CN102641281B - A kind of injection GM1 and preparation method thereof - Google Patents
A kind of injection GM1 and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to medical art, be specifically related to a kind of injection GM1 and preparation method thereof.Injection GM1 of the present invention comprises GM1, gelatin and PLGA.By micro-balloon injection prepared by the present invention, favorable reproducibility, envelop rate is high, improves drug loading, and drug release continues and stablizes, single-dose amount obviously reduces, reduce foreign body sensation, effective blood drug concentration can be maintained for a long time, avoid defect daily, improve the quality of life of patient, solve the problem of the blood concentration fluctuation that conventional formulation brings.
Description
Technical field
The invention belongs to medical art, relate to a kind of injection GM1 and preparation method thereof.
Background technology
Monostalotetrahexosylgangliside is containing sialic aphingolipid, the reparation of damaged nerve cell can be accelerated, promote growth and the regeneration of neurocyte, improve nerve conduction etc., be mainly used in reparation and the treatment of maincenter and disorder of peripheral autonomic nervous system, be considered to one of the most effective medicine of current clinical treatment spinal cord injury (SCI), had import to inject liquid drugs injection listing at present, effective ingredient is GM1 (GM1).
GM1 is clinically mainly through the long-time heavy dose of repetitively administered treatment SCI of periphery approach.Although exogenous Monostalotetrahexosylgangliside has and fat-solublely can pass blood brain barrier, but pharmacokinetic confirms, be injected into GM1 after in body to absorb mainly through liver, central nervous system's intensive amount is little, about 20% is only had to enter brain, the positions such as spinal cord play a role, and GM1 content just will reach peak in 8 to 16 hours upon administration in central nervous system, often strengthen frequency of utilization clinically to maintain required drug level, but the thing followed is the reduction with patient compliance that increases of untoward reaction, limit the performance of the good drug effect of its clinical practice.
Research display in recent years, GM1 is a kind of effective ways for the treatment of SCI by a small amount of administration of subarachnoid space approach.GM1 ordinary preparation is along with metabolic exhaustion, single-dose can not maintain it for a long time in valid density locally, and GM1 quantity large (20-100mg/60kg/ day), repeated multiple timesly carry out subarachnoid space puncture administration and will inevitably increase infection chance, be unworthy recommending.Thus, the research of GM1 slow releasing preparation is had very important significance.
Microsphere refers to medicine dispersion or is attracted to the microparticulate system formed in macromolecule, polymeric matrix, pharmaceutical pack can be rolled in biodegradable carrier material, medicine discharges gradually along with the corrosion of carrier material, the level that vivo medicine concentration remains certain for a long time can be made, play the effect of long-acting slow-release, reduce times for spraying, increase patient compliance.Poly lactic coglycolic acid (PLGA) has good biocompatibility and degradability, is the biodegradable polymer material for the preparation of sustained-release micro-spheres, is used for subcutaneous injection microsphere by FDA approval at present.Jiang Tao etc. are in " preparation of the PLGA microsphere of Monostalotetrahexosylgangliside " (volume the 4th phase in " medical Leader " April the 25th in 2006,335th ~ 337 pages) disclosed in the preparation technology of GM-1-PLGA microsphere, its form rule, particle diameter is (19.3 ± 8.5) μm about, and drug loading only has 4.7%.In the technical scheme disclosed in Jiang Qingbin " preparation of GM-1-PLGA microsphere and tablets in vitro evaluation thereof " (on April 17th, 2010, Shandong University's master thesis), the drug loading of GM1 microsphere only has 17%.Can learn from published document, the drug loading of GM-1-PLGA microsphere prepared by prior art is very low, wants to reach and effectively treats window, need during administration to larger dose, during subcutaneous injection, patient has foreign body sensation, reduces compliance and comfort level.
Summary of the invention
The present invention is by the preferred component proportion of GM1 microball preparation of a large amount of tests, optimize preparation technology, provide a kind of injection GM1, said preparation is subcutaneous injection microsphere, is made up of the poly lactic-co-glycolic acid (PLGA) of the GM1 (GM-1) of 0.05 ~ 0.15 weight portion, the gelatin of 0.1 ~ 0.5 weight portion and 1 ~ 10 weight portion.
The present invention carries out preferably the content of GM1, and preferably, above-mentioned injection GM1 contains the GM1 (GM-1) of 0.1 weight portion.
The present invention carries out preferably the content of gelatin, and preferably, above-mentioned injection GM1 contains the gelatin of 0.3 weight portion.
The content of the present invention to poly lactic-co-glycolic acid (PLGA) carries out preferably, and preferably, above-mentioned injection GM1 contains the poly lactic-co-glycolic acid (PLGA) of 5 weight portions.
The molecular weight of the present invention to poly lactic-co-glycolic acid (PLGA) carries out preferably, and preferably, the molecular weight of above-mentioned poly lactic-co-glycolic acid (PLGA) is 6000 ~ 35000, and more preferably molecular weight is 6000.
The present invention carries out preferred to lactide in poly lactic-co-glycolic acid (PLGA) and the ratio of Acetic acid, hydroxy-, bimol. cyclic ester, preferably, in above-mentioned poly lactic-co-glycolic acid (PLGA), the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 50/50 or 65/35 or 75/25, and more preferably the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25.
The present invention also optimizes a kind of preparation method of injection GM1: the GM1 of recipe quantity and gelatin are dissolved in the water of 2 ~ 6 parts by volume, dissolves and mixes as interior water (W1) phase; The poly lactic-co-glycolic acid of recipe quantity is dissolved in the dichloromethane of 30 ~ 60 parts by volume as oil (O) phase; Using the polyvinyl alcohol dissolution of 5 ~ 10 weight portions in the water for injection of 500 ~ 1000 parts of 80 DEG C as outer water (W2) phase; W1 phase is slowly added dropwise in O phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in W2 phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 3000 ~ 6000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, uses subpackage after water for injection washing 3 ~ 7 times, lyophilization and get final product.
In microball preparation, the drug loading of effective ingredient should not be too low, otherwise during to patient's administration, the amount of injectable microsphere is excessive, can cause the side effect that pain etc. is unnecessary to patient; If contrary drug loading is excessive, when to patient's administration, burst drug release is comparatively serious, easily causes overdose.The present inventor is learnt by lot of experiments research, in oil phase, the increase of polylactic-co-glycolic acid concentration can improve the viscosity of oil phase, reduce the loss of the outside aqueous phase of GM1, improve drug loading and envelop rate, but after its concentration reaches certain level, improve concentration again and can reduce drug loading on the contrary, the present invention in microsphere preparation process to the volume ratio of each component proportion in aqueous phase (comprising interior aqueous phase and outer aqueous phase) and oil phase and aqueous phase and oil phase, colostrum and poly-vinyl alcohol solution volume ratio are carried out preferably, improve the envelop rate of microsphere, drug loading is increased to 60.8 ~ 72.6%.
If the microspherulite diameter preparing gained is too small, be difficult to maintain long drug effect, likely block blood capillary simultaneously, affect microcirculation, and particle diameter is excessive, initial stage release is too slow, do not reach treatment effective blood drug concentration, poly-vinyl alcohol solution concentration improves the viscosity that can increase outer aqueous phase, makes microsphere be more prone to formation spherical, significantly improves the microsphere form of said preparation.By the present invention's preparation-obtained injection GM1 microsphere span 1 ~ 5, mean diameter 5 ~ 50 μm, preferable particle size 15 ~ 23 μm, so both can make this microsphere reach the effect of slow release, and can ensure again to be injected into after in body does not affect blood circulation.
The preparation that the present invention prepares gained also needs to use water for injection washing 3 ~ 7 times, to remove the polyvinyl alcohol of microsphere surface, decreases the harm of polyvinyl alcohol to human body; After simultaneously microball preparation of the present invention uses water for injection washing, do not need to add excipient, direct packaging lyophilizing and get final product.
Injection GM1 disclosed in this invention, it is a kind of subcutaneous injection microsphere, by the component proportion in optimizing prescriptions, optimized fabrication method, impel effective ingredient GM1 along with carrier material polylactic-co-glycolic acid corrosion degraded discharge gradually, valid density can be maintained for a long time, play long-acting slow-release effect, add patient's compliance.By the present invention's preparation-obtained injection GM1 microsphere span 1 ~ 5, mean diameter 5 ~ 50 μm, preferable particle size 15 ~ 23 μm, envelop rate >=85.7%, and be up to 93.2%; Drug loading >=60.8%, be up to 72.6%, vitro release test shows that burst size in beginning 1 hour is lower than 30%, sustainable 14 days of the release in vitro time of microsphere, single-dose amount obviously reduces, reduce foreign body sensation, improve the quality of life of patient, avoid defect daily.By micro-balloon injection prepared by the present invention, favorable reproducibility, envelop rate and drug loading is high, drug release continue and stablize, effective blood drug concentration can be maintained for a long time, solve the problem of the blood concentration fluctuation that conventional formulation brings.
Accompanying drawing explanation
The outer cumulative release curve of Fig. 1, GM1 microsphere
Detailed description of the invention:
In order to better the present invention is described, set forth the present invention further by embodiment, but therefore do not limit the present invention in described embodiment.
Embodiment 1, injection GM1
The gelatin of the GM1 of 0.1 weight portion, 0.3 weight portion is dissolved in the water of 4 parts by volume, dissolves and mix as interior water (W1) phase; The poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25, molecular weight 6000) of 5 weight portions is dissolved in the dichloromethane of 40 parts by volume as oil (O) phase; Using the polyvinyl alcohol dissolution of 5 weight portions in the water for injection of 500 parts of 80 DEG C as outer water (W2) phase; W1 phase is slowly added dropwise in O phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in W2 phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 5000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, subpackage after using water for injection to wash 5 times, lyophilization and get final product.
Embodiment 2, injection GM1
The gelatin of the GM1 of 0.1 weight portion, 0.3 weight portion is dissolved in the water of 4 parts by volume, dissolves and mix as interior water (W1) phase; The poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25, molecular weight 20000) of 5 weight portions is dissolved in the dichloromethane of 40 parts by volume as oil (O) phase; Using the polyvinyl alcohol dissolution of 5 weight portions in the water for injection of 500 parts of 80 DEG C as outer water (W2) phase; W1 phase is slowly added dropwise in O phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in W2 phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 5000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, subpackage after using water for injection to wash 5 times, lyophilization and get final product.
Embodiment 3, injection GM1
The gelatin of the GM1 of 0.1 weight portion, 0.3 weight portion is dissolved in the water of 4 parts by volume, dissolves and mix as interior water (W1) phase; The poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25, molecular weight 35000) of 5 weight portions is dissolved in the dichloromethane of 40 parts by volume as oil (O) phase; Using the polyvinyl alcohol dissolution of 5 weight portions in the water for injection of 500 parts of 80 DEG C as outer water (W2) phase; W1 phase is slowly added dropwise in O phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in W2 phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 5000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, subpackage after using water for injection to wash 5 times, lyophilization and get final product.
Embodiment 4, injection GM1
The gelatin of the GM1 of 0.1 weight portion, 0.3 weight portion is dissolved in the water of 4 parts by volume, dissolves and mix as interior water (W1) phase; The poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 65/35, molecular weight 6000) of 5 weight portions is dissolved in the dichloromethane of 40 parts by volume as oil (O) phase; Using the polyvinyl alcohol dissolution of 5 weight portions in the water for injection of 500 parts of 80 DEG C as outer water (W2) phase; W1 phase is slowly added dropwise in O phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in W2 phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 5000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, subpackage after using water for injection to wash 5 times, lyophilization and get final product.
Embodiment 5, injection GM1
The gelatin of the GM1 of 0.1 weight portion, 0.3 weight portion is dissolved in the water of 4 parts by volume, dissolves and mix as interior water (W1) phase; The poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 50/50, molecular weight 6000) of 5 weight portions is dissolved in the dichloromethane of 40 parts by volume as oil (O) phase; Using the polyvinyl alcohol dissolution of 5 weight portions in the water for injection of 500 parts of 80 DEG C as outer water (W2) phase; W1 phase is slowly added dropwise in O phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in W2 phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 5000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, subpackage after using water for injection to wash 5 times, lyophilization and get final product.
Embodiment 6, injection GM1
The gelatin of the GM1 of 0.05 weight portion, 0.1 weight portion is dissolved in the water of 2 parts by volume, dissolves and mix as interior water (W1) phase; The poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25, molecular weight 6000) of 1 weight portion is dissolved in the dichloromethane of 30 parts by volume as oil (O) phase; Using the polyvinyl alcohol dissolution of 5 weight portions in the water for injection of 500 parts of 80 DEG C as outer water (W2) phase; W1 phase is slowly added dropwise in O phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in W2 phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 3000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, subpackage after using water for injection to wash 3 times, lyophilization and get final product.
Embodiment 7, injection GM1
The gelatin of the GM1 of 0.15 weight portion, 0.5 weight portion is dissolved in the water of 6 parts by volume, dissolves and mix as interior water (W1) phase; The poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25, molecular weight 6000) of 10 weight portions is dissolved in the dichloromethane of 60 parts by volume as oil (O) phase; Using the polyvinyl alcohol dissolution of 10 weight portions in the water for injection of 1000 parts of 80 DEG C as outer water (W2) phase; W1 phase is slowly added dropwise in O phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in W2 phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 6000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, subpackage after using water for injection to wash 7 times, lyophilization and get final product.
The physicochemical property of embodiment 8. injection GM1 and release behavior test:
8.1 microsphere somatometry of physique
Lyophilizing thus obtained microsphere, with after water for injection dispersion, is observed the form of microsphere by optical microscope and camera system and is calculated microspherulite diameter.
8.1.1 microsphere form
Injection GM1 microsphere features smooth surface made by the present invention or have a small amount of aperture.
8.1.2 microspherulite diameter
Span is between 1 ~ 5, and major part is distributed within the scope of 5.0 ~ 50.0 μm, shows that microspherulite diameter is evenly distributed.The concrete detection data of the preparation-obtained microspherulite diameter of embodiment 1-7 are in table 1.
8.2 entrapment efficiency determination
Envelop rate (EE) refers to that the medication amount in microsphere accounts for the percentage rate of total dosage.Envelop rate is low, then the loss of medicine is large, and cost increases, so the envelop rate most important index that is microsphere.Supernatant and microsphere washing liquid, by after centrifugation microsphere, merge, amalgamation liquid are crossed the microporous filter membrane of 0.45 μm by the present invention, are measured the content of GM1, by following formulae discovery envelop rate by HPLC method:
Envelop rate %=[(dropping into medicine total amount-supernatant fluid content of dispersion)/drop into medicine total amount] × 100%
The concrete data that embodiment 1-7 preparation-obtained microsphere encapsulation rate measures are in table 1.
8.3 microsphere drug loading
Drug loading (DL) refers to the weight percent of contained drug in microsphere, is the important indicator evaluating microspheres quality, is directly connected to industrialization and the clinical practice of preparation.Drug loading is calculated as follows usually:
Drug loading (%)=(microsphere drug content/microspheres weight) * 100%
In the present invention, we test concrete grammar is amalgamation liquid is crossed the microporous filter membrane of 0.45 μm, is measured the content of GM1, the drug loading by following formulae discovery microsphere by HPLC method:
Drug loading %=(dropping into medicine total amount-amalgamation liquid Chinese medicine amount/microspheres quality in system) * 100%
The concrete data of embodiment 1-7 preparation-obtained microsphere drug loading are in table 1.
Table 5 microsphere form and envelop rate
| Mean diameter (μm) | Drug loading (%) | Envelop rate (%) | |
| Embodiment 1 | 15 | 72.6 | 93.2 |
| Embodiment 2 | 18 | 68.1 | 87.6 |
| Embodiment 3 | 16 | 65.3 | 85.7 |
| Embodiment 4 | 19 | 63.5 | 87.2 |
| Embodiment 5 | 23 | 60.8 | 89.5 |
| Embodiment 6 | 5 | 66.4 | 85.7 |
| Embodiment 7 | 50 | 67.3 | 88.2 |
As seen from the above table, this technique thus obtained microsphere particle size distribution is even, drug loading 60.8 ~ 72.6%, envelop rate all more than 85.7%, illustrate this technique can effectively by drug encapsulation in carrier material.
8.4 microsphere extracorporeal releasing tests
Precision weighing GM1 microsphere 20mg is in test tube, using pH7.4 phosphate buffer (0.02% sodium azide prevents microsphere adhesion as antiseptic, 0.02% polysorbas20 as surfactant) 10tnL, for release medium whirlpool 1min is in 37 DEG C, 100r/min constant-temperature table vibration release, respectively at 0.5,1,2,3,5,7,10,14d time test tube is taken out, get whole supernatant and supplement same volume release medium, again after suspendible, putting back to shaking table concussion.Supernatant microporous filter membrane (0.45 μm) filters to obtain subsequent filtrate, get subsequent filtrate and carry out assay, make cumulative release curve (see the outer cumulative release curve of Fig. 1, GM1 microsphere), known at 0.5h microsphere extracorporeal releasing quantity lower than 30%, stabilization in vitro can continue 14 days release time.
Claims (6)
1. an injection GM1, is characterized in that it is made up of the poly lactic-co-glycolic acid of the GM1 of 0.05 ~ 0.15 weight portion, the gelatin of 0.1 ~ 0.5 weight portion and 1 ~ 10 weight portion; Wherein, the molecular weight of described poly lactic-co-glycolic acid is 6000 ~ 35000; In poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 50/50,65/35 or 75/25; Its preparation method is as follows: described GM1 and gelatin are dissolved in the water of 2 ~ 6 parts by volume, dissolves and mixes as interior aqueous phase; Described poly lactic-co-glycolic acid is dissolved in the dichloromethane of 30 ~ 60 parts by volume as oil phase; Using the polyvinyl alcohol dissolution of 5 ~ 10 weight portions in the water for injection of 500 ~ 1000 parts of 80 DEG C as outer aqueous phase; Interior aqueous phase is slowly added dropwise in oil phase, 15000r/min vibrates at a high speed after emulsifying 3 ~ 5min, be cooled to 10 DEG C, as colostrum, and join in outer aqueous phase, 15000r/min is vibration emulsifying 3 ~ 5min at a high speed, 3000 ~ 6000r/min keeps 4h to fling to dichloromethane, 10000r/min high speed centrifugation, uses subpackage after water for injection washing 3 ~ 7 times, lyophilization and get final product.
2. injection GM1 according to claim 1, is characterized in that it contains the GM1 of 0.1 weight portion.
3. injection GM1 according to claim 1, is characterized in that it contains the gelatin of 0.3 weight portion.
4. injection GM1 according to claim 1, is characterized in that it contains the poly lactic-co-glycolic acid of 5 weight portions.
5. injection GM1 according to claim 1, is characterized in that, the molecular weight of described PLGA lactic-co-glycolic acid is 6000.
6. injection GM1 according to claim 1, is characterized in that, it is characterized in that the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester in poly lactic-co-glycolic acid is 75/25.
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| CN102988284B (en) * | 2012-12-13 | 2014-04-02 | 哈药集团技术中心 | Preparation method for monosialotetrahexosyl ganglioside sodium injection |
| CN103006587A (en) * | 2013-01-14 | 2013-04-03 | 山东新时代药业有限公司 | Decitabine for injection and preparation method thereof |
| CN103083260A (en) * | 2013-02-05 | 2013-05-08 | 南京正宽医药科技有限公司 | Gemcitabine hydrochloride for injection as well as preparation method thereof |
| CN106511359A (en) * | 2016-12-06 | 2017-03-22 | 郑州郑先医药科技有限公司 | Western medicine mixture for treating spinal cord injury, and application thereof |
| CN109705176A (en) * | 2019-01-23 | 2019-05-03 | 苏州纳微科技股份有限公司 | The isolation and purification method of one boar gangliosides |
| CN114642634A (en) * | 2020-12-17 | 2022-06-21 | 中国科学院深圳先进技术研究院 | Blood brain barrier penetrating drug-carrying micelle and preparation method and application thereof |
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