CN105769771B - A kind of Exenatide release microsphere composition and preparation method thereof - Google Patents
A kind of Exenatide release microsphere composition and preparation method thereof Download PDFInfo
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- CN105769771B CN105769771B CN201410829179.1A CN201410829179A CN105769771B CN 105769771 B CN105769771 B CN 105769771B CN 201410829179 A CN201410829179 A CN 201410829179A CN 105769771 B CN105769771 B CN 105769771B
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- 108010011459 Exenatide Proteins 0.000 title claims abstract description 83
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 title claims abstract description 82
- 229960001519 exenatide Drugs 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- 239000004005 microsphere Substances 0.000 title claims abstract description 43
- 239000000203 mixture Substances 0.000 title claims abstract description 25
- 239000000725 suspension Substances 0.000 claims abstract description 29
- 229920000642 polymer Polymers 0.000 claims abstract description 27
- 239000002245 particle Substances 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 230000014759 maintenance of location Effects 0.000 claims abstract description 10
- 230000004071 biological effect Effects 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- 239000011859 microparticle Substances 0.000 claims description 21
- 239000002798 polar solvent Substances 0.000 claims description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 229960000583 acetic acid Drugs 0.000 claims description 11
- 239000012362 glacial acetic acid Substances 0.000 claims description 11
- 230000001804 emulsifying effect Effects 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 229920002545 silicone oil Polymers 0.000 claims description 6
- 239000008394 flocculating agent Substances 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000002480 mineral oil Substances 0.000 claims description 3
- 235000010446 mineral oil Nutrition 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 41
- 229940079593 drug Drugs 0.000 abstract description 39
- 238000005538 encapsulation Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003223 protective agent Substances 0.000 abstract description 5
- 239000004626 polylactic acid Substances 0.000 abstract description 4
- 229920000747 poly(lactic acid) Polymers 0.000 abstract description 3
- 229920002732 Polyanhydride Polymers 0.000 abstract description 2
- 239000008187 granular material Substances 0.000 abstract description 2
- 229920001610 polycaprolactone Polymers 0.000 abstract description 2
- 239000004632 polycaprolactone Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 37
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 206010013786 Dry skin Diseases 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000013557 residual solvent Substances 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000011806 microball Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000013074 reference sample Substances 0.000 description 3
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
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- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101710173663 Glucagon-1 Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 239000011805 ball Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 1
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- JLJNENVYAVKECZ-HRXVJLLUSA-N eoxin E4 Chemical compound CCCCC[C@H](O)[C@H](SC[C@H](N)C(O)=O)\C=C\C=C\C=C/C\C=C/CCCC(O)=O JLJNENVYAVKECZ-HRXVJLLUSA-N 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
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- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
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- 238000011866 long-term treatment Methods 0.000 description 1
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- 210000000496 pancreas Anatomy 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of Exenatide release microsphere compositions, it is made of drug Exenatide with polymer；The Exenatide accounts for 2~15%w/w of microballoon total weight；The polymer is selected from one or more of polycaprolactone, polylactic acid, poly lactide-glycolide acid, polyanhydride；The partial size of the microballoon is 20-90 μm；The Relative biological activity retention rate of the Exenatide is greater than 90%.The present invention also provides the preparation methods of the microsphere composition.It using preparation method of the invention, can avoid drug caused by the use of water phase in the loss of activity problem of oil-water interfaces completely when being not necessarily to and adding protective agent, and improve the bioactivity retention rate of encapsulation rate and Exenatide；Using drug, dissolubility difference forms the suspension or uniform solution of uniform submicron order drug granule in different solvents, it is not necessary that micronized drug particles are prepared separately, to simplify preparation process and avoid burst effect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations.It is more particularly related to a kind of Exenatide release microsphere combination
Object and preparation method thereof.
Background technique
Most protein and peptide drugs (hereinafter referred to as drug) oral administration biaavailabilities are low, and half-life period is shorter in blood, usually
Need frequently to be subcutaneously injected maintenance therapy level.Sustained-release micro-spheres are that have life using Biodegradable material (such as polymer) package
The active drug of object, controls the release of drug, reaches long-term treatment effects, reduces administration frequency, improves patient compliance.
The technology of preparing of the microball preparation of reported protein and peptide drugs includes emulsification-evaporation method, coacervation
With spray drying process etc., wherein generalling use the preparation of W/O/W emulsification-evaporation method, but since protein and peptide drugs are water
Dissolubility, during the preparation process, drug are easily diffused into outer aqueous phase, and drug is typically distributed on the surface of microballoon, leads to encapsulation rate
It is usually lower, and burst effect with higher.There is research by drug micronization, prepared using S/O/W emulsion-solvent evaporation method,
Diffusion of the drug to microsphere surface effectively is controlled, burst release is reduced, but is not avoided that microsphere surface drug is gradually dissolved in
Outer aqueous phase, the lower encapsulation rate of bring.In addition, drug is easy to cause space to be tied in oil-water interfaces in microballoon preparation process
The destruction of structure causes Ingredients Active to reduce or degrade.
Exenatide (exenatide, code name AC-2993) is artificial synthesized exendin-4.Exenatide is that intestines promote pancreas
Island element analog is glucagon -1 (GLP-1) receptor stimulating agent, is made of 39 amino acid residues.Exenatide has
Promote pancreatic Beta cell proliferation, improve its function, and promotes insulin secretion, increases body to the sensibility of insulin and prolong
The effects of slow gastric emptying, there is that traditional treatment diabetes medicament is incomparable.U.S. Food and Drug Administration
(FDA) it has approved Exenatide in April, 2005 to list in the U.S., due to half-life short, commercialized product is to inject 2 times a day
Agent.This restrict its developments and utilizations as drug, in order to improve the compliance of patient medication, it is necessary to Exenatide
Sustained release preparation is studied, to achieve the purpose that long-acting slow-release.The preparation method for the Exenatide release microsphere reported at present is deposited
More difficult to control in preparation process complexity, encapsulation rate is low, and is difficult to the problems such as retaining pharmaceutical activity, it is therefore desirable to a kind of new system
Preparation Method improves microball preparation.
Summary of the invention
To solve the above-mentioned problems, the technical solution of the present invention is to provide a kind of Relative biological activity retention rate height, packet
The high Exenatide release microsphere composition of envelope rate, there is provided Exenatide release microsphere groups for another technical solution of the invention
Close the preparation method of object.
The present invention provides a kind of Exenatide release microsphere compositions, it is by drug Exenatide and polymer group
At；The Exenatide drug accounts for 2~15%w/w of the microballoon total weight；The polymer is selected from polycaprolactone, polylactic acid
(PLA), one or more of poly lactide-glycolide acid (PLGA), polyanhydride；The partial size of the Exenatide microballoon is
20~90 μm；The Relative biological activity retention rate of the Exenatide is greater than 90%.
Wherein, the polymer is selected from polylactic acid, poly lactide-glycolide acid or its mixing, wherein polylactic acid, poly-
Poly lactic coglycolic acid can be selected from commercially available medical PLA and PLGA, preferably be purchased from the LAKESHORE of EVONIK company
BIOMATERIALSTM, Boehringer Ingelheim companyOr Alkermes company
Wherein, the Exenatide accounts for 5~10%w/w of the microballoon total weight.
The present invention also provides a kind of preparation methods for preparing Exenatide release microsphere composition, it includes following step
It is rapid:
A, Exenatide powder is dissolved in intensive polar solvent；
B, take polymer that weak polar solvent dissolution is added；
C, the solution for preparing step a is added in the solution of step b, is prepared into suspension or uniform solution；
D, flocculating agent is added in the suspension of step c, preparation forms embryonic microparticles；
E, the embryonic microparticles of step d are transferred to be quenched in solvent and are hardened；Collect hardened particles；It is dry；
Wherein, the volume ratio of the intensive polar solvent and weak polar solvent is 1:5~1:50.
Preferably, the volume ratio of the intensive polar solvent and the weak polar solvent is 1:20~1:40.
It is further preferred that the volume ratio of the intensive polar solvent and the weak polar solvent is 1:30.
Wherein, partial size≤2 μm of the particle of suspension described in step c.
Wherein, intensive polar solvent described in step a is selected from dimethyl sulfoxide, n,N-Dimethylformamide, methanol, glacial acetic acid
One or more of；
Weak polar solvent described in step b in ethyl acetate, methyl ethyl ketone, methylene chloride, tetrahydrofuran one
Kind is several；
Flocculating agent described in step d is selected from one or more of silicone oil, atoleine, mineral oil and its derivative；
One of solvent in normal octane, normal heptane, n-hexane, hexamethylene or cyclic annular liquid alkane is quenched described in step e
Kind is several.
It is further preferred that intensive polar solvent described in step a is selected from glacial acetic acid or dimethyl sulfoxide.
Wherein, the processing time of emulsifying described in step d is 2-5min；
The method for curing of particle in step e are as follows: the initial stage microballoon of Step d is gone to -5 DEG C to 5 DEG C of temperature range and is quenched
In solvent, 1~2h is stirred；
Collection method described in step e and is collected using multi-deck screen with being quenched solvent rinse.
The present invention relates to a kind of improved methods for preparing Exenatide release microsphere, without adding protective agent situation
Under, drug caused by water phase use can be avoided in the loss of activity problem of oil-water interfaces completely, and from improving encapsulation rate and Ai Sai
That peptide Relative biological activity retention rate (bioactivity retention rate is greater than 90%), using drug in different solvents dissolubility difference
The suspension or uniform solution for forming uniform submicron order drug granule, it is not necessary that micronized drug particles are prepared separately, thus
Simplify preparation process and avoids burst effect.
Detailed description of the invention
Fig. 1 is the In-vitro release curves of Exenatide release microsphere composition；
Fig. 2 is Exenatide release microsphere composition Drug-time curve in rat body.
Specific embodiment
Following experimental examples and embodiment are for further illustrating but being not limited to the present invention.
Conditional filtering test (the particle diameter in suspension of the Exenatide microsphere composition of the present invention of experimental example 1 preparation
Screening) 50mg Exenatide is dissolved in 2ml glacial acetic acid, the 0.62g 50:50DLG3A PLGA purified is dissolved in 9ml dichloromethane
Alkane forms polymer solution, by the glacial acetic acid solution of Exenatide and is dissolved with PLGA (poly lactide-glycolide acid)
After dichloromethane solution mixing, the partial size for stirring S/O type drug suspension Chinese medicine object particle obtained is respectively 4 μm, 2 μm, 1 μ
M, 0.3 μm, 0.1 μm (suspension partial size is measured using Malvern ZEN1690- nano particle size instrument), other operations and embodiment 1
It is essentially identical, Exenatide release microsphere is prepared, the release in vitro measuring method detection using (4) in experimental example 5 is prepared micro-
The starting release of ball is respectively 22.6%, 4.7%, 1.32%, 0.86% and 0.63%.With drug particle in suspension
The reduction of partial size, microballoon initial release degree reduce, and burst release can be effectively reduced by the partial size of drug particle in control suspension,
It is preferred that partial size≤2 μm of suspended liquid particles.
The conditional filtering of the Exenatide microsphere composition of the present invention of experimental example 2 preparation tests (intensive polar solvent screening test)
20mg Exenatide is dissolved separately in 2ml dimethyl sulfoxide or 2ml glacial acetic acid or 2mlN, dinethylformamide
Or in 2ml methanol, it is mixed with the dichloromethane solution of PLGA, particle diameter is 0.3 μm in suspension, other operations and reality
It is essentially identical to test example 1, prepares Exenatide release microsphere, prepared by the entrapment efficiency determination method detection using (2) in experimental example 5
The encapsulation rate of microballoon is respectively 91.2%, 89.6%, 36.4% and 42.7%.It is preferably highly polar to meet higher encapsulation rate
Solvent is dimethyl sulfoxide and glacial acetic acid, more preferable dimethyl sulfoxide.
(intensive polar solvent/low pole is molten for the conditional filtering test of the Exenatide microsphere composition of the present invention of experimental example 3 preparation
The screening of agent ratio)
Screening experiment is carried out by taking dimethyl sulfoxide as an example, and Exenatide is dissolved in the dimethyl sulphoxide solution of different volumes
In, dimethyl sulfoxide and dichloromethane solution ratio are respectively 1:5,1:10,1:20,1:30,1:40,1:50, other operations with
Experimental example 2 is essentially identical, prepares Exenatide release microsphere, measures institute using the release in vitro measuring method of (4) in experimental example 5
The encapsulation rate for preparing microballoon is respectively 30.2%, 44.9%, 86.1%, 92.2%, 89.4%, 49.4%.It is higher to meet
The volume ratio of encapsulation rate, preferably dimethyl sulfoxide and dichloromethane solution is 1:20 to 1:40, more preferable 1:30.
(Exenatide drug accounts for described for the conditional filtering test of the Exenatide microsphere composition of the present invention of experimental example 4 preparation
The screening of microballoon total weight ratio)
It is that 1:30 carries out screening experiment with the volume ratio of dimethyl sulfoxide and dichloromethane solution, prepares Ai Saina in microballoon
Peptide content is respectively 1%, 2%, 5%, 7.5%, 10%, 12.5%, 15%, 18%, other operations and the basic phase of experimental example 3
Together, Exenatide release microsphere is prepared, the release in vitro measuring method measurement encapsulation rate using (4) in experimental example 5 is respectively
60.9%, 81.5%, 89.3%, 90.2%, 90.6%, 86.7%, 80.3%, 70.2%, it is excellent to meet higher encapsulation rate
Select 2~15%w/w of Exenatide content, more preferable 5~10%w/w.
The preparation of embodiment 1S/O type drug suspension:
(1) 0.62g purifying PLGA 50:50DLG3A is dissolved in 9ml methylene chloride, forms polymer solution；
(2) 50mg Exenatide is dissolved in 0.3ml dimethyl sulfoxide；
(3) polymer solution in step (1) is mixed with Exenatide solution in step (2), is stirred to get uniform
Suspension, particle diameter is 0.33 μm in suspension；
Embryonic microparticles preparation:
(4) 15ml silicone oil is added in the suspension in step (3), emulsifying handles 2-5min；
It is microsphere hardening:
(5) embryonic microparticles grain in step (4) is transferred in the cold normal heptane of 150ml, stirs 1-2h at 5 DEG C.Use 200ml
Cold normal heptane is impregnated to rinse microparticle surfaces residual solvent；
Dry and collection:
(6) it is collected using multi-deck screen, is rinsed with normal heptane.For 24 hours, for 24 hours, 35 DEG C of vacuum are dry for 25 DEG C of vacuum drying for 4 DEG C of dryings
It is dry for 24 hours.
The preparation of the Exenatide microsphere composition of the present invention of embodiment 2
The preparation of S/O type drug suspension:
(1) 0.62g purifying PLGA 50:50DLG3A is dissolved in 9ml methylene chloride, forms polymer solution；
(2) 50mg Exenatide is dissolved in 0.3ml dimethyl sulfoxide,
(3) polymer solution in step (1) is mixed with Exenatide solution in step (2), is stirred to get uniform
Suspension, particle diameter is 0.2 μm in suspension；
Embryonic microparticles preparation:
(4) 15ml silicone oil is added in the suspension in step (3), emulsifying handles 2-5min；
It is microsphere hardening:
(5) embryonic microparticles in step (4) are transferred in the mixed solution of 150ml normal heptane and 15ml ethyl alcohol, are stirred at 5 DEG C
Mix 1-2h.It is impregnated with 200ml cold normal heptane to rinse microparticle surfaces residual solvent；
Dry and collection:
(6) it is collected using multi-deck screen, is rinsed with normal heptane.For 24 hours, for 24 hours, 35 DEG C of vacuum are dry for 25 DEG C of vacuum drying for 4 DEG C of dryings
It is dry for 24 hours.
The preparation of the Exenatide microsphere composition of the present invention of embodiment 3
The preparation of S/O type drug suspension:
(1) 0.21g purifying PLGA 50:50DLG1A and 0.42g purifying 50:50DLG4A is dissolved in 9ml methylene chloride, shape
At polymer solution；
(2) 50mg Exenatide is dissolved in 0.3ml glacial acetic acid；
(3) polymer solution in step (1) is mixed with Exenatide solution in step (2), is stirred to get uniform
Suspension, particle diameter is 0.27 μm in suspension；
Embryonic microparticles preparation:
(4) 15ml atoleine is added in the suspension in step (3), emulsifying handles 2-5min；
It is microsphere hardening:
(5) embryonic microparticles in step (4) are transferred in the cold normal heptane of 150ml, stir 1-2h at 5 DEG C.It is cold with 200ml
Normal heptane impregnate to rinse microparticle surfaces residual solvent；
Dry and collection:
(6) it is collected using multi-deck screen, is rinsed with n-hexane.For 24 hours, for 24 hours, 35 DEG C of vacuum are dry for 25 DEG C of vacuum drying for 4 DEG C of dryings
It is dry for 24 hours.
The preparation of the Exenatide microsphere composition of the present invention of embodiment 4
Drug-polymer solution preparation:
(1) 0.21g purifying PLGA 50:50DLG1A and 0.42g purifying 50:50DLG4A is dissolved in 9ml methylene chloride, shape
At polymer solution；
(2) 50mg Exenatide is dissolved in 1.5ml glacial acetic acid；
(3) polymer solution in step (1) is mixed with Exenatide solution in step (2), is stirred to get uniform
Solution；
Embryonic microparticles preparation:
(4) 15ml atoleine is added in the solution in step (3), emulsifying handles 2-5min；
It is microsphere hardening:
(5) embryonic microparticles in step (4) are transferred in the cold normal heptane of 150ml, stir 1-2h at 5 DEG C.It is cold with 200ml
Normal heptane impregnate to rinse microparticle surfaces residual solvent；
Dry and collection:
(6) it is collected using multi-deck screen, is rinsed with n-hexane.For 24 hours, for 24 hours, 35 DEG C of vacuum are dry for 25 DEG C of vacuum drying for 4 DEG C of dryings
It is dry for 24 hours.
Comparative example 1
Protectant W/O/O method preparation reference sample is not added:
(1) 0.62g purifying PLGA 50:50DLG3A is dissolved in 10ml methylene chloride, forms polymer solution；
(2) 40mg Exenatide is dissolved in 0.5ml purified water,
(3) Exenatide solution in step (2) is added into the polymer solution in step (1), shears 1min, obtained just
Cream；
Embryonic microparticles preparation:
(4) 15ml silicone oil is added in the suspension in step (3), emulsifying handles 2-5min；
It is microsphere hardening:
(5) embryonic microparticles in step (4) are transferred in the mixed solution of 200ml normal heptane and 20ml ethyl alcohol, are stirred at 5 DEG C
Mix 1-2h.It is impregnated with 400ml cold normal heptane to rinse microparticle surfaces residual solvent；
Dry and collection:
(6) it is collected using multi-deck screen, is rinsed with normal heptane.For 24 hours, for 24 hours, 35 DEG C of vacuum are dry for 25 DEG C of vacuum drying for 4 DEG C of dryings
It is dry for 24 hours.
Comparative example 2 adds protectant W/O/O method preparation reference sample:
(1) 0.62g purifying PLGA 50:50DLG3A is dissolved in 10ml methylene chloride, forms polymer solution；
(2) 40mg Exenatide and protective agent sucrose 15mg are dissolved in 0.5ml purified water,
(3) Exenatide solution in step (2) is added into the polymer solution in step (1), shears 1min, obtained just
Cream；
Embryonic microparticles preparation:
(4) 15ml silicone oil is added in the suspension in step (3), emulsifying handles 2-5min；
It is microsphere hardening:
(5) embryonic microparticles in step (4) are transferred in the mixed solution of 200ml normal heptane and 20ml ethyl alcohol, are stirred at 5 DEG C
Mix 1-2h.It is impregnated with 400ml cold normal heptane to rinse microsphere surface residual solvent；
Dry and collection:
(6) it is collected using multi-deck screen, is rinsed with normal heptane.For 24 hours, for 24 hours, 35 DEG C of vacuum are dry for 25 DEG C of vacuum drying for 4 DEG C of dryings
It is dry for 24 hours.
The detection method of 5 sample of experimental example:
(1) particle size distribution measuring: using the particle diameter distribution of laser particle analyzer (Malvern 3000) measurement microballoon.
(2) entrapment efficiency determination:
10mg microballoon is weighed, 2ml dimethyl sulfoxide is added, eddy oscillating makes to be completely dissolved, and purified water is added and is settled to
10ml.Pass through HPLC analytical column: TSK-GEL carries out quantitative detection.Computational envelope rate.
(3) determination of drug activity:
By ELISA method measure Exenatide bioactivity, with microplate reader measurement target sample absorbance, then with
The absorbance of Exenatide standard items calculates the Relative biological activity retention rate of drug after embedding as control.Implemented with comparing
Example 4, comparative example 5 are using the microballoon of W/O/O method preparation as reference sample.
(4) release in vitro measures:
By the concentration for measuring the different time Exenatide in release buffer.30 ± 2mg microballoon is placed at room temperature
In 200ml buffer, about 30s is vibrated with the solution that suspends, is subsequently placed in 37 DEG C of waters bath with thermostatic control.Oscillation is mixed after a certain period of time
It closes, stands 30min, take supernatant, pass through HPLC analytical column immediately: TSK-GEL carries out quantitative detection.Release after measuring 4h
For initial release.
(5) release measurement in vivo:
Exenatide in interlayer immune quantitative blood plasma, captures analyte with solid phase monoclonal antibody EXE4:2-8.4, leads to
Radioiodination monoclonal antibody GLP-1:3-3 is crossed to detect.Standards calibration curve quantifies.
(6) testing result (testing result is shown in Table 1, Fig. 1, Fig. 2):
1 product property of table characterization
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Comparative example 1 | Comparative example 2 | |
| Average grain diameter μm | 57.2 | 61.4 | 68.0 | 66.3 | 63.6 | 62.8 |
| Encapsulation rate/% | 90.5 | 92.7 | 92.4 | 90.1 | 89.2 | 90.3 |
| Active reservation/% | 95.9 | 94.3 | 96.1 | 93.2 | 42.8 | 94.0 |
| Initial release/% | 0.95 | 0.86 | 0.91 | 1.82 | 0.96 | 1.02 |
As can be known from the results, compared with comparative example 1, using ending in Exenatide microballoon prepared by preparation method of the present invention
Fill in that peptide active constituent loss of activity in the case where not adding protectant situation is smaller, and Relative biological activity retention rate is greater than
90%, much higher than the Relative biological activity retention rate (42.8%) of Exenatide in the Exenatide microballoon of the preparation of comparative example 1.With
Comparative example 2 is compared, and higher Exenatide Relative biological activity guarantor can be realized without adding protective agent in preparation method of the present invention
Rate is stayed, but due to not needing to reduce costs using protective agent, improves Drug safety.
From fig. 1, it can be seen that can effectively control burst effect using glacial acetic acid and dimethyl sulfoxide as solvent, obtains 0-30d and connect
Nearly zero-order release curve, Exenatide is higher in glacial acetic acid and dmso solution degree, uses both as active constituent solvent
Smaller, the encapsulation rate height for the Exenatide microballoon being prepared is measured, and is released low.
It can be obtained more smoothly using single polymers, and by Exenatide microballoon prepared by solvent of dimethyl sulfoxide
Release.Releasing for microballoon is prepared after wherein different molecular weight PLGA 50:50DLG1A is mixed in a certain proportion with 50:50DLG4A
Medicine curve can be adjusted by adjusting the molecular weight of polymer or using different proportion mixed with polymers close to Zero order release
The drug release behavior of microballoon, to obtain the sustained release microsphere agents in different drug release periods.
As can be seen from Figure 2, blood concentration reaches peak value in rat body after administration 7d, and 2-30d blood concentration maintains 100-
Between 200pg/ml, fluctuation is smaller, illustrates steadily to discharge one month in vivo using the microball preparation of technology preparation, and have
Lesser blood concentration fluctuation.
Claims (7)
1. a kind of preparation method of Exenatide release microsphere composition,
It includes the following steps:
A, Exenatide powder is dissolved in intensive polar solvent；The intensive polar solvent is selected from dimethyl sulfoxide or glacial acetic acid；
B, take polymer that weak polar solvent dissolution is added；The weak polar solvent is selected from ethyl acetate, methyl ethyl ketone, dichloromethane
One or more of alkane, tetrahydrofuran；
C, the solution for preparing step a is added in the solution of step b, is prepared into suspension or uniform solution；The suspension
Partial size≤2 μm of particle；
D, flocculating agent is added in the suspension of step c or uniform solution, preparation forms embryonic microparticles；The flocculating agent is selected from silicone oil
Or one or both of mineral oil；
E, the embryonic microparticles of step d are transferred to be quenched in solvent and are hardened；Collect hardened particles；It is dry；It is described that solvent choosing is quenched
From one or more of normal octane, normal heptane, n-hexane or cyclic annular liquid alkane；
Wherein, the volume ratio of the intensive polar solvent and weak polar solvent is 1:20~1:40；
The Exenatide release microsphere composition is made of Exenatide and polymer, and the Exenatide accounts for described micro-
2~15%w/w of ball total weight；The polymer is poly lactide-glycolide acid；The partial size of the Exenatide microballoon
It is 20~90 μm；The Relative biological activity retention rate of the Exenatide is greater than 90%.
2. the preparation method of Exenatide release microsphere composition according to claim 1, it is characterised in that: the Ai Sai
That peptide accounts for 5~10%w/w of the microballoon total weight.
3. the preparation method of Exenatide release microsphere composition according to claim 1, it is characterised in that: the strong pole
Property solvent and the weak polar solvent volume ratio be 1:30.
4. the preparation method of Exenatide release microsphere composition according to claim 1 or 3, it is characterised in that:
Flocculating agent is added in step d: step c suspension or uniform solution, emulsifying handles 2~5min, and preparation is formed just
Phase particle；
The method for curing of particle in step e are as follows: it is molten that the initial stage framboid of Step d is gone into -5 DEG C to 5 DEG C of temperature range be quenched
In agent, 1~2h is stirred；
Collection method described in step e and is collected using multi-deck screen with being quenched solvent rinse.
5. the preparation method of Exenatide release microsphere composition according to claim 1, it is characterised in that: the mineral
Oil is atoleine.
6. the preparation method of Exenatide release microsphere composition according to claim 1, it is characterised in that: the ring-type
Liquid alkane is hexamethylene.
7. the Ai Saina that the preparation method of Exenatide release microsphere composition described in any one of claims 1-6 is prepared
Peptide sustained-release microspherical composition.
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| CN1968700A (en) * | 2004-04-15 | 2007-05-23 | 阿尔克姆斯有限公司 | Polymer-based sustained release device |
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| CN1968700A (en) * | 2004-04-15 | 2007-05-23 | 阿尔克姆斯有限公司 | Polymer-based sustained release device |
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