material of forming of block copolymerization is in varing proportions arranged, have excellent biological compatibility and degradability, its final catabolite is carbon dioxide and water.Vicryl Rapide described in the present invention is an Acetic acid, hydroxy-, bimol. cyclic ester: lactide is the copolymer of 25:75 ~ 75:25, and its molecular weight is 2000 ~ 25000 dalton, and intrinsic viscosity is 0.1 ~ 0.5dL/g.
In order to realize that Exenatide release microsphere has ideal drug loading, it is used clinically becomes a kind of possibility.The inventor studies the physicochemical property and the prescription factor of Exenatide, found that, adopt Exenatide 0.1%-12.5%, the prescription of Vicryl Rapide 77.5%-99% is prepared into sustained-release micro-spheres, can realize that drug loading is the Exenatide release microsphere of 0.5%-9.8%, can regulate the drug loading of microsphere by the consumption that changes Vicryl Rapide in the prescription, make things convenient for 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 the mannitol.Because Exenatide is 39 peptides, the 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; Simultaneously,, 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 owing to add protective agent; And, make sustained release microsphere agents keep the good slow release characteristic owing to add protective agent.The applicant finds, when protectant concentration less than 0.1% the time, it improves a little less than the effect of Exenatide stability, DeGrain; And the density and the viscosity of water increase in protectant concentration can cause because consumption is excessive greater than 10.0% the time, and the particle diameter of prepared colostrum can increase, and further cause the particle diameter of the sustained-release micro-spheres that finally obtains to become greatly, are unfavorable for controlled delivery of pharmaceutical agents release; Concentration is excessive in addition also can cause separating out of Exenatide on the contrary.
The inventor finds that in research process protectant concentration is when 0.1-10.0%, owing to add the stability that protective agent can improve Exenatide; The 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 comprises that also 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, the polyvinyl alcohol.When if the present invention adopts multi-emulsion method (W/O/W) preparation Exenatide release microsphere, because Exenatide is soluble in water, meeting in preparation process is because owing to Exenatide causes envelop rate very low from the outside water migration of interior water, and the drug loading of the sustained release microsphere agents that finally obtains is very low; And in preparation process, add above-mentioned suspending agent can increase in water viscosity so that hindered the migration of Exenatide, thereby increased the drug loading of envelop rate and sustained-release micro-spheres, the inventor finds in research process, when suspending agent concentration less than 0.01% the time, its effect of drug loading that has increased envelop rate and sustained-release micro-spheres is not obvious, and when its concentration can preparation microsphere brings difficulty because viscosity is excessive greater than 10.0% the time.
Form rationally because the present invention writes out a prescription, can prepare by common sustained-release micro-spheres technology, the slow release cycle of this sustained-release micro-spheres can realize reaching 7-35 days.Adopt multi-emulsion method (W/O/W) preparation Exenatide release microsphere to have better technique effect.
In finishing process of the present invention, the applicant finds that following preparation method can make above-mentioned sustained release microsphere agents obtain better effect, and this preparation method may further comprise the steps:
(a) Vicryl Rapide is dissolved in organic solvent, forms oil phase, wherein organic solvent is a kind of or its combination in dichloromethane, the ethyl acetate;
(b) Exenatide, protective agent, suspending agent is water-soluble, water in forming;
(c) interior water is mixed the formation colostrum with described oil phase, and this colostrum is joined the outer aqueous phase formation emulsion that contains surfactant.Described surfactant is selected from a kind of or two or more the combination arbitrarily in polyvinyl alcohol, poloxamer, enuatrol, sodium stearate, tween or the span.
(d) treat organic solvent volatilization after, 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 preparation colostrum required semi-finished product, so preparation method (a) step and (b) step can carry out the carrying out of order in no particular order simultaneously.
Above-mentioned preparation method preferably includes following steps:
Vicryl Rapide is dissolved in 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, the ethyl acetate.
Exenatide, protective agent, suspending agent is water-soluble, and forming Exenatide concentration is 5%-50%(W/V) interior water.
Interior water is mixed the formation colostrum with described oil phase, and this colostrum is joined the outer aqueous phase formation emulsion that contains surfactant.Described surfactant is selected from a kind of or two or more the combination arbitrarily in polyvinyl alcohol, poloxamer, enuatrol, sodium stearate, tween or the span.Preferred surfactants is a polyvinyl alcohol, and its concentration is 0.1%-5%(W/V).
After treating the organic solvent volatilization, obtain being enclosed with the sustained-release micro-spheres of Exenatide.
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 among the present invention.Though the inventor finds can improve when volume ratio when interior water and oil phase is greater than 1:5 the drug loading of microsphere in research process, the envelop rate of medicine can descend, and causes the waste of medicine; When its volume ratio then can cause the decline of drug loading during less than 1:100.When the volume ratio of outer water and colostrum can cause the curing of microsphere slow because the volume of outer water is too small during less than 20:1, prolong hardening time, and a large amount of medicines can enter in the water, causes drug loading decline; When its volume ratio during greater than 2000:1 can owing to outside the excessive microsphere curing rate that makes of water too fast, influence the 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 among the present invention can adopt modes such as high-speed stirred, high pressure homogenize or ultrasonication to prepare, and meets the requirements as long as can guarantee the particle diameter of colostrum.Prepared colostrum will leave in the environment below 20 ℃ to increase the stability of colostrum.
Description of drawings:
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 one:
Take by weighing 800mg Exenatide and 300mg gelatin and be dissolved in the 1ml water for injection, as interior water; Taking by weighing the 6g Vicryl Rapide is dissolved in the dichloromethane of 15ml as oil phase; Oil phase is joined interior aqueous phase, adopted high-speed stirred (23000rpm) 15 seconds, get colostrum, leave in the environment below 20 ℃; This colostrum is joined 6000 milliliters of 0.5%(W/V under the state that stirs) poly-vinyl alcohol solution get emulsion, this emulsion is continued to stir flung to dichloromethane in 3 hours, 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 two:
Take by weighing 200mg Exenatide, 300mg sodium carboxymethyl cellulose and 100mg sucrose and be dissolved in the 1ml water for injection, as interior water; Taking by weighing the 12.5g Vicryl Rapide is dissolved in the dichloromethane of 50ml as oil phase; Oil phase is joined interior aqueous phase, adopted high-speed stirred (23000rpm) 15 seconds, get colostrum, leave in the environment below 20 ℃; This colostrum is joined 6000 milliliters of 0.5%(W/V under the state that stirs) poly-vinyl alcohol solution get emulsion, this emulsion is continued to stir flung to dichloromethane in 3 hours, 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 three:
Take by weighing 500mg Exenatide, 300mg gelatin and 100mg mannitol and be dissolved in the 2ml water for injection, as interior water; Taking by weighing the 8g Vicryl Rapide is dissolved in the dichloromethane of 80ml as oil phase; Oil phase is joined interior aqueous phase, adopt ultrasonic cell disruption instrument (Branson S-250D) to carry out ultrasonic 30 seconds, get colostrum, leave in the environment below 20 ℃; This colostrum is joined 10000 milliliters of 1.0%(W/V under the state that stirs) poly-vinyl alcohol solution get emulsion, this emulsion is continued to stir flung to dichloromethane in 3 hours, 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 four:
The mensuration of Exenatide release microsphere release in vitro
The Exenatide release microsphere preparation of the foregoing description preparation is carried out the mensuration of release in vitro, assay method is: precision takes by weighing pastille microsphere 50mg and places 10ml tool plug test tube, with pH is that 7.4 phosphate buffer (contains 0.02% Hydrazoic acid,sodium salt as antibacterial, 0.05% Tween 80 is a wetting agent) 10ml is release medium, place the water bath with thermostatic control shaking table, under hunting speed 100rpm, 37 ℃ ± 0.5 ℃ condition of temperature, carry out the release in vitro degree of microsphere and measure.Respectively get the content that the 0.5ml release medium is used for the high effective liquid chromatography for measuring Exenatide at 1d, 2d, 4d, 7d, 14d, 21d, 28d respectively, and replenish 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 as can be seen, the prepared Exenatide release microsphere preparation of the present invention has the good slow release effect, prominent the releasing all less than 25% in 1 day.Its slow release cycle can be a week, also can be one month.
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 (10)
1. Exenatide release microsphere preparation, it is characterized in that: comprise Exenatide and Vicryl Rapide, its mass percent is respectively: Exenatide 0.1%-12.5%, Vicryl Rapide 77.5%-99%.
2. Exenatide release microsphere preparation according to claim 1; it is characterized in that: contain the protective agent that mass percent is 0.1%-10%, describedly protect agent and be a kind of or two or more the combination arbitrarily among the human serum albumin, gelatin, trehalose, sucrose, mannitol.
3. according to claim 1 or 2 any described Exenatide release microsphere preparations, it is characterized in that: contain the suspending agent that mass percent is 0.01%-10%, described suspending agent is 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, the polyvinyl alcohol.
4. the preparation method according to any described Exenatide release microsphere preparation of claim 1-3 is characterized in that, may further comprise the steps:
(a) Vicryl Rapide is dissolved in organic solvent, forms oil phase; Wherein organic solvent is a kind of or its combination in dichloromethane, the ethyl acetate;
(b) Exenatide, protective agent, suspending agent is water-soluble, water in forming;
(c) interior water is mixed the formation colostrum with described oil phase, and this colostrum is joined the outer aqueous phase formation emulsion that contains surfactant; Described surfactant is a kind of or two or more the combination arbitrarily in polyvinyl alcohol, poloxamer, enuatrol, sodium stearate, tween, the span;
(d) treat organic solvent volatilization after, obtain containing the sustained-release micro-spheres of Exenatide.
5. the preparation method of Exenatide release microsphere preparation according to claim 4 is characterized in that:
(a) the described oil phase of step is 10%-40%(W/V for Vicryl Rapide concentration) oil phase.
6. the preparation method of Exenatide release microsphere preparation according to claim 4 is characterized in that:
(b) step described in water be 5%-50%(W/V for Exenatide concentration) interior water.
7. the preparation method of Exenatide release microsphere preparation according to claim 5 is characterized in that:
(b) step described in water be 5%-50%(W/V for Exenatide concentration) interior water.
8. according to the preparation method of any described Exenatide release microsphere preparation of claim 4 to 7, it is characterized in that: (c) the described surfactant concentration of step is 0.1%-5%(W/V).
9. according to the preparation method of any described Exenatide release microsphere preparation of claim 4 to 7, it is characterized in that: the volume ratio of interior water and oil phase is 1:5-1:100.
10. according to the preparation method of any described Exenatide release microsphere preparation of claim 4 to 7, it is characterized in that: the volume ratio of outer water and colostrum is 20:1-2000:1.
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| CN102198103B (en) | 2014-07-23 |
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