CN105769771A - Exenatide slow-release microsphere composition and preparation method thereof - Google Patents
Exenatide slow-release microsphere composition and preparation method thereof Download PDFInfo
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Abstract
The invention provides an exenatide slow-release microsphere composition prepared from an exenatide drug and polymers.The exenatide accounts for 2 %w/w-15 %w/w of the total weight of the microsphere, the polymers are selected from one or more of polycaprolactone, polylactic acid, a polylactic acid-hydroxyacetic acid copolymer and polyanhydride, the particle size of the microsphere ranges from 20 micrometers to 90 micrometers, and the relative biological activity retention rate of the exenatide is higher than 90%.The invention further provides a preparation method of the microsphere composition.According to the preparation method, the problem that the activity losses of the drug on an oil-water interface are caused due to usage of a water phase can be completely avoided on the condition that a protective agent does not need to be added, and the encapsulation rate and the biological activity retention rate of the exenatide are increased; homogeneous turbid liquid or a homogenous solution of submicron drug particles is formed through the solubility differences of the drug in different solvents, micronized drug particles do not need to be prepared, therefore, the preparation technology is simplified, and the burst release effect is avoided.
Description
Technical field
The present invention relates to field of pharmaceutical preparations.It is more particularly related to a kind of Exenatide release microsphere composition and method of making the same.
Background technology
Most protein and peptide drugs (hereinafter referred to as medicine) oral administration biaavailabilities are low, and in blood, the half-life is shorter, it usually needs frequently subcutaneous injection maintaining treatment level.Sustained-release micro-spheres is to use Biodegradable material (such as polymer) parcel to have bioactive medicine, controls the release of medicine, reaches long-term treatment effects, reduce administration frequency, improves patient compliance.
The technology of preparing of the microball preparation of the protein and peptide drugs reported includes emulsification-evaporation method, coacervation and spray drying method etc., wherein prepared by commonly used W/O/W emulsification-evaporation method, but owing to protein and peptide drugs is water solublity, in preparation process, medicine is easily diffused in outer aqueous phase, and medicine is typically distributed on the surface of microsphere, causes that envelop rate is generally relatively low, and there is higher burst effect.There is research by drug micronization, adopt S/O/W emulsion-solvent evaporation method to prepare, effectively control the medicine diffusion to microsphere surface, reduce prominent releasing, but cannot be avoided microsphere surface medicine and be dissolved in outer aqueous phase gradually, the relatively low envelop rate brought.Additionally, be easy to cause the destruction of space structure at oil-water interfaces at microsphere preparation process Chinese medicine, Ingredients Active is caused to reduce or degraded.
Exenatide (exenatide, code name AC-2993) is the exendin-4 of synthetic.Exenatide is exendin-4, is glucagon-1 (GLP-1) receptor stimulating agent, is made up of 39 amino acid residues.Exenatide has promotion pancreatic Beta cell proliferation, improves its function, and promotes insulin secretion, increase body to the sensitivity of insulin and delay the effects such as gastric emptying, has the advantage that traditional treatment diabetes medicament is incomparable.U.S. food Drug Administration (FDA) have approved Exenatide in April, 2005 and lists in the U.S., and owing to the half-life is short, its commercialized product is 2 injections every day.This restrict its development and utilization as medicine, in order to improve the compliance of patient medication, it is necessary to the slow releasing preparation of Exenatide is studied, to reach the purpose of long-acting slow-release.There is the more difficult control of complicated process of preparation in the preparation method of the Exenatide release microsphere of report at present, and envelop rate is low, and is difficult to retain the problems such as pharmaceutically active, it is therefore desirable to microball preparation is improved by a kind of new preparation method.
Summary of the invention
In order to solve the problems referred to above, the technical scheme is that and provide the Exenatide release microsphere compositions that a kind of Relative biological activity retention rate is high, envelop rate is high, the preparation method that another technical scheme of the present invention there is provided Exenatide release microsphere compositions.
The invention provides a kind of Exenatide release microsphere compositions, it is made up of medicine Exenatide and polymer；Described Exenatide medicine accounts for 2～15%w/w of described microsphere gross weight；One or more in polycaprolactone, polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA), polyanhydride of described polymer；The particle diameter of described Exenatide microsphere is 20～90 μm；The Relative biological activity retention rate of described Exenatide is more than 90%.
Wherein, described polymer is selected from polylactic acid, Poly(D,L-lactide-co-glycolide or its mixing, and wherein polylactic acid, Poly(D,L-lactide-co-glycolide are selected from commercially available medical PLA and PLGA, it is preferable that purchased from the LAKESHOREBIOMATERIALS of EVONIK companyTM, BoehringerIngelheim companyOr Alkermes company
Wherein, described Exenatide accounts for 5～10%w/w of described microsphere gross weight.
Present invention also offers a kind of preparation method preparing Exenatide release microsphere compositions, it comprises the steps:
A, Exenatide powder is dissolved in intensive polar solvent；
B, take polymer add weak polar solvent dissolve；
C, the solution prepared by step a add in the solution of step b, prepare into suspension or uniform solution；
D, step c suspension in add flocculating agent, preparation formed embryonic microparticles；
E, the embryonic microparticles of step d is transferred in cancellation solvent harden；Collect hardened particles；Dry；
Wherein, described intensive polar solvent is 1:5～1:50 with the volume ratio of weak polar solvent.
Preferably, described intensive polar solvent is 1:20～1:40 with the volume ratio of described weak polar solvent.
It is further preferred that the volume ratio of described intensive polar solvent and described weak polar solvent is 1:30.
Wherein, particle diameter≤2 μm of the particle of suspension described in step c.
Wherein, one or more in dimethyl sulfoxide, DMF, methanol, glacial acetic acid of intensive polar solvent described in step a；
One or more in ethyl acetate, methyl ethyl ketone, dichloromethane, oxolane of weak polar solvent described in step b；
One or more in silicone oil, liquid paraffin, mineral oil and derivant thereof of flocculating agent described in step d；
One or more in normal octane, normal heptane, normal hexane, hexamethylene or ring-type liquid alkane of cancellation solvent described in step e.
It is further preferred that intensive polar solvent described in step a is selected from glacial acetic acid or dimethyl sulfoxide.
Wherein, the process time of emulsifying described in step d is 2-5min；
In step e, the method for curing of microgranule is: gone to by the initial stage microsphere of Step d in the cancellation solvent of temperature range-5 DEG C to 5 DEG C, stirs 1～2h；
Collection method described in step e is to use cancellation solvent rinse, and adopts multi-deck screen to collect.
The present invention relates to a kind of method preparing Exenatide release microsphere of improvement; without adding in protective agent situation; aqueous phase can be avoided completely to use the medicine that causes in the loss of activity problem of oil-water interfaces; and improve envelop rate and Exenatide Relative biological activity retention rate (biological activity retention rate is more than 90%); medicine dissolubility difference in different solvents is utilized to form suspension or the uniform solution of homogeneous submicron order drug particles; without individually preparing micronized drug particles, thus simplifying preparation technology and avoiding burst effect.
Accompanying drawing explanation
Fig. 1 is the In-vitro release curves of Exenatide release microsphere compositions；
Fig. 2 is Exenatide release microsphere compositions Drug-time curve in rat body.
Detailed description of the invention
Following experimental example and embodiment are used for further illustrating but are not limited to the present invention.
null50mg Exenatide is dissolved in 2ml glacial acetic acid by conditional filtering test (in suspension the screening of particle diameter) prepared by experimental example 1 Exenatide microsphere composition of the present invention，The 50:50DLG3APLGA of 0.62g purification is dissolved in 9ml dichloromethane，Form polymer solution，After the glacial acetic acid solution of Exenatide is mixed with the dichloromethane solution being dissolved with PLGA (Poly(D,L-lactide-co-glycolide)，The particle diameter respectively 4 μm of the S/O type medicine suspension Chinese medicine particle that stirring prepares、2μm、1μm、0.3μm、0.1 μm (suspension particle diameter adopts MalvernZEN1690-nano particle size instrument to measure)，Other operations are substantially the same manner as Example 1，Prepare Exenatide release microsphere，Adopt the initial release respectively 22.6% of the prepared microsphere of release in vitro assay method detection of (4) in experimental example 5、4.7%、1.32%、0.86% and 0.63%.Along with the reduction of the particle diameter of suspension Chinese medicine particle, microsphere initial release degree reduces, and can effectively reduce prominent releasing by controlling the particle diameter of suspension Chinese medicine particle, it is preferable that particle diameter≤2 μm of suspension particle.
Conditional filtering test (intensive polar solvent screening test) prepared by experimental example 2 Exenatide microsphere composition of the present invention
20mg Exenatide is dissolved separately in 2ml dimethyl sulfoxide or 2ml glacial acetic acid or 2mlN, in dinethylformamide or 2ml methanol, it is mixed with the dichloromethane solution of PLGA, in suspension, particle diameter is 0.3 μm, other operations are essentially identical with experimental example 1, prepare Exenatide release microsphere, adopt the envelop rate respectively 91.2%, 89.6%, 36.4% and 42.7% of the prepared microsphere of entrapment efficiency determination method detection of (2) in experimental example 5.For meeting higher envelop rate, it is preferable that intensive polar solvent is dimethyl sulfoxide and glacial acetic acid, more preferably dimethyl sulfoxide.
Conditional filtering test (screening of intensive polar solvent/weak polar solvent ratio) prepared by experimental example 3 Exenatide microsphere composition of the present invention
Screening experiment is carried out for dimethyl sulfoxide, Exenatide is dissolved in the dimethyl sulphoxide solution of different volumes, dimethyl sulfoxide and dichloromethane solution ratio respectively 1:5,1:10,1:20,1:30,1:40,1:50, other operations are essentially identical with experimental example 2, prepare Exenatide release microsphere, adopt the release in vitro assay method of (4) in experimental example 5 to measure the envelop rate of prepared microsphere respectively 30.2%, 44.9%, 86.1%, 92.2%, 89.4%, 49.4%.For meeting higher envelop rate, it is preferable that the volume ratio of dimethyl sulfoxide and dichloromethane solution is 1:20 to 1:40, more preferably 1:30.
Conditional filtering prepared by experimental example 4 Exenatide of the present invention microsphere composition tests (screening that Exenatide medicine accounts for described microsphere gross weight ratio)
Screening experiment is carried out for 1:30 with the volume ratio of dimethyl sulfoxide Yu dichloromethane solution, prepare in microsphere Exenatide content respectively 1%, 2%, 5%, 7.5%, 10%, 12.5%, 15%, 18%, other operations are essentially identical with experimental example 3, prepare Exenatide release microsphere, the release in vitro assay method of (4) in experimental example 5 is adopted to measure envelop rate respectively 60.9%, 81.5%, 89.3%, 90.2%, 90.6%, 86.7%, 80.3%, 70.2%, for meeting higher envelop rate, preferred Exenatide content 2～15%w/w, more preferably 5～10%w/w.
Prepared by embodiment 1S/O type medicine suspension:
(1) 0.62g purification PLGA50:50DLG3A is dissolved in 9ml dichloromethane, forms polymer solution；
(2) 50mg Exenatide is dissolved in 0.3ml dimethyl sulfoxide；
(3) being mixed with Exenatide solution in step (2) by the polymer solution in step (1), stirring obtains homogeneous suspension, and in suspension, particle diameter is 0.33 μm；
Prepared by embryonic microparticles:
(4) being added to by 15ml silicone oil in the suspension in step (3), emulsifying processes 2-5min；
Microsphere hardening:
(5) embryonic microparticles grain in step (4) is transferred in the cold normal heptane of 150ml, at 5 DEG C, stirs 1-2h.Soak with normal heptane cold for 200ml to rinse microparticle surfaces residual solvent；
Dry and collect:
(6) use multi-deck screen to collect, rinse with normal heptane.4 DEG C of dry 24h, 25 DEG C of vacuum drying 24h, 35 DEG C of vacuum drying 24h.
The preparation of embodiment 2 Exenatide microsphere composition of the present invention
Prepared by S/O type medicine suspension:
(1) 0.62g purification PLGA50:50DLG3A is dissolved in 9ml dichloromethane, forms polymer solution；
(2) 50mg Exenatide is dissolved in 0.3ml dimethyl sulfoxide,
(3) being mixed with Exenatide solution in step (2) by the polymer solution in step (1), stirring obtains homogeneous suspension, and in suspension, particle diameter is 0.2 μm；
Prepared by embryonic microparticles:
(4) being added to by 15ml silicone oil in the suspension in step (3), emulsifying processes 2-5min；
Microsphere hardening:
(5) embryonic microparticles in step (4) is transferred in the mixed solution of 150ml normal heptane and 15ml ethanol, at 5 DEG C, stirs 1-2h.Soak with normal heptane cold for 200ml to rinse microparticle surfaces residual solvent；
Dry and collect:
(6) use multi-deck screen to collect, rinse with normal heptane.4 DEG C of dry 24h, 25 DEG C of vacuum drying 24h, 35 DEG C of vacuum drying 24h.
The preparation of embodiment 3 Exenatide microsphere composition of the present invention
Prepared by S/O type medicine suspension:
(1) 0.21g purification PLGA50:50DLG1A and 0.42g purification 50:50DLG4A is dissolved in 9ml dichloromethane, forms polymer solution；
(2) 50mg Exenatide is dissolved in 0.3ml glacial acetic acid；
(3) being mixed with Exenatide solution in step (2) by the polymer solution in step (1), stirring obtains homogeneous suspension, and in suspension, particle diameter is 0.27 μm；
Prepared by embryonic microparticles:
(4) being added to by 15ml liquid paraffin in the suspension in step (3), emulsifying processes 2-5min；
Microsphere hardening:
(5) embryonic microparticles in step (4) is transferred in the cold normal heptane of 150ml, at 5 DEG C, stirs 1-2h.Soak with normal heptane cold for 200ml to rinse microparticle surfaces residual solvent；
Dry and collect:
(6) use multi-deck screen to collect, rinse with normal hexane.4 DEG C of dry 24h, 25 DEG C of vacuum drying 24h, 35 DEG C of vacuum drying 24h.
The preparation of embodiment 4 Exenatide microsphere composition of the present invention
Prepared by drug-polymer solution:
(1) 0.21g purification PLGA50:50DLG1A and 0.42g purification 50:50DLG4A is dissolved in 9ml dichloromethane, forms polymer solution；
(2) 50mg Exenatide is dissolved in 1.5ml glacial acetic acid；
(3) being mixed with Exenatide solution in step (2) by the polymer solution in step (1), stirring obtains homogeneous solution；
Prepared by embryonic microparticles:
(4) being added to by 15ml liquid paraffin in the solution in step (3), emulsifying processes 2-5min；
Microsphere hardening:
(5) embryonic microparticles in step (4) is transferred in the cold normal heptane of 150ml, at 5 DEG C, stirs 1-2h.Soak with normal heptane cold for 200ml to rinse microparticle surfaces residual solvent；
Dry and collect:
(6) use multi-deck screen to collect, rinse with normal hexane.4 DEG C of dry 24h, 25 DEG C of vacuum drying 24h, 35 DEG C of vacuum drying 24h.
Comparative example 1
Reference sample is prepared without protectant W/O/O method:
(1) 0.62g purification PLGA50:50DLG3A is dissolved in 10ml dichloromethane, forms polymer solution；
(2) 40mg Exenatide is dissolved in 0.5ml purified water,
(3) Exenatide solution in step (2) is added to the polymer solution in step (1), shear 1min, obtain colostrum；
Prepared by embryonic microparticles:
(4) being added to by 15ml silicone oil in the suspension in step (3), emulsifying processes 2-5min；
Microsphere hardening:
(5) embryonic microparticles in step (4) is transferred in the mixed solution of 200ml normal heptane and 20ml ethanol, at 5 DEG C, stirs 1-2h.Soak with normal heptane cold for 400ml to rinse microparticle surfaces residual solvent；
Dry and collect:
(6) use multi-deck screen to collect, rinse with normal heptane.4 DEG C of dry 24h, 25 DEG C of vacuum drying 24h, 35 DEG C of vacuum drying 24h.
Comparative example 2 is added protectant W/O/O method and is prepared reference sample:
(1) 0.62g purification PLGA50:50DLG3A is dissolved in 10ml dichloromethane, 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 to the polymer solution in step (1), shear 1min, obtain colostrum；
Prepared by embryonic microparticles:
(4) being added to by 15ml silicone oil in the suspension in step (3), emulsifying processes 2-5min；
Microsphere hardening:
(5) embryonic microparticles in step (4) is transferred in the mixed solution of 200ml normal heptane and 20ml ethanol, at 5 DEG C, stirs 1-2h.Soak with normal heptane cold for 400ml to rinse microsphere surface residual solvent；
Dry and collect:
(6) use multi-deck screen to collect, rinse with normal heptane.4 DEG C of dry 24h, 25 DEG C of vacuum drying 24h, 35 DEG C of vacuum drying 24h.
The detection method of experimental example 5 sample:
(1) particle size distribution measuring: adopt laser particle analyzer (Malvern3000) to measure the particle size distribution of microsphere.
(2) entrapment efficiency determination:
Weighing 10mg microsphere, add 2ml dimethyl sulfoxide, eddy oscillating makes to be completely dissolved, and adds purified water and is settled to 10ml.By HPLC analytical column: TSK-GEL carries out detection by quantitative.Computational envelope rate.
(3) determination of drug activity:
Measured the biological activity of Exenatide by ELISA method, measure the absorbance of target sample by microplate reader, then using the absorbance of Exenatide standard substance as comparison, calculate the Relative biological activity retention rate of medicine after embedding.Adopt microsphere prepared by W/O/O method as reference sample using comparative example 4, comparative example 5.
(4) release in vitro measures:
By measuring the concentration of different time Exenatide in release buffer.Being placed in 200ml buffer by 30 ± 2mg microsphere under room temperature, the about 30s that vibrates, with this solution that suspends, is subsequently placed in 37 DEG C of waters bath with thermostatic control.Vibration mixing after certain time, stands 30min, takes supernatant, immediately by HPLC analytical column: TSK-GEL carries out detection by quantitative.Measuring the release after 4h is initial release.
(5) internal release measures:
Exenatide in interlayer immune quantitative blood plasma, is caught analyte with solid single clonal antibody EXE4:2-8.4, is detected by radioiodination monoclonal antibody GLP-1:3-3.Standards calibration curve comes quantitatively.
(6) testing result (testing result is in Table 1, Fig. 1, Fig. 2):
Table 1 product property characterizes
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Comparative example 1 | Comparative example 2 | |
| Mean diameter μm | 57.2 | 61.4 | 68.0 | 66.3 | 63.6 | 62.8 |
| Envelop rate/% | 90.5 | 92.7 | 92.4 | 90.1 | 89.2 | 90.3 |
| Activity 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; adopt in Exenatide microsphere prepared by preparation method of the present invention Exenatide active component loss of activity in without protectant situation less; its Relative biological activity retention rate is more than 90%, far above the Relative biological activity retention rate (42.8%) of Exenatide in the Exenatide microsphere of comparative example 1 preparation.Compared with comparative example 2, preparation method of the present invention can realize higher Exenatide Relative biological activity retention rate without adding protective agent, but owing to protective agent need not be used to reduce cost, improves Drug safety.
As can be seen from Figure 1, burst effect can be effectively controlled for solvent with glacial acetic acid and dimethyl sulfoxide, obtain 0-30d close to zero-order release curve, Exenatide is higher at glacial acetic acid and dmso solution degree, less both as active component solvent load, the envelop rate of the Exenatide microsphere prepared is high, and prominent release low.
Adopt single polymers, and can obtain with dimethyl sulfoxide for Exenatide microsphere prepared by solvent and discharge more smoothly.The drug release profiles of microsphere is prepared with certain proportion close to Zero order release after wherein being mixed by different molecular weight PLGA50:50DLG1A and 50:50DLG4A, therefore by regulating the molecular weight of polymer or different proportion polymer mixed can be adopted to regulate the drug release behavior of microsphere, to obtain the sustained release microsphere agents in different release cycle.
As can be seen from Figure 2, after administration 7d, in rat body, blood drug level reaches peak value, and 2-30d blood drug level maintains between 100-200pg/ml, fluctuates less, illustrate that the microball preparation adopting this technology to prepare steadily discharges one month in vivo, and there is less blood concentration fluctuation.
Claims (10)
1. an Exenatide release microsphere compositions, it is characterised in that: it is made up of Exenatide and polymer；Described Exenatide accounts for 2～15%w/w of described microsphere gross weight；One or more in polycaprolactone, polylactic acid, Poly(D,L-lactide-co-glycolide, polyanhydride of described polymer；The particle diameter of described Exenatide microsphere is 20～90 μm；The Relative biological activity retention rate of described Exenatide is more than 90%.
2. Exenatide release microsphere compositions according to claim 1, it is characterised in that: described polymer is selected from polylactic acid, Poly(D,L-lactide-co-glycolide or its mixing.
3. Exenatide release microsphere compositions according to claim 1 and 2, it is characterised in that: described Exenatide accounts for 5～10%w/w of described microsphere gross weight.
4. the preparation method preparing Exenatide release microsphere compositions described in claim 1-3 any one, it comprises the steps:
A, Exenatide powder is dissolved in intensive polar solvent；
B, take polymer add weak polar solvent dissolve；
C, the solution prepared by step a add in the solution of step b, prepare into suspension or uniform solution；
Adding flocculating agent in d, the suspension of step c or uniform solution, preparation forms embryonic microparticles；
E, the embryonic microparticles of step d is transferred in cancellation solvent harden；Collect hardened particles；Dry；
Wherein, described intensive polar solvent is 1:5～1:50 with the volume ratio of weak polar solvent.
5. the preparation method of Exenatide release microsphere compositions according to claim 4, it is characterised in that: the volume ratio of described intensive polar solvent and described weak polar solvent is 1:20～1:40.
6. the preparation method of Exenatide release microsphere compositions according to claim 5, it is characterised in that: the volume ratio of described intensive polar solvent and described weak polar solvent is 1:30.
7. the preparation method of Exenatide release microsphere compositions according to claim 4, it is characterised in that: particle diameter≤2 μm of the particle of suspension described in step c.
8. the preparation method of the Exenatide release microsphere compositions according to claim 4-6 any one, it is characterised in that:
One or more in dimethyl sulfoxide, N,N-dimethylformamide, methanol, glacial acetic acid of intensive polar solvent described in step a；
One or more in ethyl acetate, methyl ethyl ketone, dichloromethane, oxolane of weak polar solvent described in step b；
One or more in silicone oil, liquid paraffin, mineral oil and derivant thereof of flocculating agent described in step d；
One or more in normal octane, normal heptane, normal hexane, hexamethylene or ring-type liquid alkane of cancellation solvent described in step e.
9. the preparation method of the Exenatide release microsphere compositions according to claim 4-6 or 8 any one, it is characterised in that: intensive polar solvent described in step a is selected from glacial acetic acid or dimethyl sulfoxide.
10. the preparation method of the Exenatide release microsphere compositions according to claim 4-6 any one, it is characterised in that:
The process time of emulsifying described in step d is 2～5min；
In step e, the method for curing of microgranule is: gone to by the initial stage framboid of Step d in the cancellation solvent of temperature range-5 DEG C to 5 DEG C, stirs 1～2h；
Collection method described in step e is to use cancellation solvent rinse, and adopts multi-deck screen to collect.
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| CN108653740B (en) * | 2018-05-18 | 2021-06-08 | 上海济群医药科技有限公司 | Method for preparing PLGA sustained-release microspheres by improved phase separation method |
| CN113116861A (en) * | 2018-05-18 | 2021-07-16 | 上海济群医药科技有限公司 | Method for preparing PLGA sustained-release microspheres by improved phase separation method |
| CN113116861B (en) * | 2018-05-18 | 2022-09-16 | 上海济群医药科技有限公司 | Method for preparing PLGA sustained-release microspheres by improved phase separation method |
| CN109432397A (en) * | 2018-11-28 | 2019-03-08 | 苏州天马医药集团天吉生物制药有限公司 | Polypeptide microballoon and preparation method thereof |
| CN109432397B (en) * | 2018-11-28 | 2022-03-18 | 苏州天马医药集团天吉生物制药有限公司 | Polypeptide microsphere and preparation method thereof |
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