CN103494772A - Compound phosphatide transfer body with high deformability and application thereof in preparing transdermal drug delivery preparation - Google Patents
Compound phosphatide transfer body with high deformability and application thereof in preparing transdermal drug delivery preparation Download PDFInfo
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Abstract
The invention provides a compound phosphatide transfer body with high deformability. The compound phosphatide transfer body with high deformability comprises the following components in parts by weight: 0.5-5 parts of a surfactant, 1-10 parts of dipalmitoyl phosphorylcholine and 1-10 parts of dimyristoyl phosphorylcholine, wherein the surfactant is selected from sodium cholate, sodium deoxycholate, Twain and Span; the molar ratio of the dipalmitoyl phosphorylcholine to the dimyristoyl phosphorylcholine is (1: 1)-(1: 6); and the compound phosphatide transfer body with high deformability can be prepared by adopting any method of preparing lipidosome. Compared with the frequently-used granulesten and lecithin transfer bodies in the prior art, the deformability of the provided compound phosphatide transfer body is improved remarkably, the stability of a carrier is also improved remarkably, and the capability of a packaged drug of passing through a skin barrier is finally and remarkably improved, i.e. the percutaneous penetration effect is improved. By applying the transfer body technology to the transdermal drug delivery preparation, the capability of the drug of passing through a horny layer is improved obviously, and the drug effect can be improved obviously.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to a kind of have the composite phospholipid carrier of high deformation and the application in preparing percutaneous drug administration preparation thereof.
Background technology
Carrier (transfersomes) is a kind of self aggregation vesicle grown up on the basis of liposome, its composition is generally some kinds surfactant in phospholipid bilayer, thereby give its special morphotropism, can be under external pressure, crimp is only duct (Cevc G.Transfersomes between the corneocyte of self particle diameter 1/5～1/10 through aperture, liposomes and other lipid suspensions on the skin:permeation enhancement, vesicle penetration, and transdermal drug delivery.Crit Rev Ther Drug Carrier Syst.1996, 13 (3 – 4): 257 – 388.), thereby the medicine of parcel is carried to percutaneous main barrier horny layer, it is the percutaneous dosing carrier that there are at present the research and development potentiality, oral, the vagina administration aspect has also obtained the effect that improves bioavailability.
Morphotropism is that carrier promote to see through cuticular basic mechanism, and different according to carrier prescription composition and release characteristics, through after horny layer, can be brought into play part or whole body therapeutic effect.If can significantly improve the morphotropism of carrier, will fundamentally improve undoubtedly the transdermal effect of carrier and the curative effect after administration.In addition, carrier mainly be take unsaturated phospholipid at present as soybean phospholipid (SPC), egg phosphatide (EPC) are the underlying membrane material, adds surfactant simultaneously, and surfactant used is mainly sodium cholate, NaTDC, tween and span.Except morphotropism, because phospholipid material and surfactant itself also have the effect of Percutaneous absorption enhancer, so this is also one of carrier mechanism of promoting transdermal penetration, but generally acknowledges that at present morphotropism is the main transdermal mechanism of carrier.
It is composite phospholipid film material that DPPC (DPPC) and SPC once be take before this in this seminar, the sorbester p17 of take has prepared the composite phospholipid carrier as surfactant, and effect (Propranolol composite phospholipid carrier that can promote percutaneous to absorb and preparation method thereof and application of certain promotion Transdermal absorption have been obtained, application number 201210130344.5), this composite phospholipid carrier is compared and is significantly increased with conventional carrier 37 ℃ of distortion differences with 32 ℃, its mechanism that improves Transdermal absorption may be that in absorption process, the variation with the morphotropism of temperature change more is conducive to Transdermal absorption, or corresponding Lipid composition has the Percutaneous absorption enhancer effect.And composite phospholipid carrier proposed by the invention Lipid composition difference not only, and be directly to significantly improve morphotropism rather than improve the difference of morphotropism under different temperatures, so both have essential distinction.
Summary of the invention
Problem for the morphotropism that solves preparation in prior art is improved, the invention provides a kind of composite phospholipid carrier that can significantly improve morphotropism, and technical scheme is as follows:
A kind of composite phospholipid carrier with high deformation, comprise the component of following weight fraction: 0.5～5 part, surfactant, 1～10 part of DPPC, 1～10 part of dimyristoyl phosphatidyl choline.
As a further improvement on the present invention, above-mentioned surfactant is selected from sodium cholate, NaTDC, tween and span.Being more preferably surfactant is Arlacel-80.
As of the present invention, further improve, in the component of above-mentioned composite phospholipid carrier, DPPC: dimyristoyl phosphatidyl choline=1:1～1:6.Be more preferably DPPC: dimyristoyl phosphatidyl choline=1:2.
Composite phospholipid carrier provided by the present invention can adopt any method preparation for preparing liposome, such as film dispersion method, active loading method, reverse evaporation, injection method etc.
The present invention simultaneously also provides the application of the composite phospholipid carrier with high deformation in preparing percutaneous drug administration preparation, by this application, can significantly improve medicine by cuticular ability.
As a kind of scheme of the present invention, prepared medicine is the strychnine composite phospholipid carrier, the component that it comprises following weight fraction: in claim 1～5, the described composite phospholipid carrier of any one is 1～10 part, 0.2～4 part of strychnine.
Beneficial effect
Composite phospholipid carrier with high deformation provided by the invention, carrier with soybean phospholipid and egg phosphatide commonly used in prior art, morphotropism is significantly improved, and can significantly improve institute's entrapped drug by the ability of skin barrier, has improved the transdermal penetration effect.As be applied to percutaneous drug administration preparation, be expected to significantly improve drug effect by this this carrier technology.
The accompanying drawing explanation
The comparison of the morphotropism of the composite phospholipid carrier in Fig. 1 embodiment 1, the morphotropism of composite phospholipid carrier and conventional soybean phospholipid (SPC), egg phosphatide (EPC) carrier compares (n=3)
Accumulation transit dose-the time graph (n=5) of the different Lipid composition strychnine composite phospholipid of Fig. 2 carrier
The specific embodiment
Further illustrate the present invention below in conjunction with specific embodiment, should understand these embodiment only is not used in and limits the scope of the invention for the present invention is described, after having read the present invention, those skilled in the art all fall within the application's claims limited range to the modification of the various equivalent form of values of the present invention.
The preparation of embodiment 1 composite phospholipid carrier
Composite phospholipid consists of DPPC (DPPC), dimyristoyl phosphatidyl choline (DMPC).Precision takes 0.2mmol phospholipid (DMPC/DPPC mixes with certain proportion) and is dissolved in altogether appropriate dehydrated alcohol with the sorbester p17 that accounts for phospholipid gross weight 15%, inject the phosphate solution of the pH7.4 of water bath with thermostatic control and magnetic agitation, take out and let cool after waving most ethanol, and with the ultra-pure water standardize solution; Probe Ultrasonic Searching reduces the carrier particle diameter, obtains.
The preparation of embodiment 2 composite phospholipid carrier gels
Composite phospholipid consists of DPPC (DPPC), dimyristoyl phosphatidyl choline (DMPC).Precision takes 0.2mmol phospholipid (DMPC/DPPC mixes with certain proportion) and is dissolved in altogether appropriate dichloromethane with the sodium cholate that accounts for phospholipid gross weight 10%, 40 ℃ of rotary evaporations are removed the organic solvent film forming, after vacuum is placed and is spent the night, add the normal saline hydration, aqua liquid adopts high pressure homogenize to reduce the carrier particle diameter.Separately get Acritamer 940, glycerol in the mixing of 1:5 ratio, add appropriate purified water and stir evenly, drip 4% sodium hydrate aqueous solution and regulate pH to 6～11, then add ethyl hydroxybenzoate to mix, make gel-type vehicle.Get the composite phospholipid carrier suspension made and add gel-type vehicle to stir, obtain.
The preparation of embodiment 3 composite phospholipid carrier sprays
Composite phospholipid consists of DPPC (DPPC), dimyristoyl phosphatidyl choline (DMPC).Precision takes 0.2mmol phospholipid (DMPC/DPPC mixes with certain proportion) and is dissolved in altogether in appropriate chloroform with the NaTDC that accounts for phospholipid gross weight 12%, add phosphate buffer, ultrasonic formation Emulsion, reduction vaporization is removed organic solvent and is formed liposome turbid liquor, adopts polycarbonate membrane to extrude and reduces the carrier particle diameter, filters, fill is in spray bottle, sealing, packing, obtain finished product.
Embodiment 4 measures the morphotropism of the composite phospholipid carrier in embodiment 1
Adopt the microporous filter membrane extrusion molding to measure morphotropism, this is also generally acknowledged method at present, and according to formula: D=J * (rv/rp) 2 ask the calculation morphotropism, in above formula, D represents the morphotropism of carrier; J representative passes under certain external pressure (as: 0.2MPa) effect, passs the volume that the body suspension (mostly is 10min) and is pressed through certain pore size (50nm, 100nm do not wait) microporous filter membrane within a certain period of time; Rv was the carrier particle diameter after film; Rp is the microporous filter membrane aperture.
By the composite phospholipid carrier of the different proportion that makes from adopt identical prescription (except Lipid composition different) the SPC carrier for preparing with technique, be pressed through 50nm aperture microporous filter membrane and measure morphotropism under 0.5MPa, 10min condition, the result morphotropism of visible composite phospholipid carrier as shown in Figure 1 significantly improves, and peak is compared with conventional EPC, SPC carrier has increased by 7.4 times (the results are shown in Figure 1).
The preparation of embodiment 5 strychnine composite phospholipid carriers
Precision takes 0.2mmol phospholipid (DMPC/DPPC mixes with certain mol proportion) and is dissolved in altogether appropriate dehydrated alcohol with the sodium cholate that accounts for phospholipid gross weight 10%, inject the ammonium sulfate of 250mM under 50 ℃ of conditions, fling to ethanol under the magnetic agitation condition, Probe Ultrasonic Searching reduces particle diameter, adopt 10 times of volume pH7.4 phosphate buffer dialysis 4 times, the gained carrier adds strychnine by medicine fat weight ratio 1:6, and 40 ℃ of constant temperature oscillation 20min, obtain.With the standby strychnine SPC of legal system and EPC carrier.Embodiment 6 measures the morphotropism for preparing the strychnine composite phospholipid carrier of gained in embodiment 5
Measure the morphotropism of different Lipid composition strychnine carriers, method, with embodiment 4, the results are shown in Table 1.Visible medicine carrying does not change the result that the composite phospholipid carrier significantly improves morphotropism.
The morphotropism measurement result (n=3) of the different Lipid composition strychnine of table 1 carrier
Embodiment 7 Transdermal absorption experiments---measure the Transdermal absorption effect for preparing the strychnine composite phospholipid carrier of gained in embodiment 5
On the strychnine carrier that embodiment 5 is made, the gel column eluting is removed free drug, regulates concentration to 100 μ g/mL.Transdermal experiment adopts the isolated rat skin of abdomen, vertical Franz diffusion cell, acceptable solution is normal saline, effective diffusion area 3.14cm2, the strychnine that adds the different Lipid compositions of 0.5mL at skin surface transmits body fluid, adopt the HPLC method to measure the strychnine concentration in the different time points acceptable solution, calculate the transdermal diffusion velocity.Result as shown in Figure 2, the composite phospholipid carrier of the DPPC:DMPC=1:2 that visible morphotropism is the highest, the Transdermal Absorption effect is also best, it is 2.21 times (the results are shown in Figure 2) of conventional strychnine SPC carrier that the accumulation after 10h sees through percent.
Adopt the acetic acid twisting test evaluation.Get 40 of male mices, be divided at random 4 groups, 10 every group, give respectively normal saline, strychnine solution, strychnine composite phospholipid carrier and positive drug Diclofenac Sodium Gel.Test and lose hair or feathers in the mouse web portion same area in first 24 hours, give reagent by 24mg/kg dosage, be applied in animal abdominal part depilation zone, after administration 30min, lumbar injection 1% glacial acetic acid solution 0.2mL/ (10g), then mice is put into separately to transparent plastics cage, count its writhing number of times in 20min.The results are shown in Table 2.Suppression ratio (%) is: (blank group average time-administration group average time)/blank group average time * 100%.
The impact of table 2 mice analgesic test result (
n=10)
Annotate: with the normal saline group, compare
*p<0.01,
* *p<0.001.
Claims (7)
1. the composite phospholipid carrier with high deformation, comprise the component of following weight fraction: 0.5 ~ 5 part, surfactant, 1 ~ 10 part of DPPC, 1 ~ 10 part of dimyristoyl phosphatidyl choline.
2. composite phospholipid carrier according to claim 1, it is characterized in that: described surfactant is selected from sodium cholate, NaTDC, tween and span.
3. composite phospholipid carrier according to claim 1, it is characterized in that: described surfactant is Arlacel-80.
4. according to the described composite phospholipid carrier of claim 1 ~ 3 any one, it is characterized in that: described DPPC: the mole ratio of dimyristoyl phosphatidyl choline equals 1:1 to 1:6.
5. composite phospholipid carrier according to claim 4, it is characterized in that: described DPPC: the mole ratio of dimyristoyl phosphatidyl choline equals 1:2.
6. the application of the described composite phospholipid carrier of any one in preparing percutaneous drug administration preparation in claim 1 ~ 5.
7. the application of composite phospholipid carrier in preparing percutaneous drug administration preparation according to claim 6, it is characterized in that: prepared medicine is the strychnine composite phospholipid carrier, the component that it comprises following weight fraction: in claim 1 ~ 5, the described composite phospholipid carrier of any one is 1 ~ 10 part, 0.2 ~ 4 part of strychnine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107998070A (en) * | 2017-12-12 | 2018-05-08 | 南京中医药大学 | A kind of composite phospholipid carrier and its application in percutaneous drug administration preparation is prepared |
| CN108635330A (en) * | 2018-04-17 | 2018-10-12 | 胡柳嘉 | A kind of long-acting slow-release progesterone gel agent composition |
| CN115501181A (en) * | 2021-06-07 | 2022-12-23 | 武汉科福新药有限责任公司 | Nadolol flexible nano gel emulsion and preparation method thereof |
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| CN101874763A (en) * | 2009-04-29 | 2010-11-03 | 上海家化联合股份有限公司 | Resveratrol flexible liposome and preparation method thereof |
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2013
- 2013-09-29 CN CN201310456946.4A patent/CN103494772A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101874763A (en) * | 2009-04-29 | 2010-11-03 | 上海家化联合股份有限公司 | Resveratrol flexible liposome and preparation method thereof |
Non-Patent Citations (3)
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| 张路等: "纳米马钱子碱脂质体制备工艺研究", 《中成药》 * |
| 李俊等: "马钱子优化总生物碱复合磷脂传递体的制备与性质研究", 《光明中医》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107998070A (en) * | 2017-12-12 | 2018-05-08 | 南京中医药大学 | A kind of composite phospholipid carrier and its application in percutaneous drug administration preparation is prepared |
| CN108635330A (en) * | 2018-04-17 | 2018-10-12 | 胡柳嘉 | A kind of long-acting slow-release progesterone gel agent composition |
| CN115501181A (en) * | 2021-06-07 | 2022-12-23 | 武汉科福新药有限责任公司 | Nadolol flexible nano gel emulsion and preparation method thereof |
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Application publication date: 20140108 |