CN103083677A - Permeation accelerator and application thereof to permeation acceleration - Google Patents
Permeation accelerator and application thereof to permeation acceleration Download PDFInfo
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- CN103083677A CN103083677A CN2012105026583A CN201210502658A CN103083677A CN 103083677 A CN103083677 A CN 103083677A CN 2012105026583 A CN2012105026583 A CN 2012105026583A CN 201210502658 A CN201210502658 A CN 201210502658A CN 103083677 A CN103083677 A CN 103083677A
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Abstract
The invention discloses a permeation accelerator. An effective component of the permeation accelerator is a natural extractive. The invention further provides the application of the permeation accelerator to permeation acceleration. The permeation accelerator disclosed by the invention has the beneficial effects that the permeation accelerator and the application of the permeation accelerator disclosed by the invention have good permeation acceleration effect; and the natural extractive is used so that the toxic side effect is low, the irritation is low and the market prospect is good.
Description
Technical field
The present invention relates to field of traditional Chinese, be specifically related to a kind of transdermal enhancer and application thereof.
Background technology
Transdermal delivery system (transdermal drug delivery systems, be called for short TDDs) be the class new formulation be popular most at present, there is the advantages such as the blood drug level that can remain stable, " first pass effect " of avoiding the effect of gastrointestinal tract enzymolysis and liver, the toxic and side effects that reduces medicine, convenient drug administration.But due to the barrier action of skin and the reasons such as physicochemical property of medicine itself, the penetrating rate of a lot of medicine transdermals is very low, and the medicine that percutaneous arrives in body is difficult to reach effective treatment concentration.Application Percutaneous absorption enhancer (penetration enhancers, PE) is the prefered method that increases Drug Percutaneous Absorption.At present Percutaneous absorption enhancer commonly used has two kinds of synthetic penetration enhancer and natural penetration enhancer.The more synthetic PE of research has azone (Asone), dimethyl sulfoxide (DMSO), propylene glycol (PG), oleic acid (OA) and linoleic acid etc. at present.The specificity of the chemical PE that these are synthetic is not strong, and larger to the effect of human body mucosa irritation.And natural penetration enhancer comprises volatile oil, terpenoid, alkaloid etc. having good transdermal enhancing effect, zest is little, and untoward reaction is few, has the value of exploitation, becomes the focus of penetration enhancer research in recent years.Because natural percutaneous promoter has its corresponding physiologically active, therefore, should note the selection of penetration enhancer in the application of natural penetration enhancer, consider the biological activity of penetration enhancer self and principal agent, different natural penetration enhancer have different ranges of application.
Summary of the invention
Purpose of the present invention is exactly for above-mentioned defect of the prior art, provides a kind of transdermal effect good, non-stimulated avirulent transdermal enhancer.
To achieve these goals, technical scheme provided by the invention is: a kind of transdermal enhancer, the effective ingredient of described transdermal enhancer is natural extract.
Further, above-mentioned a kind of transdermal enhancer, described natural extract is: Fructus Evodiae total alkaloids, Sinapine Thiocyanate, berberine hydrochloride, Fructus Evodiae volatile oil, mustard oil or total Radix Et Rhizoma Rhei anthraquinone.
Further, above-mentioned a kind of transdermal enhancer, described natural extract is: the Sinapine Thiocyanate of the Fructus Evodiae total alkaloids that content is 40%-90%, the total Radix Et Rhizoma Rhei anthraquinone of 70%-95%, 70%-96% or 90% above berberine hydrochloride.
Second purpose of the present invention has been to provide the application of above-mentioned a kind of transdermal enhancer in urging thoroughly.
Further, above-mentioned application, described is small molecular organic acid and derivant thereof by short saturating thing.
Further, above-mentioned application, described is cinnamic acid derivative by short saturating thing.
Further, above-mentioned application, described is the pharmaceutical composition that ferulic acid or the ferulic acid of take are effective ingredient by short saturating thing.
Further, above-mentioned application, described is Radix Angelicae Sinensis or Rhizoma Et Radix Notopterygii by short saturating thing.
Further, above-mentioned application, described is the medicament that is used for the treatment of cardiovascular and cerebrovascular disease and leukopenia that contains ferulic acid or the externally applied transdermal absorption preparation for promoting blood circulation and stopping pain, dispelling wind and removing obstruction in the collateral that contains ferulic acid by short saturating thing.
Further, above-mentioned application, the valid density of described natural extract is according to mass percentage concentration meter 1%-5%.
Beneficial effect of the present invention is: transdermal enhancer provided by the invention and application, and short thoroughly respond well, due to what adopt, be natural extract, therefore its toxic and side effects is low, zest, good market prospects.
The accompanying drawing explanation
Fig. 1 means the transdermal enhancing effect of different natural accelerators to ferulic acid.
Fig. 2 means the transdermal enhancing effect of Fructus Evodiae volatile oil to ferulic acid.
Fig. 3 means the transdermal enhancing effect of mustard oil to ferulic acid.
Fig. 4 means the transdermal enhancing effect of berberine to ferulic acid.
Fig. 5 means the transdermal enhancing effect of evodia alkaloid to ferulic acid.
Fig. 6 means the transdermal enhancing effect of sinapic acid choline ester. to ferulic acid.
The specific embodiment
embodiment 1:
one, the preparation of natural percutaneous promoter:
1, the extraction purification of evodia alkaloid:
Take respectively three parts of Fructus Evodiae medical materials, every part of 500g, every part adds 6 times of amount 70% ethanol, heating and refluxing extraction 2 times, each 3h, filter, and merging filtrate reclaims ethanol, concentrated, drying, 452g gets dry extract.Perhaps, first by after medicinal material extract volatile oil, the residue drying, continue to use 70% ethanol extraction, and the extracting solution concentrate drying gets dry extract.Get dry cream 40g, porphyrize, be placed in the 1000mL round-bottomed flask, adds acetone 250mL and put 60 ℃ of reflux 1h of water-bath, filter, filtrate is reclaimed acetone, concentrated near dry, obtains about 5.0g thick paste, add appropriate neutral alumina to stir, be ground into fine-powdered, upper neutral alumina (100～200 order) post.Post one: with 5BV ethyl acetate-dichloromethane (70:30) eluting; Flow velocity is 1.0ml min
-1, point sample is collected filtrate, and filtrate is reclaimed to the evodia alkaloid after solvent obtains purification.Post two: take ethyl acetate as eluant.Adopt the HPLC method to measure content, the Fructus Evodiae total alkaloids after purification is in rutaecarpin and rutaecarpine sum, and the content of four batch samples is respectively 86.6%, 71.3%, and 41.5%, 64.32%.
2. the extraction of Sinapine Thiocyanate and purification:
Take three parts of Semen Sinapis Albae medical materials, every part of 100g, pulverize, be placed in the 2000mL round-bottomed flask, with twice of defat with petroleum ether (500mL * 2), each 2h, residue volatilizes petroleum ether, use respectively 80% alcohol reflux twice (500mL * 2), each 2h, filter, merging filtrate, the concentrated syrupy shape that is, after adding distil water 60 mL dilutions, adding 20%KSCN solution 15mL(distilled water and 20% potassium thiocyanate solution proportion is 4:1), put 4 ℃ of refrigerators, placement overnight, crystallization, sucking filtration, collect crystallization, filtrate is adding distil water again, repeat aforesaid operations, so repeatedly, recrystallization is three times altogether, obtain yellow crystal 0.45g altogether, yield is 0.51%.Adopt the HPLC method to measure content.Sinapic acid choline ester. after purification is in Sinapine Thiocyanate as a result, and the content of three batch samples is respectively: 96.1%, 83.5%, 75.6%.
3. the extraction of berberine hydrochloride and purification:
Get 1500g Rhizoma Coptidis coarse powder, divide 3 parts, every part adds 22 times of amount 70% alcohol reflux 3 times, and each 1 hour, extracting solution reclaimed ethanol, and the thick paste water-bath is concentrated, the 419.2g that gets dry extract, and paste-forming rate is 27.9%.Get Rhizoma Coptidis alcohol extract 100.4g, put in the 1000mL beaker, add 10 times of amount 0.5%H
2sO
4dissolve, standing, filter, acid liquid adds lime cream and adjusts pH to 10～12, filter, filtrate adds concentrated hydrochloric acid and adjusts pH to 1～2, add amount of liquid medicine 8%NaCL to saltout, place, sucking filtration, precipitation is dissolved in to 1000mL hot water, adjust pH to 8.5～9, filtered while hot, filtrate adds hydrochloric acid and adjusts pH2～3, place, sucking filtration, precipitation is washed to neutrality, obtain the berberine hydrochloride crude product, it is dissolved in to hot water again, add hydrochloric acid and adjust pH2～3, place, sucking filtration, precipitation is washed to neutrality, be further purified, the berberine hydrochloride 15.8g after purification, adopt ultraviolet visible spectrophotometry to measure content, berberine hydrochloride after purification is in berberine hydrochloride, three batch sample content are respectively 93.45%, 92.23%, 92.85%.
4, the preparation of Fructus Evodiae volatile oil:
Take Fructus Evodiae medical material 1.5kg, be divided into three parts, every part of 500g, every part adds 6 times of amount distilled water in the 10000mL round-bottomed flask, and reflux, extract, 5h must 5.7mL volatile oil, and content is 0.38%.
5, the preparation of mustard oil:
Take three parts of Semen Sinapis Albae medical materials, every part of 100g, pulverize, be placed in the 2000mL round-bottomed flask, by petroleum ether (60-90 ℃) soaked overnight, then use petroleum ether (60-90 ℃) to extract (500mL * 2) twice, petroleum ether extract low temperature is flung to solvent, obtains mustard oil 21.0mL, content 7.0%.
6, the extraction of total Radix Et Rhizoma Rhei anthraquinone and purification:
(1) extract:
Take respectively three parts of Radix Et Rhizoma Rhei decoction piece, every part of 500g, pulverize, and is placed in the 10000mL round-bottomed flask, every part of alcohol reflux that adds respectively 8 times of amounts 75% 3 times, each 2h.Extracting solution is reclaimed to ethanol, and the thick paste drying with water bath obtained, obtain dry extract 575g.Get above-mentioned dry cream 50g and be placed in the 2000mL round-bottomed flask, add the HCl of 500mL 8%, ultrasonic 10min, then add chloroform 1000mL reflux, extract, 2h, and extracting solution is reclaimed to solvent, drying, obtain thick yellow general anthraquinone 2.6g.Process again in this way the dry cream of 100g Radix Et Rhizoma Rhei, be total to obtain total Radix Et Rhizoma Rhei anthraquinone crude product 8.6g.
(2) purification by macroporous resin:
The processing of D301 macroporous resin: take D301 macroporous resin 150g, soak diel in water, then carry out backwash and just washing, be washed till water outlet limpid, 3-4% HCl and the NaOH alternate treatment doubly with resin volume 2-3 again, should be with water wash between soda acid, and alternate treatment be take " acid-water-alkali-water " as a circulation, at least process three circulations, pretreatment can be come into operation by Regeneration Treatment.
The dress post: resin is adopted to wet method dress post, make its fine and close evenly tight, till opening piston to distilled water liquid level and just having flooded resin, recording column volume is 60mL.
Loading: by 20 times of amount 75% dissolve with ethanols for the total Radix Et Rhizoma Rhei anthraquinone crude product, filter, with ammonia, regulate pH9, shake up rear upper prop.Open piston after upper prop, allow the medicinal liquid liquid level drop to and just flood resin, closure piston, standing 4-6h carries out dynamic exchange absorption.
Eluting: after anthraquinone is adsorbed fully, open piston, first with the distilled water of 5 times of amounts, be washed till out clarification of water, carry out eluting with the HCl of 120mL 0.1mol/L again, discard pickle, finally use 75% ethanol elution, flow velocity is 0.75mL/min, be washed till the eluent color yellowish till.
The processing of eluent: eluent is reclaimed to ethanol, and drying, obtain yellow powder, is the total Radix Et Rhizoma Rhei anthraquinone that purity is higher, and the 0.8g that weighs adopts the UV method to measure content.After purification, two batch samples in emodin, are 77.2%, 94.6% containing total Radix Et Rhizoma Rhei anthraquinone.
two, transdermal promotes experiment:
1, isolated mouse skin preparation:
Get the male mice in kunming (Gansu college of traditional Chinese medicine Experimental Animal Center) of body weight 18～22 g, before experiment, 24h sloughs abdominal part fine hair with depilatory cream, and water is can't help in fasting.During experiment, the dislocation of mice cervical vertebra is put to death, careful peeling, be laid in the skin of abdomen taken off on clean glass plate, and horny layer down.Subcutaneous fatty tissue and the adhesion thing of careful rejecting, rinse well repeatedly with normal saline, with normal saline, soaks, and puts Refrigerator store, standby in one day.Before each experiment, the integrity of visual examination skin, can not have any breakage.
2, supply the preparation of feeding and acceptable solution:
Form 1mL altogether for feeding by ferulic acid supersaturated solution and finite concentration transdermal enhancer.1 part of ferulic acid (aws) saturated solution that does not add transdermal enhancer is separately arranged in contrast.For feeding, be respectively: not containing promoter (comparing), respectively containing 1%, 3%, 5% Fructus Evodiae volatile oil (wzyy), 1%, 3%, 5% mustard oil (jzy), 1%, 3%, 5% evodia alkaloid (wzyj), 1%, 3%, 5% sinapic acid choline ester. (jzj), 1%, 3%, 5% berberine hydrochloride (xbj), the test liquid of 1%, 3%, 5% total Radix Et Rhizoma Rhei anthraquinone (dhzek).Acceptable solution is normal saline.
3, transdermal test in vitro experiment:
Adopt YB-P6 type intelligence transdermal tester, effectively diffusion area is 0.785 cm
2, the receiving chamber volume is 10mL.Take out rat skin in vitro from refrigerator, clean with normal saline, with filter paper, blot surface moisture, then the Corium Mus of handling well is fixed between the supply pool and acceptance pool of diffusion cell naturally, stratum corneum side is to supply pool, and the skin nexine just contacts with acceptable solution.Add ferulic acid supersaturated solution 1 mL containing (or not containing) transdermal enhancer in supply chamber.Add normal saline in acceptance pool, constant temperature water bath, to (32 scholar 0.1) ℃, adds the stirrer constant speed and stirs (100 r.min
-1), add the medicinal liquid rear enclosed for coyote hole, 2.0,4.0,6.0. 8.0,10.0 after starting respectively at experiment, 12.0h regularly takes out whole acceptable solutions from the sample acceptance pool, respectively adds the test solution of 32 ℃ of preheatings of same volume simultaneously.Acceptable solution filters and ultrasonic bubble removing in advance.By liquid water bath method to be measured, the residue methanol constant volume, adopt HPLC to measure content, calculates accumulation infiltration capacity, percutaneous rate constant and enhancing rate.
4, the accumulation infiltration capacity (Q) of ferulic acid:
In experiment, the diffusion cell volume is 10.0mL, and effectively diffusion area is 0.785cm
2, the unit are of take accumulation infiltration capacity (Q) is vertical coordinate, the time (t), for the abscissa mapping, obtains the drug accumulation penetration curve, and curve obtained is returned, and obtains slope, is infiltration rate J (the μ gcm of medicine
-2h
-1).The intersection point of straight line and X-axis is lag time (Tlag).Anatonosis than (ER) for adding after penetration enhancer the ratio of the percutaneous rate constant of medicine in 12h when not adding penetration enhancer.
Accumulation transit dose (μ g/cm under the penetrating agent effect of various concentration in ferulic acid 12h as a result
2.h) in Table 1, the osmotic engine mathematic(al) parameter is in Table 2, and infiltration rate is shown in Fig. 1-6.
Result shows, six kinds of natural percutaneous promoter all have transdermal enhancing effect to a certain degree to ferulic acid, and short saturating effect is sequentially: 5% Fructus Evodiae total alkaloids>5% Sinapine Thiocyanate>5% mustard oil>5% berberine>5% total Radix Et Rhizoma Rhei anthraquinone>5% Fructus Evodiae volatile oil.
Each penetration enhancer is analyzed from the angle of different concentration: mustard oil: 5%>3%>1%; Fructus Evodiae total alkaloids: 5%>1%>3%; Berberine: 5%>1%>3%; Sinapine Thiocyanate: 5%>3%>1%; Fructus Evodiae volatile oil: 1%>3%>5%.
Can find out, the mustard oil in Semen Sinapis Albae and sinapic acid choline ester. be along with the increase transdermal facilitation of concentration strengthens, and have obvious dose-effect relationship; Evodia alkaloid and berberine are also the increase transdermal facilitation enhancings along with concentration, but dose-effect relationship is not obvious; Fructus Evodiae volatile oil reduces on the contrary along with the increase transdermal facilitation of concentration, demonstrates inhibitory action.The concentration of Fructus Evodiae volatile oil is higher, and mechanism is poorer, may be that volatile oil makes skin surface form one deck hypothallus, and medicine (ferulic acid) enters hypothallus, and therefore transdermal amount reduces, thereby short saturating effect reduces.
5, identical with above-mentioned test method, with mice, rat skin is barrier, the short saturating result of 12h shows, the Fructus Evodiae total alkaloids that content prepared by the present invention is 40%-90%, the total Radix Et Rhizoma Rhei anthraquinone of 70%-95%, the Sinapine Thiocyanate of 70%-96%, berberine hydrochloride more than 90% and Fructus Evodiae volatile oil and mustard oil with the concentration of 1%-5% to small molecular organic acid classes such as ferulic acids, the Chinese medicine angelica that the ferulic acid of take is main effective ingredient and Rhizoma Et Radix Notopterygii etc. and common promoting blood circulation and stopping pain, the dispelling wind and removing obstruction in the collateral externally applied transdermal absorption preparation has obvious transdermal enhancing effect as preparations such as ZHITONG GAO.
Finally it should be noted that: the foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment, the present invention is had been described in detail, for a person skilled in the art, its technical scheme that still can put down in writing aforementioned each embodiment is modified, or part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. a transdermal enhancer, is characterized in that, the effective ingredient of described transdermal enhancer is natural extract.
2. a kind of transdermal enhancer according to claim 1, is characterized in that, described natural extract is: Fructus Evodiae total alkaloids, Sinapine Thiocyanate, berberine hydrochloride, Fructus Evodiae volatile oil, mustard oil or total Radix Et Rhizoma Rhei anthraquinone.
3. a kind of transdermal enhancer according to claim 2, it is characterized in that, described natural extract is: the Sinapine Thiocyanate of the Fructus Evodiae total alkaloids that content is 40%-90%, the total Radix Et Rhizoma Rhei anthraquinone of 70%-95%, 70%-96% or 90% above berberine hydrochloride.
4. the application of described a kind of transdermal enhancer as arbitrary as claim 1-3 in urging thoroughly.
5. application as claimed in claim 4, is characterized in that, described is small molecular organic acid and derivant thereof by short saturating thing.
6. application as claimed in claim 5, is characterized in that, described is cinnamic acid derivative by short saturating thing.
7. application as claimed in claim 6, is characterized in that, described is the pharmaceutical composition that ferulic acid or the ferulic acid of take are effective ingredient by short saturating thing.
8. application as claimed in claim 7, is characterized in that, described is Radix Angelicae Sinensis or Rhizoma Et Radix Notopterygii by short saturating thing.
9. application as claimed in claim 8, is characterized in that, described is the medicament that is used for the treatment of cardiovascular and cerebrovascular disease and leukopenia that contains ferulic acid or the externally applied transdermal absorption preparation for promoting blood circulation and stopping pain, dispelling wind and removing obstruction in the collateral that contains ferulic acid by short saturating thing.
10. described application as arbitrary as claim 4-9, is characterized in that, the valid density of described natural extract is according to mass percentage concentration meter 1%-5%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732402A (en) * | 2016-03-07 | 2016-07-06 | 大连大学 | Method for preparing sinapine thiocyanate from rapeseed cakes and application |
| CN106045866A (en) * | 2016-07-05 | 2016-10-26 | 大连大学 | Synthesis and application of sinapine chlorate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829218A (en) * | 2010-05-06 | 2010-09-15 | 安徽省药物研究所 | New medical application of fructus evodiae total alkaloid |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829218A (en) * | 2010-05-06 | 2010-09-15 | 安徽省药物研究所 | New medical application of fructus evodiae total alkaloid |
Non-Patent Citations (1)
| Title |
|---|
| 杨冬梅 等: "不同溶媒在不同提取方法下对吴茱萸总碱提取率的影响", 《安徽医药》, vol. 16, no. 6, 30 June 2012 (2012-06-30), pages 765 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732402A (en) * | 2016-03-07 | 2016-07-06 | 大连大学 | Method for preparing sinapine thiocyanate from rapeseed cakes and application |
| CN106045866A (en) * | 2016-07-05 | 2016-10-26 | 大连大学 | Synthesis and application of sinapine chlorate |
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