CN102784096B - A kind of Asiatic acid self-microemulsifyindrug drug delivery system and preparation method thereof - Google Patents
A kind of Asiatic acid self-microemulsifyindrug drug delivery system and preparation method thereof Download PDFInfo
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- CN102784096B CN102784096B CN201110129337.9A CN201110129337A CN102784096B CN 102784096 B CN102784096 B CN 102784096B CN 201110129337 A CN201110129337 A CN 201110129337A CN 102784096 B CN102784096 B CN 102784096B
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Abstract
The invention discloses a kind of Asiatic acid self-microemulsifyindrug drug delivery system (AA SMEDDS) and preparation method thereof.Comprising: 0.5%～5% asiatic acid, oil phase 10% 50%, emulsifying agent 30% 75% and co-emulsifier 0% 30%, percentage ratio is mass percent.Preparation method comprises the following steps: weigh appropriate asiatic acid, adds co-emulsifier and the emulsifying agent of recipe quantity, makes it dissolve 25～45 DEG C of stirrings, then according to recipe quantity adds oil phase and other adjuvants, stirs and get final product.The asiatic acid self-emulsifying microemulsion oral preparation composition of the present invention, after oral chance body fluid, spontaneous emulsification becomes the emulsion droplet of its below particle diameter 100nm.Preparation is simple, and medicine stability is good, and bioavailability is high.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly to a kind of Asiatic acid self-microemulsifyindrug drug delivery system and
Its preparation method.
Background technology
Herba Centellae is Umbelliferae Centella plant, and asiatic acid (Asiatic acid, AA) is wherein content
Higher triterpene acids component, has pharmacologically active widely.It is mainly used in early days treating skin trauma,
Along with to its bioactive further investigation, find asiatic acid and derivant thereof have antiinflammatory, antioxidation,
The biological activitys such as antitumor, anti-hepatic fibrosis, pulmonary fibrosis resistant, cardiovascular protection.
The preparation Jixuedaipian of current domestic listing, oral one time 2,3 times on the one, patients clinical is suitable
Answering property is poor.Studies have reported that, asiaticoside changes into asiatic acid in vivo and plays curative effect.Due to long-pending
Snow oxalic acid dissolubility in water is minimum, at present and independent of its preparation research.Speculate that reason is probably
Cause oral administration biaavailability low owing to the water solublity of asiatic acid is poor, thus be necessary that exploitation one is long-pending
The oral formulations of snow oxalic acid, to improve dissolubility and the vivo biodistribution availability of asiatic acid.
Self-microemulsifyindrug drug transfer system (Self-microemulsifying drug delivery system,
SMEDDS) refer to by oil phase, emulsifying agent and coemulsifier formed homogeneous, transparent and drug containing
Solution, under conditions of physiological condition or gentle agitation, due to the existence of emulsifying agent, meets water spontaneous emulsification
Form particle diameter < 100nm oil-in-water emulsion, referred to as self-microemulsifyindrug drug transfer system.SMEDDS
It it is the excellent carrier of the medicine unstable in slightly solubility, water, oral administration biaavailability is low.Along with ciclosporin
Soft capsule (Neoral), ritonavir soft capsule (Norvir) and Saquinavir soft capsule (Fortovase) etc. are certainly
The successful appearance of emulsification preparation, SMEDDS the most also receives much attention as insoluble drug carrier.
SMEDDS, as a kind of novel nano-lipid drug-supplying system, has a lot of advantage.Due to certainly
Microemulsion system is by oil phase, emulsifying agent and co-emulsifier composition, can be greatly improved the dissolubility of medicine.
Simultaneously because self-microemulsion spontaneous emulsification in gastrointestinal tract becomes the emulsion droplet that particle diameter is the least, there is huge specific surface
Long-pending, the dissolution rate of medicine can be improved.And relative to traditional Emulsion, self microemulsifying preparation is stable
Property is preferable.
Summary of the invention
It is poor that the technical problem to be solved in the present invention is aiming at asiatic acid water solublity, bioavailability
Low, lack the defect of asiatic acid preparation at present, it is provided that a kind of asiatic acid self microemulsifying preparation and system thereof
Preparation Method, preparation technology is simple, and the bioavailability of asiatic acid is greatly improved.
A first aspect of the present invention provides a kind of Asiatic acid self-microemulsifyindrug drug delivery system, mainly includes effect
The asiatic acid of amount and oil phase, emulsifying agent and co-emulsifier.Preferably include: 0.5%～5% asiatic acid,
Oil phase 10%-50%, emulsifying agent 30%-75% and co-emulsifier 0%-30%.Preferred described accumulated snow
Oxalic acid self-micro emulsifying medicament delivery system includes: 1%-4% asiatic acid, oil phase 20%-50%, emulsifying agent
30%-60% and co-emulsifier 0%-25%.Percentage ratio is mass percent.
In the present invention, described oil phase can be natural plants oils, or through structure of modification or hydrolysis
After plant oil.Described oil phase can also is that fatty acid lipid.Described oil phase is preferably for being selected from
Octanoic acid/certain herbaceous plants with big flowers acid triglyceride (GTCC), isopropyl myristate (IPM), ethyl oleate, medium-chain fatty acid
Glyceride (MCT), oleic acid polyethyleneglycol glyceride (Labrafil M 1944CS), Masine 35-1
(Masine35-1) one or more and in polypropylene glycol caprylate (Sefsol 218).Preferred oil of the present invention
Acid polyethylene glycol glyceride (Labrafil M 1944CS) is oil phase, its mass percent preferably 40%.
In the present invention, described emulsifying agent is the nonionic emulsifier of high HLB, preferably for selected from poly-
Oxygen ethylene castor oil (Cremophor EL), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH40), poly-
In ethylene glycol stearate 15 (Solutol HS 15) and Labraso (Labrasol)
One or more.The preferred polyoxyethylene castor oil of the present invention (Cremophor EL) is emulsifying agent.Emulsifying agent
There is the strongest emulsifying capacity, contact energy spontaneous emulsification after body fluid, and medicine to be had by emulsifying agent itself
The biggest solvability, is possible to prevent medicine Precipitation in gastrointestinal tract.
In the present invention, described co-emulsifier can be ethanol, ethylene glycol, Polyethylene Glycol, diethylene glycol
One or more in single base ether, propylene carbonate and propylene glycol.It is preferably selected from dehydrated alcohol, PEG
400 and TC (Transcutol HP) in one or more.The preferred diethyl of the present invention two
Alcohol list ethylether (Transcutol HP) is co-emulsifier.The existing hydrophilic of described co-emulsifier has again parent
Oiliness, co-emulsifier contributes to active component and forms the solution of transparent and homogeneous and keep the stability of solution.
The addition of co-emulsifier is possible not only to reduce interfacial tension, reduces the consumption of co-emulsifier, simultaneously can also
Increase medicine dissolubility in the formulation.
The Asiatic acid self-microemulsifyindrug drug delivery system of the present invention, it is also possible to farther include antioxidant etc..
Antioxidant is preferably such as vitamin C and/or vitamin E, and consumption is less than 5%, and percentage ratio is matter
Amount percentage ratio.
Second aspect present invention provides the preparation method of a kind of Asiatic acid self-microemulsifyindrug drug delivery system.This
Bright Asiatic acid self-microemulsifyindrug drug delivery system can be according to the conventional method system of self-micro emulsifying medicament delivery system
Standby, preparation method preferably comprises the following steps: weigh appropriate asiatic acid, adds recipe quantity
Co-emulsifier and emulsifying agent, make medicine dissolution 25-45 DEG C of stirring, then according to recipe quantity adds oil phase
With other adjuvants, stir and get final product.
The Asiatic acid self-microemulsifyindrug drug delivery system of the present invention, can be made into hard capsule, soft capsule, granule,
Tablet, the dosage form such as oral liquid.
The Asiatic acid self-microemulsifyindrug drug delivery system of the present invention may be used for preparing antiinflammatory, antioxidation, resisting and swell
The medicine of tumor, fibrosis or cardiovascular protection, preferably anti-inflammatory, antioxidation, antitumor, anti-liver fiber
Change, pulmonary fibrosis resistant or the medicine of cardiovascular protection, such as treat wound, operation wound, burn,
Keloid or sclerodermatous medicine.
Raw material used by the present invention or reagent are in addition to special instruction, the most commercially.
Compared to prior art, beneficial effects of the present invention is as follows: the asiatic acid self-emulsifying microemulsion of the present invention
Meeting body fluid spontaneous emulsification after drug-supplying system is oral in gastrointestinal tract becomes particle diameter at the emulsion droplet of 10～100nm, shows
Write dissolubility and the bioavailability improving asiatic acid, improve clinical drug curative effect, for asiatic acid
Exploitation provides wide prospect.The Asiatic acid self-microemulsifyindrug drug delivery system preparation of the present invention is simple, medicine
Thing good stability.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, inventive feature and beneficial effect are described.
Fig. 1 is particle size distribution after AA-SMEDDS dilution.
Fig. 2 is AA-SMEDDS transmission electron microscope photo (amplification: 20000).
Fig. 3 is that rat oral gavage is dense to average blood medicine internal after AA-SMEDDS and AA crude drug suspension
Degree-time graph (ng/ml, n=5).
Detailed description of the invention
Further illustrate the present invention by embodiment below, but the present invention is not intended to be limited thereto.Following enforcement
The experimental technique of unreceipted actual conditions in example, generally according to normal condition, or is built according to manufacturer
The condition of view.
Embodiment 1
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, spend water-bath at 37 DEG C
Middle magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Physicochemical property: use Nicomp-380/ZLS laser granulometry to measure asiatic acid self-microemulsion
Particle diameter after dilution and zeta potential, Fig. 1 is shown in particle diameter distribution；NDJ-8S viscometer is used to measure Herba Centellae
Acid self-microemulsion viscosity.
The physicochemical property of table 1. asiatic acid self-microemulsion
Outward appearance:
Take 500 times of volumes of AA-SMEDDS is preheated to 37 DEG C of distilled water dilutings, shakes up gently,
Point sample, phosphotungstic acid negative staining, transmission electron microscope observing result shows that AA-SMEDDS is formed after water dilutes
Uniform oil-in-water type emulsion droplet.Fig. 2 is shown in by transmission electron microscopy picture.
Asiatic acid is administered orally self-microemulsion drug-supplying system pharmacokinetic characteristics:
Take SD male rat 10, be randomly divided into 2 groups.First group of according to dosage 12mg/Kg body weight filling
Stomach, to asiatic acid self-microemulsion, presses identical dosage gavage to asiatic acid suspension for second group.After administration
In 0,5,15,30,60,120,240,360,480,720min posterior orbit take blood, 10000rpm/min
Lower centrifugal, take determination of plasma drug level.Using asiatic acid crude drug suspension as comparison.Blood medicine is dense
Degree-time graph is shown in that Fig. 3, main pharmacokinetic parameters are shown in Table 2, and result shows asiatic acid self-microemulsion, inhales
Receive rapidly, significantly improve the bioavailability in rat body.
The pharmacokinetic parameters (n=5) of table 2. rat oral gavage AA-SMEDDS and AA crude drug suspension
Embodiment 2
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 3
Prescription forms:
Asiatic acid 500mg
Oleic acid polyethyleneglycol glyceride (Labrafil M 1944CS) 3g
Polyoxyethylene castor oil (Cremophor EL) 7g
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 4
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 5
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 6
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 7
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 8
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniformly
Can.
Embodiment 9
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 10
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 11
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Embodiment 12
Prescription forms:
Preparation technology:
Weigh the medicine of recipe quantity, add co-emulsifier and the emulsifying agent of recipe quantity, in 37 DEG C of water-baths
Magnetic agitation uniformly makes it dissolve, and adds oil phase and other adjuvants according to recipe quantity, and magnetic agitation is uniform.
Claims (6)
1. an Asiatic acid self-microemulsifyindrug drug delivery system, it is characterised in that including: 0.5%～5% amasss
Snow oxalic acid, oil phase 10%-50%, emulsifying agent 30%-75% and co-emulsifier 0%-30%, percentage ratio is matter
Amount percentage ratio；
Described oil phase is oleic acid polyethyleneglycol glyceride；
Described emulsifying agent is hard selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Polyethylene Glycol
One or more in fat acid ester 15 and Labraso；
Described co-emulsifier selected from ethanol, ethylene glycol, Polyethylene Glycol, TC, third
One or more in olefinic carbon acid esters and propylene glycol.
2. Asiatic acid self-microemulsifyindrug drug delivery system as claimed in claim 1, it is characterised in that institute
The Asiatic acid self-microemulsifyindrug drug delivery system stated, still further comprises antioxidant.
3. Asiatic acid self-microemulsifyindrug drug delivery system as claimed in claim 2, it is characterised in that anti-
Oxidant is vitamin C and/or vitamin E, and consumption is less than 5%, and percentage ratio is mass percent.
4. the Asiatic acid self-microemulsifyindrug drug delivery system as described in any one of claims 1 to 3, its feature
Being, described Asiatic acid self-microemulsifyindrug drug delivery system is hard capsule, soft capsule, granule, tablet
Or oral liquid formulation.
5. the system of the Asiatic acid self-microemulsifyindrug drug delivery system as described in any one of Claims 1 to 4
Preparation Method, it is characterised in that comprise the following steps: weigh asiatic acid, add recipe quantity helps emulsifying
Agent and emulsifying agent, make it dissolve 25～45 DEG C of stirrings, then according to recipe quantity adds oil phase and other are auxiliary
Material, stirs and get final product.
6. the Asiatic acid self-microemulsifyindrug drug delivery system as described in any one of Claims 1 to 4 is anti-in preparation
Application in the medicine of inflammation, antioxidation, antitumor, fibrosis or cardiovascular protection.
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| CN105943640A (en) * | 2016-06-24 | 2016-09-21 | 安徽高山药业有限公司 | Traditional Chinese medicine self-microemulsion instant release pill for treating myocardial ischemia and preparation method thereof |
| CN105878815A (en) * | 2016-06-24 | 2016-08-24 | 凌云 | Traditional Chinese medicinal self-microemulsion fast-release drop pill for treating coronary heart disease and preparation method |
| CN105943604A (en) * | 2016-06-24 | 2016-09-21 | 赵晶晶 | Self-microemulsion rapid-release compound Danshen dripping pill and preparation method |
| CN105943687A (en) * | 2016-06-24 | 2016-09-21 | 赵晶晶 | Traditional Chinese medicine self-microemulsion instant release pill for treating angina pectoris and preparation method thereof |
| CN106038930A (en) * | 2016-06-24 | 2016-10-26 | 凌云 | Traditional Chinese medicine fast release droppill for treating venomous snake bite and preparation method thereof |
| CN111840223A (en) * | 2019-04-22 | 2020-10-30 | 上海现代药物制剂工程研究中心有限公司 | Alisol A self-microemulsion composition and preparation method thereof |
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| CN101474157A (en) * | 2009-01-19 | 2009-07-08 | 浙江省医学科学院 | Asiatic acid injectable sustained-release microballoons and preparation method thereof |
| CN101991532A (en) * | 2009-08-14 | 2011-03-30 | 上海开拓者医药发展有限公司 | Self-microemulsion composition, microemulsion and preparation methods thereof |
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| CN1228042C (en) * | 2003-01-30 | 2005-11-23 | 上海家化联合股份有限公司 | Asiaticoside liposome and its use |
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| CN1582946A (en) * | 2004-06-09 | 2005-02-23 | 崔福贵 | Use of centellosic acid derivative in preparation of medicines for diseases of cardio-cerebral blood vessels |
| CN101474157A (en) * | 2009-01-19 | 2009-07-08 | 浙江省医学科学院 | Asiatic acid injectable sustained-release microballoons and preparation method thereof |
| CN101991532A (en) * | 2009-08-14 | 2011-03-30 | 上海开拓者医药发展有限公司 | Self-microemulsion composition, microemulsion and preparation methods thereof |
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