CN104706588A - Vinpocetine fat emulsion concentrated solution, preparation method and application thereof - Google Patents
Vinpocetine fat emulsion concentrated solution, preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmacology and pharmaceutics and relates to a vinpocetine fat emulsion concentrated solution, a preparation method and an application thereof. According to the invention, the defect that a traditional fat emulsion preparation technology is complex and has poor stability is overcome. The preparation technology provided by the invention is simple; the general physical stirring process is only needed; and no homogenization technology is required. A product prepared in the invention can be sterilized through a 0.22-micron microfiltration membrane; in clinical use, the product can be spontaneously emulsified after diluted by the use of an aqueous solution such as normal saline or a glucose solution, etc. and slightly oscillated; and under optimized conditions, average particle size is about 0.2 micron, and injection fat emulsion characteristics are fully embodied. The product has good fluidity, will not be retained on the wall, is single-phase, transparent and clear in appearance, can undergo clarification detection, will not cause preparation stratification after multigelation and is used in improving various symptoms induced by diseases such as sequel of cerebral infarction, cerebral hemorrhage sequelae, cerebral arteriosclerosis and the like.
Description
Technical field
The invention belongs to materia medica and pharmaceutical art, relate to vinpocetine fat milk concentrated solution, Preparation Method And The Use.
Background technology
Vinpocetine (Vinpocetine), is cerebral vasodilator, can suppresses phosphodiesterase activity, increases the effect of the courier c-GMP of vascular smooth muscle relaxation, optionally increases cerebral blood flow.Vinpocetine is the drug of first choice as improving cerebral circulation, because it has more comprehensive therapeutical effect, this medicine is for Cardial or cerebral vascular diseases, not only can prevent and treat cerebral arteriosclerosis and apoplexy sequela, also there is defying age, improve the effect of gerontal patient's audition and visual performance, be with a wide range of applications.
Vinpocetine is insoluble drug, add the dissolubility that organic acid can increase vinpocetine, therefore a large amount of organic acid is contained in commercially available vinpocetine injection, pH value range is closely acid, cause medicine blood vessel irritation strong, with benzyl alcohol as blood vessel irritation regulator, and large usage quantity, there is the risk of haemolysis; PH value range is closely acid, causes stability of drug products poor, and need with antioxidant as chemical stabilizer, drug safety is poor.
Li Yu Mentone is crossed and is prepared vinpocetine submicron emulsion lyophilized formulations, obtains a kind of external injection without obvious haemolysis (Li Yumeng, (2009), Academy of Military Medicine, PLA, master thesis).Submicron emulsion, also known as fat milk or lipid microsphere, is that current field of medicaments develops dosage form faster, and it is mainly soft substrate with fatty oil, by medicine dissolution in fatty oil, is wrapped in the milk-globule of immobilized artificial membrane encapsulating by phospholipid emulsification.Can the coated medicine of protection, can improve medicine stability, prolong drug action time, reduce side effect etc., having certain slow-releasing and targeting, is a kind of desirable pharmaceutical carrier.
Fat milk all belongs to Unstable Systems on thermodynamics and kinetics, in commercial production, fat milk is by two step emulsion process preparations, relate to colostrum preparation, high pressure homogenize, preparation process has strict requirement to equipment, technological parameter, ratio of adjuvant etc., and temperature, emulsification times, homogenization pressure, cycle-index and production equipment all have an impact to product quality.This is because the direct constituent by fat milk is (after the mixing of materials such as phospholipid, oil, water, oil-water separation phenomenon can be there is, only have these materials, through special homogenizer process, as high pressure homogenizer, the emulsion of stable uniform could be formed, in homogenizing process, material is subject to dither, hole, shearing, and the coordinative role such as impact, finally broken up or be refined as insoluble phase granule Hiroko Shibata, et al. (2009) the Int. J. Pharm. 378:167-176 in liquid; Dirk L. Teagarden, et al.(1996) Adv. Drug. Deliv. Rev. 20:155-164), fat milk needs Special Equipment under high pressure sterilizing in addition.
Lyophilizing submicron emulsion is on the basis obtaining fat milk, crosses the means such as lyophilization, by the moisture removal in system,
Obtain lyophilized formulations; in order to ensure that lipid microsphere structure is not destroyed in freeze-drying process; need at needs before lyophilization; add the material such as cryoprotective agent, redissolution promoter; promote to redissolve as excellent Supreme Being you (injection Alprostadil liposome microsphere dry emulsion) namely adds lactose; patent CN200410021253.3; CN201110114324.4; CN201010171208.1; CN201010168597.2; also glucide or cyclodextrin must be added, to realize the redissolution of freeze-dried emulsion in CN201110195802.9 technical scheme.
A desirable vinpocetine fat milk, be preparation technology simple, without the need to special installation, can be degerming by microporous filter membrane mode, to lower preparation cost.Meanwhile, clinical practice is convenient, adds the injection solutions such as normal saline, and energy spontaneous emulsification after slight oscillatory, the preparation after emulsifying, mean diameter, at about 0.2 μm, keeps typical fat milk characteristic.
Summary of the invention
The present inventor is through deep research and performing creative labour, obtain a kind of vinpocetine fat milk concentrated solution, the present inventor is surprised to find, vinpocetine fat milk concentrated solution of the present invention, after mixing with water, without homogenizing means, stable emulsion can be formed, can effectively overcome Oil-water separation phenomenon.And the preparation lamination that product of the present invention can effectively overcome the density contrast between different auxiliary material and bring, obtains single-phase, transparent, stable thus, meeting after water can the vinpocetine fat milk concentrated solution of spontaneous emulsification.Thus provide following invention:
The present invention relates to a kind of vinpocetine fat milk concentrated solution, it comprises:
Principal agent: vinpocetine,
Oil: medium chain length fatty acid triglyceride,
Cosolvent: 1,2-PD,
Low hlb surfactant (4≤HLB≤9): phospholipid, and
High hlb surfactant (HLB >=12): polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini;
Alternatively, described low hlb surfactant also comprises polyglycerol acrylate;
Alternatively, described high hlb surfactant also comprises Tween 80.
Vinpocetine fat milk concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(5) or multinomial:
(1) content of described vinpocetine is 0.1-1.5%(w/w); Be preferably 0.2-1%(w/w);
(2) content of described oil is 45-85%(w/w); Be preferably 50-70%(w/w);
(3) content of described cosolvent is 5-30%(w/w); Be preferably 5-15%(w/w);
(4) content of described low hlb surfactant is 5%-15%(w/w);
(5) content of described high hlb surfactant is 5%-20%(w/w).
Vinpocetine fat milk concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(8) or multinomial:
(1) content of described vinpocetine is 0.2-1%(w/w), be preferably 0.4-0.6%(w/w);
(2) content of described medium chain length fatty acid triglyceride is 55%-70%, is preferably 65%-70%;
(3) content of described 1,2-PD is 5%-15%, is preferably 8%-12%;
(4) content of described phospholipid is 5%-15%, is preferably 7.5%-12%;
(5) content of described polyglycerol acrylate is 0-8%, is preferably 0-5%;
(6) content of described polyethyleneglycol-12-hydroxy stearin is 0-15%, is preferably 0-10%;
(7) content of described polyoxyethylene ether (35) Oleum Ricini is 0-15%, is preferably 0-10%;
(8) content of described Tween 80 is 0-15%, is preferably 0-5%.
Vinpocetine fat milk concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(7) or multinomial:
(1) the not moisture or water content of described vinpocetine fat milk concentrated solution is lower than 1%;
(2) described vinpocetine fat milk concentrated solution is not containing saccharide;
(3) the unambiguous essence of described vinpocetine fat milk concentrated solution;
(4) described vinpocetine fat milk concentrated solution its preparation method does not comprise removing or falls low-moisture step (such as rotary evaporation, spraying dry or lyophilization);
(5) alternatively, described vinpocetine fat milk concentrated solution also comprises antioxidant; Particularly, described antioxidant be selected from oleic acid, enuatrol, vitamin E and vitamin A any one or multiple;
(6) described vinpocetine fat milk concentrated solution is transparent, single phase soln;
(7) described vinpocetine fat milk concentrated solution adopts 0.22 μm of microporous filter membrane mode degerming.
Vinpocetine fat milk concentrated solution according to any one of the present invention, its component and content are as below 1)-2) shown in group any one group:
1）
Vinpocetine 0.4 ~ 0.6 gram
Medium chain length fatty acid triglyceride 65 ~ 70 grams
1,2-PD 8 ~ 12 grams
Soybean lecithin 7.5 ~ 12 grams
Polyglycerol acrylate 0 ~ 5 gram
Polyethyleneglycol-12-hydroxy stearin 7 ~ 10 grams
Tween 80 3 ~ 5 grams
Oleic acid 0 ~ 0.3 gram
Enuatrol 0 ~ 0.3 gram
Vitamin E 0 ~ 0.3 gram;
2）
Vinpocetine 0.4 ~ 0.6 gram
Medium chain length fatty acid triglyceride 65 ~ 70 grams
1,2-PD 8 ~ 12 grams
Soybean lecithin 7.5 ~ 12 grams
Polyglycerol acrylate 0 ~ 5 gram
Polyoxyethylene ether (35) Oleum Ricini 8 ~ 10 grams
Oleic acid 0 ~ 0.3 gram
Enuatrol 0 ~ 0.3 gram
Vitamin E 0 ~ 0.3 gram.
Vinpocetine fat milk concentrated solution according to any one of the present invention, its component and content are as shown in any a group in (1) below-(4) group:
（1）
Vinpocetine 0.4 gram
Medium chain length fatty acid triglyceride (Capmul MCM, Abitec) 67.2 grams
1,2-PD 8 grams
Soybean lecithin 7.5 grams
Polyglycerol acrylate 4 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 8.5 grams
Tween 80 4 grams
Oleic acid 0.1 gram
Vitamin E 0.3 gram;
（2）
Vinpocetine 0.6 gram
Medium chain length fatty acid triglyceride (Crodamol GTCC) 67.5 grams
1,2-PD 9 grams
Soybean lecithin 12 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 7.2 grams
Tween 80 3.5 grams
Oleic acid 0.2 gram;
（3）
Vinpocetine 0.5 gram
Medium chain length fatty acid triglyceride (Miglyol 812, SASOL) 69 grams
1,2-PD 10 grams
Soybean lecithin 7.6 grams
Polyglycerol acrylate 3 grams
Polyoxyethylene ether (35) Oleum Ricini (Cremophor EL, BASF) 9.3 grams
Oleic acid 0.3 gram
Vitamin E 0.3 gram;
（4）
Vinpocetine 0.5 gram
Medium chain length fatty acid triglyceride (Labrafac Lipo WL1349) 68 grams
1,2-PD 10 grams
Soybean lecithin 11.5 grams
Polyoxyethylene ether (35) Oleum Ricini (Cremophor EL, BASF) 10 grams.
It should be noted that; above-mentioned 1) unit of gram-2) in group or (1)-(4) group represents the ratio between each component, if be revised as other unit of weight, includes but not limited to; such as kilogram and milligram etc., also all within protection scope of the present invention.
Another aspect of the invention relates to a kind of injection vinpocetine fat milk, and its vinpocetine fat milk concentrated solution according to any one of the present invention adds water or aqueous solution self emulsifying obtains; Particularly, described injection vinpocetine fat milk mean diameter is 0.05-0.7 μm; Be preferably 0.1-0.4 μm; More preferably, be 0.16-0.22 μm.
After vinpocetine fat milk concentrated solution of the present invention meets water dilution, can spontaneous emulsification be the vinpocetine fat milk meeting injection requirement.
Another aspect of the invention relates to the preparation method of the vinpocetine fat milk concentrated solution according to any one of the present invention, comprises the steps:
1) at 20-45 DEG C, low hlb surfactant is added oil, under 2000-20000rpm condition, be stirred to and form transparent clear solution;
2) under 20-45 DEG C of condition, cosolvent, vinpocetine are added step 1) product, and under 200-2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20-45 DEG C of condition, high hlb surfactant and optional antioxidant are added step 2) product, and under 200-800rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition vinpocetine fat milk concentrated solution.
About step 1) or step 2) or step 3) in the oil, low hlb surfactant, high hlb surfactant and the cosolvent that use, wherein moisture will lower than 1%, or do not have free water.
Product in step 3), without removing or low-moisture step (such as rotary evaporation, spraying dry or lyophilization) is fallen, water content is lower than 1%(by weight percentage).
Another aspect of the invention relates to vinpocetine fat milk concentrated solution according to any one of the present invention or injection vinpocetine fat milk of the present invention and is improving the clinical applications such as various symptoms that cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis etc. bring out.
The explanation of the part term that the present invention relates to:
Fat milk, refers to also known as lipid microsphere, and after emulsion or the emulsifying of fat milk concentrated solution, the one of formation is soft substrate with fatty oil and is encapsulated by immobilized artificial membrane, and mean diameter is the microparticulate system of about 0.2 μm.
In the present invention, for the percentage ratio of the content of each component, if not otherwise specified, the percentage by weight (w/w) accounting for pharmaceutical composition gross weight is all referred to.
The beneficial effect of the invention
Good product mobility of the present invention, not wall built-up, outward appearance is single-phase, transparent, limpid shape, can accept clarity and detect, after multigelation, preparation lamination can not occur; Product of the present invention is met water and is formed in vinpocetine fat milk plant process, without the need to homogenizing process, only need slight oscillatory can spontaneous emulsification, during Clinical practice after the dilution of the aqueous solution such as normal saline or glucose solution also slight oscillatory, can spontaneous emulsification be the fat milk system meeting injection requirement, under optimum condition, after emulsifying, mean diameter is at about 0.2 μm, fully demonstrates injection fat milk characteristic.
Preparation technology of the present invention is simple, only needs General Physics whipping process, does not need homogenization, do not need dewatering process, vinpocetine fat milk concentrated solution prepared by the present invention, can be degerming by 0.22 μm of microporous filter membrane.The present invention has that preparation technology is simple, low production cost, is easy to the advantage of transporting, storing, has application prospect.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Embodiment 1: the preparation of vinpocetine fat milk concentrated solution sample 1
Its constituent is as follows:
Vinpocetine 0.4 gram
Medium chain length fatty acid triglyceride (Capmul MCM, Abitec) 67.2 grams
1,2-PD 8 grams
Soybean lecithin 7.5 grams
Polyglycerol acrylate 4 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 8.5 grams
Tween 80 4 grams
Oleic acid 0.1 gram
Vitamin E 0.3 gram
This vinpocetine fat milk concentrated solution preparation method is as follows:
1) at 20 DEG C, the soybean lecithin of above-mentioned weight, polyglycerol acrylate are added in medium chain length fatty acid triglyceride, under 20000rpm condition, be stirred to and form transparent clear solution;
2) under 20 DEG C of conditions, the 1,2-PD of above-mentioned weight, vinpocetine are added step 1) product, and under 200rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20 DEG C of conditions, the Tween 80 of above-mentioned weight, polyethyleneglycol-12-hydroxy stearin, oleic acid and vitamin E are added step 2) product, and under 200rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition vinpocetine fat milk concentrated solution.
Embodiment 2: the preparation of vinpocetine fat milk concentrated solution sample 2
Its constituent is as follows:
Vinpocetine 0.6 gram
Medium chain length fatty acid triglyceride (Crodamol GTCC) 67.5 grams
1,2-PD 9 grams
Soybean lecithin 12 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 7.2 grams
Tween 80 3.5 grams
Oleic acid 0.2 gram
This vinpocetine fat milk concentrated solution preparation method is as follows:
1) at 45 DEG C, the soybean lecithin of above-mentioned weight is added medium chain length fatty acid triglyceride, under 2000rpm condition, be stirred to and form transparent clear solution;
2) under 35 DEG C of conditions, the 1,2-PD of above-mentioned weight, vinpocetine are added step 1) product, and under 2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 30 DEG C of conditions, the Tween 80 of above-mentioned weight, polyethyleneglycol-12-hydroxy stearin and oleic acid are added step 2) product, and under 800rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition vinpocetine fat milk concentrated solution.
Embodiment 3: the preparation of vinpocetine fat milk concentrated solution sample 3
Its constituent is as follows:
Vinpocetine 0.5 gram
Medium chain length fatty acid triglyceride (Miglyol 812, SASOL) 69 grams
1,2-PD 10 grams
Soybean lecithin 7.6 grams
Polyglycerol acrylate 3 grams
Polyoxyethylene ether (35) Oleum Ricini (Cremophor EL, BASF) 9.3 grams
Oleic acid 0.3 gram
Vitamin E 0.3 gram
This vinpocetine fat milk concentrated solution preparation method is as follows:
1) at 30 DEG C, the soybean lecithin of above-mentioned weight, polyglycerol acrylate are added medium chain length fatty acid triglyceride, under 10000rpm condition, be stirred to and form transparent clear solution;
2) under 45 DEG C of conditions, the 1,2-PD of above-mentioned weight, vinpocetine are added step 1) product, and under 1000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 45 DEG C of conditions, by polyoxyethylene ether (35) Oleum Ricini, the oleic acid of above-mentioned weight, and vitamin E adds step 2) product, and under 500rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition vinpocetine fat milk concentrated solution.
Embodiment 4: the preparation of vinpocetine fat milk concentrated solution sample 4
Its constituent is as follows:
Vinpocetine 0.5 gram
Medium chain length fatty acid triglyceride (Labrafac Lipo WL1349) 68 grams
1,2-PD 10 grams
Soybean lecithin 11.5 grams
Polyoxyethylene ether (35) Oleum Ricini (Cremophor EL, BASF) 10 grams
This vinpocetine fat milk concentrated solution preparation method is as follows:
1) at 25 DEG C, the soybean lecithin of above-mentioned weight is added medium chain length fatty acid triglyceride, under 8000rpm condition, be stirred to and form transparent clear solution;
2) under 25 DEG C of conditions, the 1,2-PD of above-mentioned weight, vinpocetine are added step 1) product, and under 1000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 25 DEG C of conditions, polyoxyethylene ether (35) Oleum Ricini of above-mentioned weight is added step 2) product, and under 500rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition vinpocetine fat milk concentrated solution.
embodiment 5: spectrodensitometry is tested
With Hitachi U-2001 ultraviolet-uisible spectrophotometer, at ambient temperature, 600nm place measures optical density.Wherein vinpocetine fat milk concentrated solution is the sample 1-4 according to embodiment 1-4 preparation process gained, and result is as shown in table 1.
Table 1: the optical density value of different sample solution
Optical density represents the permeability of light, and numerical value is lower, shows that sample is more clarified homogeneous, and from result, product appearance of the present invention is homogeneous, limpid, transparent.
embodiment 6: stability test
Sample 1-4 prepared by embodiment 1-4.
Experimental technique: by different sample after-20 DEG C of freeze overnight, is positioned over 20 DEG C and naturally thaws, and multigelation like this 6 times, observe sample appearance under environmental condition, result of the test is in table 2.
Table 2: different sample is after freeze thawing, and sample appearance changes
From table 2, sample 1-4 all has fabulous stability, and through multigelation, outward appearance still can keep transparent homogeneous phase, not wall built-up, not stratified, has good mobility.
embodiment 7: particle size determination
Sample 1-4 prepared by embodiment of the present invention 1-4, adopt Mastersizer 2000 Particle Size Analyzer to detect particle diameter, sample adds the normal saline of 10 times of volumes, measures after slight oscillatory spontaneous emulsification.
Table 3: particle size distribution after different sample emulsifying
Note: d(0.1) represent that the cumulative particle sizes distribution number of sample is the particle diameter of 10% correspondence, d(0.5), d(0.9), d(1) the rest may be inferred.
Its particle size distribution is as shown in table 3, the particle size distribution of four embodiments between 0.1-0.8 μm, mean diameter about 0.2 μm, the d(0.9 of four embodiment products) be all less than 0.6 μm, meet injection fat milk Particle size requirements.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendment and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (8)
1. a vinpocetine fat milk concentrated solution, it comprises:
Principal agent: vinpocetine,
Oil: medium chain length fatty acid triglyceride,
Cosolvent: 1,2-PD,
Low hlb surfactant (4≤HLB≤9): phospholipid, and
High hlb surfactant (HLB >=12): polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini;
Alternatively, described low hlb surfactant also comprises polyglycerol acrylate;
Alternatively, described high hlb surfactant also comprises Tween 80.
2. vinpocetine fat milk concentrated solution according to claim 1, is characterized in that any one in the item of following (1)-(5) or multinomial:
(1) content of described vinpocetine is 0.1-1.5%(w/w); Be preferably 0.2-1%(w/w);
(2) content of described oil is 45-85%(w/w); Be preferably 50-70%(w/w);
(3) content of described cosolvent is 5-30%(w/w); Be preferably 5-15%(w/w);
(4) content of described low hlb surfactant is 5%-15%(w/w);
(5) content of described high hlb surfactant is 5%-20%(w/w).
3. the vinpocetine fat milk concentrated solution according to claim 1,2, is characterized in that any one in the item of following (1)-(8) or multinomial:
(1) content of described vinpocetine is 0.2-1%(w/w), be preferably 0.4-0.6%(w/w);
(2) content of described medium chain length fatty acid triglyceride is 55%-70%, is preferably 65%-70%;
(3) content of described 1,2-PD is 5%-15%, is preferably 8%-12%;
(4) content of described phospholipid is 5%-15%, is preferably 7.5%-12%;
(5) content of described polyglycerol acrylate is 0-8%, is preferably 0-5%;
(6) content of described polyethyleneglycol-12-hydroxy stearin is 0-15%, is preferably 0-10%;
(7) content of described polyoxyethylene ether (35) Oleum Ricini is 0-15%, is preferably 0-10%;
(8) content of described Tween 80 is 0-15%, is preferably 0-5%.
4. the vinpocetine fat milk concentrated solution according to claims 1 to 3, is characterized in that any one in the item of following (1)-(7) or multinomial:
(1) the not moisture or water content of described vinpocetine fat milk concentrated solution is lower than 1%;
(2) described vinpocetine fat milk concentrated solution is not containing saccharide;
(3) the unambiguous essence of described vinpocetine fat milk concentrated solution;
(4) described vinpocetine fat milk concentrated solution its preparation method does not comprise removing or falls low-moisture step (such as rotary evaporation, spraying dry or lyophilization);
(5) alternatively, described vinpocetine fat milk concentrated solution also comprises antioxidant; Particularly, described antioxidant be selected from oleic acid, enuatrol, vitamin E and vitamin A any one or multiple;
(6) described vinpocetine fat milk concentrated solution is transparent, single phase soln;
(7) described vinpocetine fat milk concentrated solution adopts 0.22 μm of microporous filter membrane mode degerming.
5. a vinpocetine fat milk concentrated solution, its component and content are as below 1)-2) shown in group any one group:
1）
Vinpocetine 0.4 ~ 0.6 gram
Medium chain length fatty acid triglyceride 65 ~ 70 grams
1,2-PD 8 ~ 12 grams
Soybean lecithin 7.5 ~ 12 grams
Polyglycerol acrylate 0 ~ 5 gram
Polyethyleneglycol-12-hydroxy stearin 7 ~ 10 grams
Tween 80 3 ~ 5 grams
Oleic acid 0 ~ 0.3 gram
Enuatrol 0 ~ 0.3 gram
Vitamin E 0 ~ 0.3 gram;
2）
Vinpocetine 0.4 ~ 0.6 gram
Medium chain length fatty acid triglyceride 65 ~ 70 grams
1,2-PD 8 ~ 12 grams
Soybean lecithin 7.5 ~ 12 grams
Polyglycerol acrylate 0 ~ 5 gram
Polyoxyethylene ether (35) Oleum Ricini 8 ~ 10 grams
Oleic acid 0 ~ 0.3 gram
Enuatrol 0 ~ 0.3 gram
Vitamin E 0 ~ 0.3 gram.
6. an injection vinpocetine fat milk, it is added water by the vinpocetine fat milk concentrated solution described in claim 1 to 5 or aqueous solution self emulsifying obtains; Particularly, described injection vinpocetine fat milk mean diameter is 0.05-0.7 μm; Be preferably 0.1-0.4 μm; More preferably, be 0.16-0.22 μm.
7. the preparation method of the vinpocetine fat milk concentrated solution described in claim 1 to 5 kind of any one, comprises the steps:
1) at 20-45 DEG C, low hlb surfactant is added oil, under 2000-20000rpm condition, be stirred to and form transparent clear solution;
2) under 20-45 DEG C of condition, cosolvent, vinpocetine are added step 1) product, and under 200-2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20-45 DEG C of condition, high hlb surfactant and optional antioxidant are added step 2) product, and under 200-800rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition vinpocetine fat milk concentrated solution.
8. the vinpocetine fat milk concentrated solution according to any one of claim 1 to 5 or injection vinpocetine fat milk according to claim 6 are improving the clinical applications such as various symptoms that cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis etc. bring out.
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| CN113499311A (en) * | 2021-08-16 | 2021-10-15 | 沈阳药科大学 | Vinpocetine nano-emulsion for nose and preparation method and application thereof |
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| CN101103962A (en) * | 2006-07-13 | 2008-01-16 | 华中科技大学同济医学院 | Vinpocetine oral self-micro-emulsification medicine-releasing system and preparation method thereof |
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