CN103690483A - Dl-praeruptorin A microemulsion and preparation method thereof - Google Patents
Dl-praeruptorin A microemulsion and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a dl-praeruptorin A microemulsion and a preparation method thereof, and relates to dl-praeruptorin A microemulsions. The dl-praeruptorin A microemulsion comprises the following components by mass: 0.1%-0.8% of dl-praeruptorin A, 5%-10% of oil, 10%-16.67% of an emulsifier, 20%-33.33% of a co-emulsifier and the balance of water. The preparation method comprises the following steps: mixing the dl-praeruptorin A, the oil, the emulsifier and the co-emulsifier to obtain an oil phase, adding the water into the oil phase, uniformly mixing and emulsifying to obtain the dl-praeruptorin A microemulsion. The indissolvable drug-Pd-Ia (dl-praeruptorin A) is prepared into the O/W (oil/water) microemulsion by auxiliary materials with good biocompatibility, so that the solubility, the stability, the drug loading capacity and the transdermal absorption of the drug are improved. The prepared dl-praeruptorin A microemulsion is good in pereutaoeous permeation, low in skin irritation, simple in preparation process, low in cost and stable in quality, and has treatment and prevention effects on the cardiovascular disease, especially the coronary heart disease.
Description
Technical field
The present invention relates to praeruptorin A microemulsion, especially relate to a kind of praeruptorin A microemulsion and preparation method thereof.
Background technology
Praeruptorin A is a kind of angle-pyrancoumarins extracting from xanthotoxin, and chemical name is 3 '-Radix Angelicae Sinensis acyloxy-4 '-acetyl group-3 ', 4 '-bis-hydrogen amyrolins, and structural formula is as follows:
Molecular weight: 386.
Chinese medicine Radix Peucedani is the dry root of samphire Peucedanum praeruptorum DUNN (Peucedanum praeruptrum Dunn) or RADIX PEUCEDANI (P.decursivum maxim), there is loose wind heat clearing away, the effect of lowering the adverse-rising QI to resolve phlegm, as antitussive and antiasthmatic drugs and extensive use.A kind of angle-pyrancoumarins of praeruptorin A (dl-praeruptorin A, Pd-Ia) for extracting in xanthotoxin, is the main effective ingredient of Peucedanum praeruptorum DUNN, and the tip-like that is white in color crystallization is fat-soluble, is soluble in organic solvent.
Pharmacological research shows in recent years, and Pd-Ia, as a kind of calcium channel blocker and potassium channel openers, has the effect of Ischemic myocardium and focal cerebral ischemia acute injury; Pd-Ia can be used as a kind of newtype drug, and the clinical treatment of cardiovascular and respiratory system disease, particularly coronary heart disease and prevention are had to potential and wide application prospect.Have the advantages that dosage is little, evident in efficacy, toxic and side effects is little.
Research discovery, Pd-Ia oral administration may be by the CYP3A metabolism in gastrointestinal tract or liver, and first pass effect is strong, and in liver, mainly by CYP3A catalysis, metabolism, the half-life is short.Oral administration does not reach therapeutic purposes, but drug administration by injection, and patient's compliance is poor and cause the problems such as wound.Therefore, Pd-Ia is prepared into transdermal administration, at present relevant praeruptorin A microemulsion Percutaneously administrable preparation there is not yet relevant report.
Microemulsion is to be mixed in the proper ratio and spontaneous a kind of transparent, low-viscosity, the isotropism forming and thermodynamically stable dispersion by water, oil phase, surfactant and cosurfactant.The particle diameter of microemulsion, generally at 10～100nm, is evenly distributed, and can make inclusive medicine dispersion improve, thereby promotes the Transdermal absorption of medicine.Microemulsion has good dissolubility to lipotropy and hydrophilic medicament, has the higher compatibility with cuticular intercellular lipid bilayer, can penetrate horny layer and enter body circulation and the effect of performance whole body therapeutic; The special tectonic of microemulsion drop, the pharmaceutical release time after percutaneous dosing is longer, and blood drug level is more steady.Microemulsion has as a kind of novel drug-supplying system that good stability, solvability are strong, preparation is simple and easy to the advantages such as industrialization, the sterilizing of available filtration method.Over nearly 20 years, microemulsion is in the research of the multiple route of administration such as transdermal, oral, injection, mucosa delivery.Aspect transdermal drug delivery system, the application of microemulsion is more and more extensive, compares with hydrogel, Emulsion, suspensoid etc., has higher drug loading and the transdermal capability of Geng Gao.Therefore, the carrier of microemulsion Chang Zuowei percutaneous dosing.
Summary of the invention
The object of this invention is to provide a kind of praeruptorin A microemulsion and preparation method thereof.
By mass percentage composed as follows of described praeruptorin A microemulsion:
Surplus is water.
Described oil can be selected from least one in ethyl oleate, isopropyl myristate, isopropyl palmitate, oleic acid, isopropyl laurate, three sad certain herbaceous plants with big flowers acid glycerides, medium chain triglyceride, Ethyl linoleate, soybean oil, Oleum Ricini, Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, safflower oil, Semen Lini oil, Oleum Gossypii semen, Oleum sesami, Oleum Camelliae etc., preferably at least one in isopropyl myristate, isopropyl palmitate, oleic acid, Oleum Camelliae, Fructus Canarii albi wet goods.
Described emulsifying agent is optional from tween, span, poloxamer, phospholipid of natural soybean, natural yolk phospholipid, native phosphatidylcholine, native phosphatidylcholine derivant, semi-synthetic phosphatidylcholine, semi-synthetic derivative of phosphatidylcholine, Myrj 45, sucrose fatty acid ester, Polyethylene Glycol-vitamin e succinate, PEG-DSPE, polyethylene glycol hydroxystearate, polyoxyethylene hydrogenated Oleum Ricini, at least one in polyoxyethylene hydrogenated Oleum Ricini derivant etc., preferred polyoxyethylene hydrogenated Oleum Ricini, tween, at least one in phospholipid of natural soybean etc.
Described co-emulsifier can be selected from least one in ethanol, propylene glycol, normal propyl alcohol, glycerol, n-butyl alcohol, n-octyl alcohol, n-heptanol, carbitol, Polyethylene Glycol, triacetyl glycerine etc., at least one in preferred alcohol, propylene glycol etc.
The preparation method of described praeruptorin A microemulsion is as follows:
Praeruptorin A, oil, emulsifying agent, co-emulsifier are mixed to get to oil phase, water is added in oil phase, mix emulsifying and obtain praeruptorin A microemulsion.
Describedly mix emulsifying and can adopt high pressure homogenize emulsion process or supersound method etc.
Prepared praeruptorin A microemulsion, its outward appearance is colourless translucent colloid substance, and average viscosity is 2706mPas, and viscosity is moderate, and pH value is 5.0～8.0, shows that microemulsion structure in gel keeps good, good stability under transmission electron microscope.
For fear of first pass effect, heighten the effect of a treatment, improve patient's compliance, facilitate clinical application, the present invention has adopted the adjuvant of good biocompatibility, first insoluble drug Pd-Ia is made to O/W microemulsion, has improved the dissolubility of Pd-Ia, improve stability and the drug loading of medicine, increase the Transdermal absorption of medicine.
The prepared praeruptorin A microemulsion of the present invention has the advantages such as percutaneous permeation is good, little to skin irritation, preparation technology is simple, cost is low, steady quality.As a kind of newtype drug, in cardiovascular disease, the particularly clinical treatment of coronary heart disease and preventive effect.
Accompanying drawing explanation
Fig. 1 is the cumulative in vitro transdermal penetration curve (n=5) of the embodiment of the present invention 1 praeruptorin A microemulsion and reference preparation (saturated oils acid solution, 33% alcoholic solution); Curve A is embodiment 1, and curve B is 33% alcoholic solution, and curve C is saturated oils acid solution.
Fig. 2 is the praeruptorin A microemulsion transmission electron microscope picture (* 25000) of the embodiment of the present invention 1 preparation, and in Fig. 2, scale is 100nm.
Fig. 3 is that the praeruptorin A microemulsion of the embodiment of the present invention 1 preparation is placed the transmission electron microscope picture of 0 month in room temperature, and in Fig. 3, scale is 100nm.
Fig. 4 is that the praeruptorin A microemulsion of the embodiment of the present invention 1 preparation is placed the transmission electron microscope picture after 6 months in room temperature, and in Fig. 4, scale is 100nm.
The specific embodiment
The present invention is further illustrated in connection with accompanying drawing for following examples.
Embodiment 1 praeruptorin A microemulsion, its formula is composed as follows:
Preparation method: oleic acid, polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH40), dehydrated alcohol mix homogeneously are obtained to oil phase, praeruptorin A is added in oil phase and dissolved completely; The oil phase that contains praeruptorin A is at room temperature stirred to 10min and make it mix homogeneously, gradually water is added again, at the airtight middle continuous stirring 10min of room temperature, last ultrasonic 5min, after the 0.22 μ m microporous filter membrane aseptic filtration of footpath, obtain colourless translucent praeruptorin A microemulsion.
Preparation method: by isopropyl myristate, poloxamer, the even oil phase that obtains of mixed with propylene glycol, praeruptorin A is added in oil phase and dissolved completely; The oil phase that contains praeruptorin A is at room temperature stirred to 10min and make it mix homogeneously, gradually water is added again, at the airtight middle continuous stirring 10min of room temperature, last ultrasonic 5min, after the 0.22 μ m microporous filter membrane aseptic filtration of footpath, obtain colourless translucent praeruptorin A microemulsion.
Embodiment 3 microemulsion, its formula is composed as follows:
Preparation method: will refine Oleum Camelliae, tween, glycerol mix homogeneously and obtain oil phase, praeruptorin A is added in oil phase and dissolved completely; The oil phase that contains praeruptorin A is at room temperature stirred to 10min and make it mix homogeneously, gradually water is added again, at the airtight middle continuous stirring 10min of room temperature, last ultrasonic 5min, after the 0.22 μ m microporous filter membrane aseptic filtration of footpath, obtain colourless translucent praeruptorin A microemulsion.
Embodiment 4 microemulsion, its formula is composed as follows:
Preparation method: olive oil, phospholipid of natural soybean, Polyethylene Glycol mix homogeneously are obtained to oil phase, praeruptorin A is added in oil phase and dissolved completely; The oil phase that contains praeruptorin A is at room temperature stirred to 10min and make it mix homogeneously, gradually water is added again, at the airtight middle continuous stirring 10min of room temperature, last ultrasonic 5min, after the 0.22 μ m microporous filter membrane aseptic filtration of footpath, obtain colourless translucent praeruptorin A microemulsion.
Preparation method: isopropyl palmitate, polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH40), dehydrated alcohol mix homogeneously are obtained to oil phase, praeruptorin A is added in oil phase and dissolved completely; The oil phase that contains praeruptorin A is at room temperature stirred to 10min and make it mix homogeneously, gradually water is added again, at the airtight middle continuous stirring 10min of room temperature, last ultrasonic 5min, after the 0.22 μ m microporous filter membrane aseptic filtration of footpath, obtain colourless translucent praeruptorin A microemulsion.
Below provide external quality evaluation:
1. permeation test in vitro
Get the male SD rat of body weight 200～250g, after etherization, with electric shaver, shave clean abdominal part chaeta, get not damaged skin, carefully reject subcutaneous fat and adhesion thing, with normal saline flushing skin surfaces externally and internally, after-20 ℃ of preservation 12h, use, before using, naturally thaw.The Franz diffusion cell that has adopted improvement, is fixed on skin between upper and lower two Room of diffusion cell, and stratum corneum side is to supply pool, and acceptance pool adds 33% ethanol/normal saline, and (acceptance pool volume is 6.5mL, and transmission area is 2.8cm
2), in supply chamber, add medicinal liquid 0.7g, device is placed in to constant temperature (37 ± 0.5 ℃) water-bath, start stirring (210rmin
-1), respectively at 1,2,4,6,8,12,24,28,32h samples 2mL, adds the fresh accepting medium of uniform temp equal-volume simultaneously.After sample is centrifugal, then use 0.22 μ m filtering with microporous membrane, sample thief subsequent filtrate 20 μ L carry out HPLC analysis.
In praeruptorin A microemulsion formula prepared by the present invention, containing Pd-Ia, be 0.5%, result shows, embodiment 1 is optimization formula, and it is that surfactant, 26.67% ethanol are cosurfactant, 52.5% ultra-pure water as oil phase, 13.33% polyoxyethylene hydrogenated Oleum Ricini that the composition of formula is respectively 5% oleic acid.Preparation is carried out transdermal permeation in vitro containing the optimum microemulsion of 0.5% praeruptorin A, and obtaining maximum transdermal penetration speed is 11.713 ± 0.513 μ gcm
-2h
-1, 32h transdermal penetration total amount is 353.266 ± 13.584 μ gcm
-2, there is good percutaneous permeation.The results are shown in Table 1 and Fig. 1.
The comparison (n=5) of the in-vitro percutaneous absorption of Pd-Ia microemulsion of the different embodiment of table 1
2. external physicochemical property
Shape, the particle diameter of measuring the Pd-Ia microemulsion of above-mentioned preparation, the results are shown in Table 2.
Shape, the size of table 2Pd-Ia microemulsion
Select optimum example, embodiment 1 observes the form of Pd-Ia microemulsion under transmission electron microscope, and the TEM figure of shooting, is shown in Fig. 2, by Electronic Speculum, can find that the emulsion droplet in Pd-Ia microemulsion is spherical in shape, form rounding, and particle diameter is distributed in 100nm mostly.
3. stability test
0,3,6 month precision, take a certain amount of enforcement 1 microemulsion sample in the volumetric flask of 10mL respectively, add appropriate methanol vortex 2min, ultrasonic 5min and carry out breakdown of emulsion, then use methanol constant volume.Sample thief is appropriate, after filtering, gets subsequent filtrate 20 μ L with 0.45 μ m microporous filter membrane, by HPLC method, surveys its content.The results are shown in Table 3.As can be known from the results, 5.0mgg
-1pd-Ia microemulsion sample is placed after 6 months in room temperature, and medicament contg RSD% is 2.11%, without significant change, illustrates that at room temperature Pd-Ia microemulsion is stable.
Table 3 is containing the content (n=3) of 0.5%Pd-Ia microemulsion sample
4. particle diameter and microscopic pattern
By aforementioned optimization of C/C composites and preparation method, preparation 4.88mgg
-1pd-Ia microemulsion sample, is divided in three batch samples in cillin bottle, packs, room temperature preservation, standby.At 0,3,6 month, get respectively appropriate sample, centrifugal rear observation outward appearance, measures size and distribution, in Table 4, Fig. 3 and 4.As can be known from the results, Pd-Ia microemulsion is after room temperature is placed 3,6 months, and color and luster, clarity do not become, and without layering, flocculation phenomenon, outward appearance is unchanged, still keeps transparent, clarification after centrifugal.Before and after placing, particle diameter is without significant change.
Table 4 is containing the particle diameter (n=3) of 0.5%Pd-Ia microemulsion sample
The form of microemulsion particle: at 0,6 month, get respectively the Pd-Ia microemulsion sample that above-mentioned sealing is preserved, the form of observing microemulsion under transmission electron microscope, the TEM figure of shooting, is shown in Fig. 3 and 4.As we know from the figure, Pd-Ia microemulsion is preserved 6 months, electric Microscopic observation droplet morphology rounding, and particle diameter is in 100nm, and microscopic pattern is without obvious variation.
Claims (9)
1. praeruptorin A microemulsion, is characterized in that by mass percentage composed as follows:
Surplus is water.
2. praeruptorin A microemulsion as claimed in claim 1, is characterized in that at least one in ethyl oleate, isopropyl myristate, isopropyl palmitate, oleic acid, isopropyl laurate, three sad certain herbaceous plants with big flowers acid glycerides, medium chain triglyceride, Ethyl linoleate, soybean oil, Oleum Ricini, Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, safflower oil, Semen Lini oil, Oleum Gossypii semen, Oleum sesami, Oleum Camelliae of described grease separation.
3. praeruptorin A microemulsion as claimed in claim 2, is characterized in that at least one in isopropyl myristate, isopropyl palmitate, oleic acid, Oleum Camelliae, olive oil of described grease separation.
4. praeruptorin A microemulsion as claimed in claim 1, is characterized in that described emulsifying agent is selected from least one in tween, span, poloxamer, phospholipid of natural soybean, natural yolk phospholipid, native phosphatidylcholine, native phosphatidylcholine derivant, semi-synthetic phosphatidylcholine, semi-synthetic derivative of phosphatidylcholine, Myrj 45, sucrose fatty acid ester, Polyethylene Glycol-vitamin e succinate, PEG-DSPE, polyethylene glycol hydroxystearate, polyoxyethylene hydrogenated Oleum Ricini, polyoxyethylene hydrogenated Oleum Ricini derivant.
5. praeruptorin A microemulsion as claimed in claim 4, is characterized in that described emulsifying agent is selected from least one in polyoxyethylene hydrogenated Oleum Ricini, tween, phospholipid of natural soybean.
6. praeruptorin A microemulsion as claimed in claim 1, is characterized in that described co-emulsifier is selected from least one in ethanol, propylene glycol, normal propyl alcohol, glycerol, n-butyl alcohol, n-octyl alcohol, n-heptanol, carbitol, Polyethylene Glycol, triacetyl glycerine.
7. praeruptorin A microemulsion as claimed in claim 6, is characterized in that described co-emulsifier is selected from least one in ethanol, propylene glycol.
8. the preparation method of praeruptorin A microemulsion as claimed in claim 1, is characterized in that its concrete steps are as follows:
Praeruptorin A, oil, emulsifying agent, co-emulsifier are mixed to get to oil phase, water is added in oil phase, mix emulsifying and obtain praeruptorin A microemulsion.
9. the preparation method of praeruptorin A microemulsion as claimed in claim 8, mixes emulsifying and adopts high pressure homogenize emulsion process or supersound method described in it is characterized in that.
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Cited By (6)
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| CN106109413A (en) * | 2016-07-29 | 2016-11-16 | 河南中医学院 | A kind of oil-in-water type nano-emulsion substrate |
| CN107318981A (en) * | 2017-06-19 | 2017-11-07 | 宁国市仙之居家庭农场 | A kind of Yoghourt based on the peaceful root of purple-flowered peucedanum |
| CN109744325A (en) * | 2019-03-06 | 2019-05-14 | 吉林大学 | A kind of nano-emulsion system and preparation method based on perilla herb oil or linseed oil |
| CN110420183A (en) * | 2019-09-04 | 2019-11-08 | 湖南宇山玉月农业科技有限公司 | A kind of schizophyllum abamectin nano-emulsion |
| CN111920766A (en) * | 2020-07-28 | 2020-11-13 | 中南林业科技大学 | Ellagic acid dispersion system and preparation method thereof |
| CN112972368A (en) * | 2021-04-19 | 2021-06-18 | 哈尔滨医科大学 | Pharmaceutical composition for promoting healing of postoperative wound surface of anorectal surgery and preparation method thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106109413A (en) * | 2016-07-29 | 2016-11-16 | 河南中医学院 | A kind of oil-in-water type nano-emulsion substrate |
| CN106109413B (en) * | 2016-07-29 | 2019-04-16 | 河南中医学院 | A kind of oil-in-water type nano-emulsion matrix |
| CN107318981A (en) * | 2017-06-19 | 2017-11-07 | 宁国市仙之居家庭农场 | A kind of Yoghourt based on the peaceful root of purple-flowered peucedanum |
| CN109744325A (en) * | 2019-03-06 | 2019-05-14 | 吉林大学 | A kind of nano-emulsion system and preparation method based on perilla herb oil or linseed oil |
| CN110420183A (en) * | 2019-09-04 | 2019-11-08 | 湖南宇山玉月农业科技有限公司 | A kind of schizophyllum abamectin nano-emulsion |
| CN110420183B (en) * | 2019-09-04 | 2021-09-21 | 湖南宇山玉月农业科技有限公司 | Schizophyllan nanoemulsion |
| CN111920766A (en) * | 2020-07-28 | 2020-11-13 | 中南林业科技大学 | Ellagic acid dispersion system and preparation method thereof |
| CN112972368A (en) * | 2021-04-19 | 2021-06-18 | 哈尔滨医科大学 | Pharmaceutical composition for promoting healing of postoperative wound surface of anorectal surgery and preparation method thereof |
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Application publication date: 20140402 |