CN102258468B - Liposome spraying agent and its preparation method - Google Patents
Liposome spraying agent and its preparation method Download PDFInfo
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- CN102258468B CN102258468B CN201010189157.5A CN201010189157A CN102258468B CN 102258468 B CN102258468 B CN 102258468B CN 201010189157 A CN201010189157 A CN 201010189157A CN 102258468 B CN102258468 B CN 102258468B
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Abstract
The invention relates to a novel liposome spraying agent and its preparation method. The spraying agent provided by the invention is prepared by the dispersion of medicine-loading ethosome in a solution system containing a macromolecular dispersing aid, and is used to helps raise the medicine loading capacity as well as the entrapment rate and promote medicines to penetrate through skin, mucous membrane or in vivo biomembrane barriers such that the medicines have long-acting effects. The novel liposome spraying agent has a wide medicine application range, especially is suitable for medicines of poor amphiphilicity or medicines of high molecular weight, and can be used to meet the requirement of treating local areas such as mucous membrane, skins, wounds and cavities or the whole body.
Description
[technical field]
The invention belongs to pharmaceutics field, more particularly, the present invention relates to a kind of liposome spray and preparation method thereof.
[background technology]
Skin and mucous layer are a kind of barrier of human body to drug absorption, and amphipathic difference or the large medicine of molecular weight are difficult to enter into deep tissues through skin and mucous membrane tissue and blood circulation plays therapeutic action.
In current promotion medicine transdermal, mucous membrane or body, the method for membranes barriers mainly relies on chemical absorption promoter [yellow strong to increase drug absorption, Gao Chunsheng, plum is made the country prosperous. the application of penetrating agent in macromolecular drug mucosal drug delivery system. and foreign medical science: pharmacy fascicle .2006,33 (6): 654-656].Although chemical absorption promoter can reduce the resistance of medicine by skin and mucous membrane, improve medicine and penetrate efficiency.But these chemical absorption promoter all can cause damage to membranes barriers in skin, mucous membrane or body or stimulate, its detrimental effect can manifest along with the prolongation of the increase of preparation consumption or Applicative time, in addition these chemical absorption promoter also may react with medicine or packaging material, affect drug effect and play.
Aerosol and spray are the better formulations of current skin or mucosal drug delivery, but the security of spray is better, preparation and use more convenient.Spray means not containing propellant, the preparation that content disengages with the form such as vaporific by the pressure by manual pump.Spray is divided into single dose and multiple dose spray by using method; Solution-type, emulsion-type and suspension type is categorized as by decentralized system.Solution type spray liquid should be clarified; Emulsion-type drops in liquid medium and should be uniformly dispersed; Fine drug powder and additives should fully mix by suspension type spray, make stable supensoid agent.
The advantage of spray has: (1) sprays the propellant not needing aerosol, does not use pressure vessel, easy to use; (2) quick curing effect is played; (3) can by the accurate control dose of quantitative valve; (4) scope of application is comparatively wide, can be used for skin, mucous membrane and the surface of a wound; (5) droplet sprayed is comparatively thin, and in the spread and the good dispersion degree of skin or mucosa, liquid not easily runs off.
But spray has some shortcomings: (1) multiple dose spray needs Reusability, easy microbiological contamination needs to add bacteriostatic agent; (2) although quick-acting effect can be played, need to add chemical absorption promoter increase medicine and penetrate efficiency; (3) duration of efficacy is short, removes very fast in body; (4) water solution system, easy moldy metamorphism, is unfavorable for drug substance stable.
Alcohol plastid is a kind of novel liposome, is proposed the earliest by Touitou in the middle and later periods nineties 20th century, and it is capsule material by phosphatide or lipid materials, and the single or multiple lift vesica be made up of ethanol participation structure.Compared with conventional liposome, its particle diameter is less, Stability Analysis of Structures, envelop rate is high, has better flexibility, the advantages such as excellent percutaneous abilities [Li Liyu, Wang Hongquan. the progress of New Percutaneous drug administration carrier--alcohol plastid. Chinese Journal of New Drugs, 2010,19 (1): 33-38].
Patent report liposome being applied to spray is more, but the patent report that alcohol plastid is applied to spray is few.Patent (CN02145124.9) discloses a kind of camphor spray and preparation method thereof, and containing high concentration ethanol solution in the spray prescription provided, but in patent, ethanol, only as the main solvent of spray, is not applied to the carriers such as liposome.Patent (CN200410054738.2), patent (CN200410054739.7), patent (CN200410054738.2) etc. apply alcohol injection and prepare liposome, but ethanol is only as the main solvent in liposomal preparation process in these patents, finally be removed, do not it can be used as liposome key component to be applied in spray.Patent (CN02139452.0) discloses a kind of liposome anti-fungus medication sprayer formulation, although contain ethanol in this patent prescription, just as percutaneous absorption transdermal enhancers, its consumption is lower, does not participate in liposome structure composition.Patent (CN200810061803.2) discloses ethosome preparation of a kind of antifungal drug and preparation method thereof, and in this patent prescription, ethanol percentage by weight is 20% ~ 45%.But this patent system standby alcohol plastid is longer for standing time, and alcohol plastid particulate is easily assembled, and particle diameter can become large.
[summary of the invention]
The technical problem to be solved in the present invention is the weak point for existing liposome spray and ethosome preparation, a kind of novel lipide spray-ol plastid spray is provided, promote that medicine enters into deep tissues and blood circulation through skin or mucous membrane quickly, play quick-acting and long-acting treatment effect, it is wide that this alcohol plastid spray is suitable for medicine scope, be particularly suitable as the medicine of amphipathic difference or the large medicine of molecular weight, mucous membrane, skin, the surface of a wound, the local of cavity or the needs of whole body therapeutic can be met.
The spray of a kind of novel lipide of the present invention, not only there is common spray advantage, have more following advantage: containing higher concentration ethanol in (1) prescription, not only there is antibacterial and mildew-proof function preferably, and promotion drug absorption, maintain drug substance stable; (2) add adding molecular dispersion aids in prescription, be conducive to alcohol plastid Stability Analysis of Structures and extend alcohol plastid Chinese traditional medicine action time; (3) alcohol plastid particle diameter is less and have better flexibility, is not only conducive to improving drug delivery amount and envelop rate, more promotes membranes barriers in medicine transdermal, mucous membrane or body, plays long-acting; (4) medicine is applied widely, can apply for the medicine of amphipathic difference or the large medicine of molecular weight; (3) applied range, can meet mucous membrane, skin, the surface of a wound, the local of cavity or the needs of whole body therapeutic.
Inventor studies discovery, the alcohol plastid that utilization comprises higher concentration (20%-45%) ethanol system makes spray can significantly improve the transdermal of spray Chinese traditional medicine or the ability of mucous membrane, has good application prospect for there is skin or mucous membrane through the medicine of the amphipathic difference of obstacle and the large medicine of molecular weight.But this alcohol plastid spray is in storage put procedure, and preparation system is unstable, and it is large that change easily assembled by alcohol plastid particulate, can not disperse by jog again, therefore cannot in clinical middle practical application.Inventor finds through great many of experiments, some macromolecule polyalcohols have good suspending effect, can join in alcohol plastid spray as large molecule dispersion aids, ensure alcohol plastid particle diameter long-time stable, thus improve the stability of medicine, extend its effective acting time.
Thus, the spray of a kind of novel lipide of the present invention, the solution system that this spray solution is scattered in containing large molecule dispersion aids by the alcohol plastid of bag medicine carrying thing forms, and ethanol accounts for the 20%-95% of spray solution cumulative volume.
Above-mentioned medicine refer to clean for the performance of mucous membrane, skin, the surface of a wound, cavity, sterilize, prevent, treat, immunity, beauty treatment, the Chinese medicine of healthcare applications, chemicals, biotech drug or biological products.
Above-mentioned alcohol plastid refers to that by the known phosphatide of pharmacy or lipid materials be capsule material, and the single or multiple lift vesica be made up of ethanol participation structure.
One or more in pharmaceutically known antioxidant, pH adjusting agent or pH buffer salt, surfactant, stabilizing agent are comprised in above-mentioned spray solution.
Above-mentioned stabilizing agent comprises propane diols, glycerine, PEG400, Macrogol 600 or its any combination.
Above-mentioned large molecule dispersion aids is biocompatibility or Biodegradable polymeric, comprises carbomer, hydroxypropyl methylcellulose, PVP, HES, poloxamer.
In above-mentioned solution system, ethanol accounts for the 30%-80% of spray solution cumulative volume.
A kind of above-mentioned method preparing liposome spray solution, that the one in phosphatide and lipoid or both are dissolved in ethanol, mix formation organic phase, large molecule dispersion aids formation aqueous phase soluble in water, the principle that medicine is close according to polarity is dissolved in organic phase or aqueous phase, organic phase is injected in aqueous phase, stirs, form the alcohol plastid spray solution of bag medicine carrying thing, wherein ethanol accounts for the 20%-95% of spray solution cumulative volume.
One or more in pharmaceutically known antioxidant, pH adjusting agent or pH buffer salt, surfactant, stabilizing agent are also dissolved with in above-mentioned spray solution.
Above-mentioned large molecule dispersion aids is biocompatibility or Biodegradable polymeric, comprises carbomer, hydroxypropyl methylcellulose, PVP, HES, poloxamer.
[accompanying drawing explanation]
[detailed description of the invention]
Now further describe the present invention in conjunction with following Examples.
Embodiment 1:
Amphipathic difference or the large medicine of molecular weight, as rubescensin, taxol, curcumin, amphotericin B, dexamethasone etc., be difficult to penetrate membranes barriers in complete skin, mucous membrane or body, therefore bioavilability is poor, is difficult to play effective therapeutic action.First embodiment of the present invention utilizes natural phospholipid material yolk phospholipid and cholesterol to be main capsule material, HES is large molecule dispersion aids, add surface active agent tween 80 and antioxidant vitamins C, adopt injection method to prepare rubescensin alcohol plastid spray.
Preparation: 20mg yolk phospholipid and 8mg cholesterol are dissolved in 10ml ethanol, add 2mg Tween 80 and 8mg rubescensin, is heated to 60 DEG C and all dissolves, form organic phase.Separately get 0.05g HES (model 130/0.4) to be dissolved in 20ml distilled water, be heated to 60 DEG C, as aqueous phase.Organic phase be injected in aqueous phase, 1000r/min stirs 10min, forms rubescensin alcohol plastid suspension, is chilled to room temperature, adds 10mg vitamin C, filling in spray special-purpose bottle, to obtain final product.Ethanol accounts for the 30%-35% of spray solution cumulative volume.
Shelf-stability is investigated: 25 DEG C, rubescensin alcohol plastid spray sample is placed 6 months, and sample thief utilizes laser diffraction analyzer to observe rubescensin alcohol plastid change of size, measures envelop rate.
Entrapment efficiency determination: get 2ml rubescensin alcohol plastid spray sample, the centrifugal 5min of 15000r/min, get precipitation, add 2ml anhydrous alcohol solution, the centrifugal 5min of 15000r/min, getting supernatant utilizes ultraviolet specrophotometer to survey ultraviolet absorption value in 221nm, be measured in the same method the 221nm ultraviolet absorption value of blank alcohol plastid spray sample, deduct as a setting, utilize the envelop rate of " envelop rate (%)=[(in rubescensin alcohol plastid rubescensin measured quantity)/rubescensin total amount] × 100 " formulae discovery rubescensin alcohol plastid.
Experimental result, the initial domain size distribution of rubescensin alcohol plastid spray sample is at 800-1000nm, and without clustering phenomena, envelop rate is 92%.Place after 6 months for 25 DEG C, domain size distribution is still at 800-1000nm, and without clustering phenomena, envelop rate is 91%, and without drug leakage phenomenon, prove rubescensin alcohol plastid spray good stability, envelop rate is high, and the medicine in put procedure in alcohol plastid is without obvious seepage.
Embodiment 2:
Implement method for making substantially with embodiment 1, but use lipid materials glycerin monostearate instead as main material, prepare rubescensin alcohol plastid spray for second of the present invention.
Preparation: be dissolved in 20ml ethanol by 10mg glycerin monostearate, add 2mg Tween 80 and 8mg rubescensin, is heated to 60 DEG C and all dissolves, form organic phase.Separately get 0.05g HES (model 130/0.4) to be dissolved in 10ml distilled water, be heated to 60 DEG C, as aqueous phase.Organic phase be injected in aqueous phase, 1000r/min stirs 10min, forms rubescensin alcohol plastid suspension, is chilled to room temperature, adds 10mg vitamin C, filling in spray special-purpose bottle, to obtain final product.Ethanol accounts for the 60%-65% of spray solution cumulative volume.
Shelf-stability is investigated: with embodiment 1.
Experimental result, the initial domain size distribution of rubescensin alcohol plastid spray sample is at 600-800nm, and without clustering phenomena, envelop rate is 89%.Place after 6 months for 25 DEG C, domain size distribution is still at 600-800nm, and without clustering phenomena, envelop rate is 88%, without drug leakage phenomenon.Result shows that rubescensin alcohol plastid spray envelop rate is high, good stability in put procedure.
Embodiment 3:
3rd embodiment of the present invention take synthetic phospholipid as main material, and PVP is large molecule dispersion aids, adds stabilizing agent propane diols, adopts injection method to prepare curcumin alcohol plastid spray.
Preparation: 6mg hydrogenated soya phosphatide, 2mg DPPC (DPPC) phosphatide and 8mg cholesterol are dissolved in 20ml ethanol, add 2mg Tween 80 and 6mg curcumin, is heated to 60 DEG C and all dissolves, form organic phase.Separately get 50mg PVP (model K30) to be dissolved in 5ml distilled water, add 20mg propane diols and be heated to 60 DEG C, as aqueous phase.Organic phase be injected in aqueous phase, 1000r/min stirs 10min, forms curcumin alcohol plastid suspension, is chilled to room temperature, fillingly to obtain final product in spray special-purpose bottle, jog mixing before use.Ethanol accounts for the 75%-80% of spray solution cumulative volume.
Shelf-stability is investigated: 25 DEG C, curcumin alcohol plastid spray sample is placed 6 months, and sample thief utilizes laser diffraction analyzer to observe curcumin alcohol plastid change of size, measures envelop rate.
Entrapment efficiency determination: get 2ml curcumin alcohol plastid spray sample, the centrifugal 5min of 15000r/min, get precipitation, add 2ml anhydrous alcohol solution, the centrifugal 5min of 15000r/min, getting supernatant utilizes visible spectrophotometer to survey absorption value in 427nm place, be measured in the same method the 427nm place absorption value of blank alcohol plastid spray sample, deduct as a setting, utilize the envelop rate of " envelop rate (%)=[(in curcumin alcohol plastid curcumin measured quantity)/curcumin total amount] × 100 " formulae discovery curcumin alcohol plastid.
Experimental result, the initial domain size distribution of curcumin alcohol plastid spray sample is at 700-900nm, and without clustering phenomena, envelop rate is 94%.Place after 6 months for 25 DEG C, domain size distribution is still at 700-900nm, and without clustering phenomena, envelop rate is 93%, without significant change.Result proves curcumin alcohol plastid spray good stability, and envelop rate is high, and the medicine in put procedure in alcohol plastid is without obvious seepage.
Embodiment 4:
4th embodiment of the present invention utilize chicken element cyst membrane measure the curcumin alcohol plastid spray that obtains of embodiment 3 through biomembranous ability.
The process of chicken element cyst membrane: get new freshly-slaughtered poultry element capsule, clean, peel off fat deposit, be soaked in physiological saline for subsequent use.
Through biofilm experiments: adopt Transdermal diffusion cell, get chicken element cyst membrane and be cut into suitable size, be fixed between supply chamber and receiving chamber, in receiving chamber, saline injection makes probe tube liquid level a little more than film, records the liquid measure added.Open magnetic stirring apparatus and constant temperature oil bath, constant speed is kept to stir, 37 DEG C of constant temperature, spray 200 μ l curcumin alcohol plastid spray solutions on the chicken element cyst membrane face of supply chamber, in 5min, 10min, 30min draws receiving chamber solution 1ml from sample tap and measures, and supplements fresh physiological salt solution 1ml in receiving chamber, three times is measured acquired sample and adopts Syrups by HPLC agent permeates therethrough rate.Performance liquid chromatographic column: C18250mm × 4.6mm (5 μm), mobile phase: acetonitrile-4% glacial acetic acid solution (50: 50), flow velocity: 1.0ml/min, UV detect wavelength: 430nm, sampling volume: 100 μ l.
Table 1 curcumin alcohol plastid spray is through the experimental result of chicken element cyst membrane
As shown in table 1, medicine carrying alcohol plastid is comparatively strong through biomembrane ability, and in 10min, transmitance is more than 60%, is conducive to medicine and enters rapidly performance drug effect in body.
Claims (3)
1. a rubescensin alcohol plastid spray preparation method, is characterized in that: 20mg yolk phospholipid and 8mg cholesterol are dissolved in 10ml ethanol, adds 2mg Tween 80 and 8mg rubescensin, is heated to 60 DEG C and all dissolves, form organic phase; Separately get 0.05g HES to be dissolved in 20ml distilled water, be heated to 60 DEG C, as aqueous phase; Organic phase be injected in aqueous phase, 1000r/min stirs 10min, forms rubescensin alcohol plastid suspension, is chilled to room temperature, adds 10mg vitamin C, and filling in spray special-purpose bottle and get final product, ethanol accounts for 30% ~ 35% of spray solution cumulative volume.
2. a rubescensin alcohol plastid spray preparation method, is characterized in that: be dissolved in 20ml ethanol by 10mg glycerin monostearate, adds 2mg Tween 80 and 8mg rubescensin, is heated to 60 DEG C and all dissolves, form organic phase; Separately get 0.05g HES to be dissolved in 10ml distilled water, be heated to 60 DEG C, as aqueous phase; Organic phase be injected in aqueous phase, 1000r/min stirs 10min, forms rubescensin alcohol plastid suspension, is chilled to room temperature, adds 10mg vitamin C, and filling in spray special-purpose bottle and get final product, ethanol accounts for 60% ~ 65% of spray solution cumulative volume.
3. a curcumin alcohol plastid spray preparation method, it is characterized in that: 6mg hydrogenated soya phosphatide, 2mg DPPC phosphatide and 8mg cholesterol are dissolved in 20ml ethanol, add 2mg Tween 80 and 6mg curcumin, be heated to 60 DEG C and all dissolve, form organic phase; Separately get 50mg PVP to be dissolved in 5ml distilled water, add 20mg propane diols and be heated to 60 DEG C, as aqueous phase; Organic phase be injected in aqueous phase, 1000r/min stirs 10min, forms curcumin alcohol plastid suspension, is chilled to room temperature, and filling in spray special-purpose bottle and get final product, jog mixing before use, ethanol accounts for 75% ~ 80% of spray solution cumulative volume.
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| CN101002787A (en) * | 2006-01-20 | 2007-07-25 | 天津药物研究院 | Inhalant containing active component of methyl astragaloside |
| CN101244027A (en) * | 2008-03-20 | 2008-08-20 | 昆明制药集团股份有限公司 | Artemether percutaneous drug administration preparation for treating dermatosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101002787A (en) * | 2006-01-20 | 2007-07-25 | 天津药物研究院 | Inhalant containing active component of methyl astragaloside |
| CN101244027A (en) * | 2008-03-20 | 2008-08-20 | 昆明制药集团股份有限公司 | Artemether percutaneous drug administration preparation for treating dermatosis |
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