CN107137345A - A kind of liposome gel formulation and its preparation and use for suppressing scar proliferation - Google Patents
A kind of liposome gel formulation and its preparation and use for suppressing scar proliferation Download PDFInfo
- Publication number
- CN107137345A CN107137345A CN201710377078.9A CN201710377078A CN107137345A CN 107137345 A CN107137345 A CN 107137345A CN 201710377078 A CN201710377078 A CN 201710377078A CN 107137345 A CN107137345 A CN 107137345A
- Authority
- CN
- China
- Prior art keywords
- liposome
- imiquimod
- gel formulation
- preparation
- phosphatide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Abstract
The present invention provide it is a kind of be used to suppressing the imiquimod liposome gel formulation of scar proliferation, the liposome gel formulation includes liposome, gel rubber material and glycerine, and described liposomal encapsulated have imiquimod bulk drug.Present invention simultaneously provides the preparation and use of the liposome gel formulation.The imiquimod liposome gel formulation of the present invention shows that, with obvious sustained release and Transdermal absorption facilitation effect, compared with imiquimod cream, Percutaneous permeability and skin accumulation are significantly improved through tablets in vitro；Compared with other anti-scar proliferation pharmaceutical preparations or therapeutic scheme of report, recurrence rate is low, and toxic side effect incidence is low, and can be applied to the position of any scar proliferation of body.The lipidosome gel of the present invention has more advantage as Drug Percutaneous Absorption carrier.
Description
Technical field
The present invention relates to a kind of liposome gel formulation, particularly a kind of imiquimod liposome gel formulation, the present invention
The preparation method and its usage of the preparation is additionally provided, belongs to medical science pharmaceutical field.
Background technology
Hyperplastic scar (Hypertrophic scars, HS) is the skin that a kind of gradual, pathologic and being difficult to is reversed
Disease, often occurs in depth wound（Such as operation, burn and scald）In repair process, by the generation of a large amount of fine vasculars, fibroblast
Propagation, collagen over-deposit cause corium excess fibrosis to cause.It is clinical at present conventional in the therapeutic scheme of hyperplastic scar
Surgery excision and class of medications.Operative treatment usually requires to carry out skin-grafting and radioactive ray or laser irradiation auxiliary treatment, and
Average recurrence rate is up to more than 50%.Medicine mainly has steroids（Local injection or smearing）, antimetabolite（Office
Inject or oral in portion)）And silicon-agent（Smear or spray）, wherein hormone medicine markedly fast, but part occurs in prolonged application
Side effect and general reaction, such as atrophoderma, local telangiectasis and pigmentation；Antimetabolite is generally anticancer
Preparation, toxic side effect is protruded, the metabolism of influence normal skin tissue cell and activity；Silicon-agent has no side effect and patient's biddability
It is good, but the only position to holding pressure（Such as four limbs）Effectively.
Imiquimod (Imiquimod) is imidazole quinoline class medicine, is uniquely done in artificial synthesized micromolecular compound
Element induction immune response modifier is disturbed, with antiviral, antineoplastic immune adjustment effect.Imiquimod effect is unique, does not have
Direct antiviral activity, will not also cause directly, the effect of non-specific cell dissolved destruction, but by reduce Toll-like by
Body TLR7 and TLR8 competitive inhibitory effect, stimulate panimmunity cell to produce a series of cytokines, inductive formation various kinds of cell
The factor, so as to strengthen immunoregulation effect.Imiquimod clinic is mainly used in treatment keloid, condyloma acuminatum, genital wart
Deng.Because imiquimod solubility property is poor, it is available for the formulation being made limited, presently commercially available product only has creme, emulsifiable paste.
Liposome has reduction drug toxicity, targeting positioning, particle diameter is small, have the spies such as good compatibility with biomembrane
Property, by medicine preparation into liposome, the stability of medicine and the hold-up in organ are added, makes curative effect of medication more notable.
Gel be a class contain dissolving, be suspended or emulsion state medicine semisolid preparation, can in a long time with site of action
Closely slit attached, with preferable biological attached property of slitting, and prepare simply, using comfortable.Gel means medicine and can form solidifying
The glop or semisolid preparation of homogeneous, suspension or emulsion type is made in the auxiliary material of glue.It has that gas permeability is good, biological utilisation
The features such as degree is high, stability is good, adverse reaction is few and easy to use.Lipidosome gel mixes liposome with gel-type vehicle, from
And increase the stability of liposome, liposome is improved as the applicability of exterior-applied formulation, and can provide the slow of packaging medicine
Release and controlled release.Liposome can promote scar different as common nanometer drug administration carrier, liposome-skin administration with unique advantage
The Medicated Permeation ability of matter epidermis, strengthens medicine corium retention performance, and aqueous administration environment meets wound healing to O2Need
Ask.Imiquimod is prepared into liposome gel by this research, on the one hand adds the solubility property of imiquimod, on the other hand
Increase hold-up of the imiquimod in skin corium, preferably play the effect that imiquimod suppresses scar.It there is no at present relevant
The document report of imiquimod liposome gel formulation.
The content of the invention
An object of the present invention is to provide a kind of liposome gel formulation for being used to suppress scar proliferation, wherein described
Liposome gel formulation includes liposome, gel rubber material and glycerine, and described liposomal encapsulated have imiquimod bulk drug, the fat
Plastid includes phosphatide, cholesterol and vitamin E.
In a preferred embodiment, the phosphatide is by selected from egg yolk lecithin, cephalin lipositol, serine
Phosphatide, nucleotide phospholipid, soybean lecithin, DSPC, DPPC, dioleoyl phospholipid acyl
Choline, DPPE, DSPG, hydrogenated soy phosphatidyl choline, cetyl phosphatidyl courage
What one or more phosphatide in alkali were constituted.Preferably, the phosphatide is in egg yolk lecithin and hydrogenated soy phosphatidyl choline
The mixture composition of one or both.It is found through experiments that, the phase transition temperature of various phospholipid materials is different, and preparation temperature needs height
In phase transition temperature.Experiment preferably uses the mixture of one or both of egg yolk lecithin, hydrogenated soy phosphatidyl choline.
In a preferred embodiment, the gel rubber material is selected from PLURONICS F87, poloxamer188, carbomer 934
With the one or more in Carbopol.
In a preferred embodiment, the particle diameter of the liposome particle is 100 to 1000 nm.
In a preferred embodiment, cholesterol and phosphatide ratio of weight and number are 1 ~ 3:2 ~ 6, imiquimod bulk drug and fat
Plastid quality parts ratio（Medicine fat ratio）For 1:10 ~ 60, it is 2 ~ 7% that vitamin E consumption, which accounts for total mass fraction,.
Another aspect of the present invention provides a kind of system of imiquimod liposome gel formulation for Inhibiting proliferation scar
Preparation Method.
The present inventor first determines the Transdermal absorption performance of imiquimod, and inquire into imiquimod Determination of oil-water partition coefficient and its
Relation between percutaneous absorption rate, then using envelop rate, particle diameter and form as inspection target, filter out rational formulation and technology and
Rate of charge, preferably goes out the higher imiquimod liposome of envelop rate, is finally prepared into lipidosome gel.
The present inventor's early stage is divided from injection method, film dispersion method, pH gradient method, ultrasonic injection method-pH gradient method and film
Screening method for preparing lipidosome is carried out in the methods such as arching pushing-pH gradient method, it is found that wherein film dispersion method-pH gradient method is fitted the most
Suitable industrialized production, and the liposome solutions particle diameter being made is suitable（100~1000nm）, envelop rate is higher（>80%）.
The method that the present invention is provided comprises the following steps：
(a) precision weighs a certain amount of imiquimod bulk drug, phospholipid material, cholesterol and vitamin E, adds three chloromethanes
Alkane, stirring dissolves each composition, obtains clear transparent solutions；
(b) clear transparent solutions that step (a) is obtained are placed in container, decompression rotary evaporation goes out solvent, makes phosphatide in container
One layer of uniform film is formed on wall, phosphate buffer is added, aquation is stayed overnight, is creamy white after suspension, adjusted with alkaline solution
It is poor that whole pH values form pH gradient, is incubated, and ultrasound, obtains imiquimod liposome under ice bath；
(c) by step（b）Obtained liposome filtering（0.8 μm of miillpore filter filter is first crossed, filtrate is filtered after 0.45 μm of micropore
Film, is repeated 3 times）Obtain liposome solutions；
(d) Macromolecule glue material is added in the liposome solutions, after being swelled completely, adds glycerine, grinding is uniform i.e.
.
In a preferred embodiment, in above method step（b）In, temperature 50 C, the rmin of rotating speed 30-1Carry out institute
Decompression rotary evaporation is stated, the time of the rotation is 15 ~ 45 minutes, and placement makes cholesterol fully be swelled hydration for 2 hours, described
Phosphate buffer pH is 6.0-7.0, and the alkaline solution is 1mol/L NaOH, and the ultrasonic time is 15 ~ 45 points under ice bath
Clock, obtains imiquimod liposome.It is highly preferred that in above method step（b）In, temperature 50 C, the rmin of rotating speed 30-1Enter
The row decompression rotary evaporation, the time of the rotation is 30 minutes, and placement makes cholesterol fully be swelled hydration, ice in 2 hours
The time of the lower ultrasound of bath is 30 minutes, obtains imiquimod liposome.
In a preferred embodiment, in the above-mentioned methods, cholesterol and phosphatide ratio of weight and number are 1 ~ 3:2 ~ 6, miaow quinoline
Not special bulk drug and liposome quality parts ratio（Medicine fat ratio）For 1:10 ~ 60, it is 2 ~ 7% that vitamin E consumption, which accounts for total mass fraction,
Incubation temperature is 30 ~ 70 DEG C, and incubation time is 20 ~ 100 minutes, and pH gradient difference is 1 ~ 5, and gel rubber material and qualities of glycerin ratio are 1
~50：1~5；Preferably, cholesterol and phosphatide mass ratio are 1:3 ~ 5, medicine fat ratio is 1:20 ~ 40, vitamin E consumption is 4 ~ 6%,
Incubation temperature is 40 ~ 60 DEG C, and incubation time is 50 ~ 90 minutes, and pH gradient difference is 1 ~ 3, gel rubber material and qualities of glycerin ratio be 1~
20：1~2；Most preferably, cholesterol and phosphatide mass ratio are 1:5, medicine fat ratio is 1:20, vitamin E consumption is 6%, incubation temperature
For 50 DEG C, incubation time is 70 minutes, and pH gradient difference is 3, gel rubber material and qualities of glycerin ratio 3:1.
Further aspect of the present invention provides the liposome gel formulation of the present invention in the medicine for preparing Inhibiting proliferation scar
Purposes.
Scar proliferation position is directly sticked on during the liposome gel formulation clinical practice of the present invention, especially performs the operation, burn
After scald, without or have the depth wound position of inflammation concurrently.Due to the imiquimod transdermal gel formulation application Human Physiology phase
The material entrapped drugs such as the good phosphatide of capacitive, can effectively improve the solubility of imiquimod, increase imiquimod is in skin corium
In hold-up, preferably play the effect that imiquimod suppresses scar, with other anti-scar proliferation pharmaceutical preparations of report or
Therapeutic scheme is compared, and recurrence rate is low, reduces toxic side effect incidence, and can be applied to the position of any scar proliferation of body.
In addition, provided by the present invention for the liposome gel formulation of Inhibiting proliferation scar preparation method have it is following
Advantage：1）Preparation is remained without toxic solvent, without may cause the auxiliary material of skin irritation or other adverse reactions；2）With market
On the anti-scar proliferation medicine now sold compare, toxic side effect is small, and patient compliance is good, and percutaneous rate is preferable, effectively adjusts skin
Immune cell factor；3）Technology of preparing can industrializing implementation, the lipidosome gel viscosity being made is suitable, and stability is good, meets medicine
Allusion quotation requirement.
Brief description of the drawings
Fig. 1 is percutaneous rate constant and lg in an embodiment of the inventionP Matched curve schematic diagram,PFor miaow quinoline
Mo Te Determination of oil-water partition coefficient, under the solvent mediums of pH 4.5 ~ 7.4, the percutaneous abilities of imiquimod and its Determination of oil-water partition coefficient
It is closely related, the percutaneous abilities of medicine can be predicted by determining the Determination of oil-water partition coefficient of medicine.
Fig. 2 is the transmission electricity of liposome particle in liposome gel formulation forming process in an embodiment of the invention
Mirror figure, particle size is homogeneous as can be seen from Figure, and outer rim is rounded, and form is regular.
Fig. 3 is liposomal particle size distribution map in liposome gel formulation forming process in an embodiment of the invention,
It can be seen that average grain diameter is about 335 nm, meet normal distribution.
Fig. 4 is the transdermal penetration of liposome gel formulation and conventional imiquimod gel in an embodiment of the invention
Kinetic curve, wherein ◇ represent the liposome gel formulation of the present invention；Represents conventional GPC, it is seen that liposome of the invention
The drug release profiles of gel preparation are substantially better than conventional imiquimod gel.
Embodiment
The liposome gel formulation that the present invention is provided includes liposome, gel rubber material and glycerine etc., and this is liposomal encapsulated to have
Following embodiment facilitates a better understanding of the present invention, but does not limit the present invention.Experimental method in following embodiments, such as without
Specified otherwise, is conventional method.
Agents useful for same and raw material of the present invention are commercially available or can be prepared by literature method.Unless otherwise indicated, otherwise hundred
Divide than being calculated by weight with number.
Embodiment 1：Imiquimod apparent partition coefficients and its correlation research with percutaneous absorption rate constant
N-octyl alcohol is placed in conical flask with cover, respectively with pH4.5,5.0,5.8,6.5,7.4 buffering salt loading, 33 ±
0.5 DEG C shakes 24h, 3500 rmin-1Centrifuge 20 min, separation n-octyl alcohol and buffer solution.Precision weighs imiquimod 1.5
Mg, is dissolved with the n-octyl alcohol of different pH buffer solution presaturation, in the volumetric flask for being placed in 25 ml, constant volume, and obtaining series concentration is
60µg·mL-1.The cushioning liquid crossed by n-octyl alcohol saturation and imiquimod n-octyl alcohol solution are taken, by 1:1 proportional volume, is placed in cone
In shape bottle, sealing.Solution in a part of conical flask is placed in 33 ± 0.5 DEG C of constant-temperature tables and rocks 72h, another part taper
Bottle 40 min of vortex, are subsequently placed in 33 ± 0.5 DEG C of waters bath with thermostatic control and stand 72h, take out, with 3500 rmin-1Centrifugation 20
Min, takes buffering salt deposit, constant volume.The concentration of buffer salt phase is determined with efficient liquid phase, Determination of oil-water partition coefficient is calculated, as a result sees
Table 1.
P=(C-Cw)/Cw formula 1
Wherein,PFor the apparent partition coefficients of imiquimod；C is the concentration of initial drug in cushioning liquid saturation n-octyl alcohol
, Cw is the concentration of medicine in cushioning liquid after balancing.
Using TP-6 transdermal diffusion apparatus, mouse skin is placed in the middle of two half ponds, keratoderma upward, clamps, prevents liquid
Body drain goes out, and effective infiltrating area is 2.25 cm2, reception tank volume is 15mL, and temperature is 33 ± 0.5 DEG C, mixing speed 350r
min-1, in 1,2,4,6,8,12,24 h samplings, each sampling amount 1mL, while 1mL is supplied, with the buffer salt of pH=6.5
For acceptable solution.Qn is calculated, Qn-t equations is drawn, the results are shown in Table 2.
Formula 2
Wherein, Qn：Unit area accumulation in n-th hour passes through dose；Cn：The concentration of sampling in n-th hour；V：Reception liquid volume；A：
The effective diffusion area of diffusion cell.
Measurement result of the imiquimod of table 1 in the Determination of oil-water partition coefficient of n-octyl alcohol-difference pH cushioning liquid
PFor the apparent partition coefficients of imiquimod
Test result indicates that, imiquimod is in the range of pH 5.8 ~ 7.3,1 ﹤ lgP﹤ 3, shows the medicine lipophilicity preferably, water
Dissolubility is poor, and shaking table method and the lg measured by vortex methodPDifference is not obvious, when solvent medium pH is when between 4.5 ~ 7.4,
lg PIncrease with pH value and increase.
The measurement result of the percutaneous absorption rate constant of table 2, slope is percutaneous rate constant（J）
It can be obtained by table 2, near pH 5.8, the percutaneous absorption rate constant of imiquimod is maximum.
Imiquimod Determination of oil-water partition coefficient and percutaneous rate constant correlation research, are as a result shown in Fig. 3, the present inventor passes through reality
Test research and find that under the solvent mediums of pH 4.5 ~ 7.4, the percutaneous abilities of imiquimod and its Determination of oil-water partition coefficient are closely related,
The percutaneous abilities of medicine can be predicted by determining the Determination of oil-water partition coefficient of medicine.
Embodiment 2：The prescription screening of imiquimod liposome
Using liposome encapsulation as inspection target, from L9(34) factor level orthogonal design progress liposome formulation optimization, system
Standby technique is 40 DEG C of incubation temperature, and the min of incubation time 50, pH gradient difference is 3, investigates phosphatide/cholesterol mass ratio（A）, medicine
Fat ratio (B) and VE consumptions（%）（C）, using film it is scattered-pH gradient method prepares imiquimod liposome, carries out orthogonal test
So that it is determined that the optimum charging ratio of each component, formulation factors water-glass is shown in Table 3.
Table 3：Formulation factors level
Precision weighs a certain amount of imiquimod bulk drug, phospholipid material, cholesterol and vitamin E, adds appropriate chloroform,
Stirring dissolves each composition, obtains clear transparent solutions；Solution is placed in 500 ml eggplant-shape bottles, temperature 50 C, rotating speed 30
r·min-1, depressurize rotary evaporation and go out solvent, phosphatide is formed one layer of uniform film on the wall, add the phosphoric acid that pH is 6.5
Salt buffer is rotated 30 minutes, and aquation is stayed overnight, and is creamy white after suspension, is formed with 1 mol/L NaOH solutions adjustment pH values
PH gradient is poor, is incubated, and ultrasound, obtains imiquimod liposome under ice bath, and obtained liposome is first crossed into 0.8 μm of miillpore filter
Filter, filtrate is repeated 3 times after 0.45 μm of miillpore filter, obtains liposome solutions.Orthogonal test and it the results are shown in Table 4, variance point
Analysis the results are shown in Table 5.
Table 4：Orthogonal test and result
Table 5：The results of analysis of variance
Obtained by table 4 and the experimental result of table 5, when imiquimod prepares liposome, A and B factors have a significant impact to it in prescription,
Understand B>A>C, optimum combination is A3B1C3, i.e. phosphatide:Cholesterol is 5:1, medicine fat ratio is 20:1, VE consumption is 6%.
Embodiment 3：Preparation technology's is preferred
In phosphatide:Cholesterol is 5:1, medicine fat ratio is 20:1, VE consumption be 6% under conditions of, from L9(34) factor level is orthogonal
Design is screened to formulation and technology, and technological factor mainly has incubation temperature (A), incubation time (B), pH gradient poor（C）, factor
Water-glass is shown in Table 6.
Table 6：The quadrature factor level of preparation technology
Table 7：The results of analysis of variance
Table 8：The orthogonal test and result of preparation technology
Obtained by table 7 and the experimental result of table 8, A and B factors have a significant impact to preparation technology tool, the A sorted by sum of square of deviations
>B>C, optimum combination is A2B2C3, i.e., temperature is 50 DEG C, and incubation time is 70 min, and pH gradient difference is 3.
Optimised process is verified：5 repeated authentication experiments have been carried out according to optimizing prescriptions, 5 batches of liposomes are prepared for.
Precision weighs the mg of cholesterol 50, phosphatide（S100 ）200 mg, VE consumption are 6%, the mg of imiquimod 10, add the chloromethanes of 20mL tri-
Alkane, stirring dissolves each composition, obtains clear transparent solutions；Solution is placed in 500 ml eggplant-shape bottles, temperature 50 C, rotating speed 30
Rmin-1, decompression rotary evaporation goes out solvent, phosphatide is formed one layer of uniform film on the wall, adds the phosphorus that pH is 6.5
Phthalate buffer is rotated 30 minutes, and placement makes cholesterol fully be swelled hydration in 2 hours, and pH is adjusted with 1 mol/L NaOH solutions
Value forms pH gradient difference and is incubated ultrasound 30 minutes under 70min, ice bath for 3,50 DEG C, imiquimod liposome is obtained, by what is obtained
Liposome first crosses 0.8 μm of miillpore filter filter, and filtrate is repeated 3 times after 0.45 μm of miillpore filter, obtains liposome solutions.Institute
Imiquimod liposome solutions be creamy white translucent, uniform color, slightly opalescence, good fluidity.As a result system is shown
5 batches of liposomal particle sizes be in normal distribution, the nm of average grain diameter 355, envelop rate (87.86 ± 0.0153) %, its RSD be
0.96% 。
Embodiment 4：The percolation ratio of imiquimod liposome is investigated
Under optimal preparation technology, the imiquimod liposome prepared is respectively placed in 4 DEG C of refrigerators, 25 DEG C of room temperatures and protected
Deposit, and the content of liposome is measured by sampling respectively at 0 d, 30 d, 60 d, and the percolation ratio in storage process is calculated as follows
P.Every group of experiment in triplicate, seeks its average value.Wherein, W1、W2Bag when respectively preparing
Envelope amount and the retention volume after storage certain time.It the results are shown in Table 9.
Table 9：Imiquimod liposome percolation ratio
Embodiment 5：The assay and stability preliminary examinations of imiquimod liposome gel formulation
The preparation of imiquimod liposome gel and ordinary gel preparation：Weigh the g of Acritamer 940 0.3, ethylparaben 0.
002 g, is added in the above-mentioned liposome solutions prepared, after being swelled completely, adds the g of glycerine 0. 1, and grinding is uniform, produces miaow
The not special liposome gel formulation of quinoline.The mg of imiquimod 10 is weighed, adding the cushioning liquid of pH 6.5 makes dissolving, and is settled to 10
mL；The g of carbomer 0.3, the g of ethylparaben 0. 002 are added, after being swelled completely, the g of glycerine 0.1 is added, grinding is uniform, produces
Imiquimod ordinary gel agent.
The assay of imiquimod liposome gel formulation：Precision weighs imiquimod liposome gel formulation and common
Each 0.3 g of gel preparation, is placed in 25 mL volumetric flasks, adds 10 mL methanol solutions, and ultrasonic 5 min after dissolving, distilled water is fixed
Hold to scale.Filtration, precision draws filtrate, in carrying out assay on high performance liquid chromatograph.Measurement result shows that miaow quinoline is not
Special liposome gel formulation content (3.03 ± 0.25) mgg-1(n=3), mean sample recovery rate 96.54% (n=9,
RSD values 4.91%).Stability test RSD values are 3.85%, and reappearance test RSD values are 2.16 %.
Imiquimod liposome gel formulation stability preliminary examinations:
Character：This gel keeps gluey, not dried up in shallow white, uniform, fine and smooth translucent, no stickiness block, normal temperature
Or liquefaction, stretchability can be good.
Viscosity：This gel modest viscosity.
PH values：Take the g of this product 3, plus 10 mL distilled water dilutings, stir, pH values measured value 6.0~7.0 it
Between.
Centrifugal test：Take 3 batches of samples each 5 g, 4500 rmin-130 min are centrifuged, uniformly, no cohesion, lamination
Occur.
Above-mentioned one or more of checking test result shows that imiquimod liposome gel formulation preparation process condition is stable
Reliably.
Embodiment 6:Imiquimod liposome gel formulation Ligustrazine hydrochloride dynamics is investigated
It is prepared by isolated skin:Male mice in kunming (18~22 g) breaks after neck execution, strips skin of abdomen, shaves belly
Mouse hair, rejects unnecessary fat, connective tissue, is cleaned with physiological saline, filter paper is blotted, and skin is paved, and -20 DEG C of refrigerators are protected
Deposit, be finished in one week.
Transdermal absorption is tested：Rat skin in vitro is recovered to room temperature, after normal saline flushing, surface liquid is blotted with filter paper
Body, being placed in Franz diffusion cells, (effectively drug release area is 1.766 cm2, reception tank volume be 15 mL) supply chamber and receiving chamber
Between, cuticula is towards supply chamber.Diffusion cell, the pH value containing 30% ethanol is filled it up with receiving chamber for 6.5 phosphate buffers,
Bubble is drained, reception medium is in close contact with skin.It is (33 ± 0.5) DEG C, magnetic stirring speed 350 to receive medium temperature
r·min-1.Each group is separately added into 0.3 g imiquimods liposome gel formulation and imiquimod gel in supply chamber, respectively
1 mL acceptable solutions are drawn in 1,2,4,6,8,10,12,24 h after experiment from receiving chamber probe tube precision (to supplement simultaneously
Equivalent isothermal acceptable solution), acceptable solution takes 20 μ L filtrates sample introductions to determine after 0.22 μm of filtering with microporous membrane.By peak area band
Enter standard curve and calculate drug concentration, the unit area Percutaneous permeability (Q at each time point is calculated by formula (2)n, µg·cm-2),
Draw Qn- t equations, parallel laboratory test 6 times, average.As a result Fig. 4 is seen.
(2)
Wherein, QnUnit area accumulation in n-th hour passes through dose；CnThe concentration of sampling in n-th hour；A diffusion cells effectively spread
Area.
Embodiment 7：Imiquimod liposome transdermal gel preparation
Formula：The mg of cholesterol 50, egg yolk lecithin（S100 ）200 mg, the mg of vitamin E 16, the mg of imiquimod 10, phosphoric acid
The mL of salt buffer 10 (pH=6.5), the g of Acritamer 940 0.3, the g of ethylparaben 0. 002, the g of glycerine 0. 1.
Preparation method：Precision weighs the mg of cholesterol 50, egg yolk lecithin（S100 ）200 mg, the mg of vitamin E 16, miaow
Not special 10 mg of quinoline, adds 20 mL chloroforms, and stirring dissolves each composition, obtains clear transparent solutions；Solution is placed in 500
In ml eggplant-shape bottles, temperature 50 C, the rmin-1 of rotating speed 30, decompression rotary evaporation goes out solvent, phosphatide is formed one on the wall
The uniform film of layer, adds pH and is rotated 30 minutes for 6.5 phosphate buffer, aquation is stayed overnight, and is creamy white after suspension, with 1
Mol/L NaOH solutions adjust pH values and are incubated 30 minutes to 10,40 DEG C, ultrasonic under ice bath, obtain imiquimod liposome and obtain
Imiquimod liposome, obtained liposome is first crossed 0.8 μm of miillpore filter and filtered, filtrate is after 0.45 μm of miillpore filter, weight
It is multiple 3 times, obtain liposome solutions.The g of Acritamer 940 0.3, the g of ethylparaben 0. 002 are weighed, the lipid prepared is added
In liquid solution, after being swelled completely, the g of glycerine 0. 1 is added, grinding is uniform, packing is applied to and mounted on material, sterilizes, produces miaow quinoline
Not special liposome gel formulation.
Embodiment 8：Imiquimod liposome transdermal gel preparation
Formula：The mg of cholesterol 50, hydrogenated soy phosphatidyl choline（S100 ）200 mg, the g of vitamin E 16, the mg of imiquimod 10,
Phosphate buffer 1 0mL (pH=6.5), the g of Acritamer 940 0.3, the g of ethylparaben 0. 002, the g of glycerine 0. 1.
Preparation method：Precision weighs the mg of cholesterol 50, hydrogenated soy phosphatidyl choline（S100 ）200 mg, vitamin E 16g,
The mg of imiquimod 10, adds 20 mL chloroforms, and stirring dissolves each composition, obtains clear transparent solutions；Solution is placed in
In 500 ml eggplant-shape bottles, temperature 50 C, the rmin of rotating speed 30-1, depressurize rotary evaporation and go out solvent, make phosphatide shape on the wall
Into one layer of uniform film, add pH and rotated 30 minutes for 6 phosphate buffer, aquation is stayed overnight, and is creamy white after suspension, with
1 mol/L NaOH solutions adjust pH values and are incubated 45 minutes to 9,50 DEG C, ultrasonic under ice bath, obtain imiquimod liposome and obtain
Imiquimod liposome, obtained liposome is first crossed 0.8 μm of miillpore filter and filtered, filtrate is after 0.45 μm of miillpore filter, weight
It is multiple 3 times, obtain liposome solutions.The g of Acritamer 940 0.3, the g of ethylparaben 0. 002 are weighed, the lipid prepared is added
In liquid solution, after being swelled completely, the g of glycerine 0. 1 is added, grinding is uniform, packing is applied to and mounted on material, sterilizes, produces miaow quinoline
Not special liposome gel formulation.
The preferred embodiment to the invention is illustrated above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make a variety of equivalent on the premise of without prejudice to the invention spirit
Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.
Claims (10)
1. a kind of be used to suppress the liposome gel formulation of scar proliferation, wherein the liposome gel formulation include liposome,
Gel rubber material and glycerine, it is described it is liposomal encapsulated have an imiquimod bulk drug, and the liposome include phosphatide, cholesterol and
Vitamin E.
2. liposome gel formulation as claimed in claim 1, wherein the phosphatide be by selected from egg yolk lecithin, cephalin,
Lipositol, serinephosphatide, nucleotide phospholipid, soybean lecithin, DSPC, two palmityl phosphatidyl courages
Alkali, DOPC, DPPE, DSPG, hydrogenated soy phosphatidyl choline, ten
What one or more phosphatide in six alkyl phospholipid phatidylcholines were constituted.
3. liposome gel formulation as claimed in claim 1 or 2, it is characterised in that the gel rubber material is selected from poloxamer
188th, the one or more in poloxamer188, carbomer 934 and Carbopol.
4. liposome gel formulation as claimed in claim 1 or 2, wherein the particle diameter of the liposome particle is 100 to 1000
nm。
5. liposome gel formulation as claimed in claim 1 or 2, wherein the cholesterol and phosphatide ratio of weight and number are 1 ~ 3:
2 ~ 6, imiquimod bulk drug and liposome quality parts ratio（Medicine fat ratio）For 1:10 ~ 60, vitamin E consumption accounts for total mass fraction
For 2 ~ 7%.
6. a kind of preparation method of the liposome gel formulation prepared described in claim 1, methods described includes：
(a) imiquimod bulk drug, phospholipid material, cholesterol and vitamin E are provided, chloroform is added, stirring makes each composition
Dissolving, obtains clear transparent solutions；
(b) clear transparent solutions that step (a) is obtained are placed in container, decompression rotary evaporation goes out solvent, makes phosphatide in container
One layer of uniform film is formed on wall, phosphate buffer is added, aquation is stayed overnight, is creamy white after suspension, adjusted with alkaline solution
It is poor that whole pH values form pH gradient, is incubated, and ultrasound, obtains imiquimod liposome under ice bath；
(c) by step（b）Obtained liposome is filtrated to get liposome solutions；
(d) Macromolecule glue material is added in the liposome solutions, after being swelled completely, adds glycerine, grinding is uniform i.e.
.
7. the preparation method of liposome gel formulation as claimed in claim 6, wherein step（b）Described in time for rotating be
15 ~ 45 minutes, the phosphate buffer pH was 6.0-7.0, and the alkaline solution is 1mol/L NaOH, is surpassed under the ice bath
The time of sound is 15 ~ 45 minutes.
8. the preparation method of liposome gel formulation as claimed in claims 6 or 7, wherein the cholesterol and phosphatide parts by weight
Number is than being 1 ~ 3:2 ~ 6, imiquimod bulk drug and liposome quality parts ratio（Medicine fat ratio）For 1:10 ~ 60, vitamin E consumption is accounted for
Total mass fraction is 2 ~ 7%.
9. the preparation method of liposome gel formulation as claimed in claims 6 or 7, wherein pH gradient difference is 1 ~ 5, it is described
The temperature of incubation is 30 ~ 70 DEG C, and the time of the incubation is 20 ~ 100 minutes.
10. purposes of the liposome gel formulation in the medicine for preparing Inhibiting proliferation scar described in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710377078.9A CN107137345A (en) | 2017-05-25 | 2017-05-25 | A kind of liposome gel formulation and its preparation and use for suppressing scar proliferation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710377078.9A CN107137345A (en) | 2017-05-25 | 2017-05-25 | A kind of liposome gel formulation and its preparation and use for suppressing scar proliferation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107137345A true CN107137345A (en) | 2017-09-08 |
Family
ID=59779349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710377078.9A Pending CN107137345A (en) | 2017-05-25 | 2017-05-25 | A kind of liposome gel formulation and its preparation and use for suppressing scar proliferation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107137345A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108635330A (en) * | 2018-04-17 | 2018-10-12 | 胡柳嘉 | A kind of long-acting slow-release progesterone gel agent composition |
| CN111956602A (en) * | 2020-08-31 | 2020-11-20 | 药大制药有限公司 | Preparation method of tranilast liposome cream with scar hyperplasia inhibition effect |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1377648A (en) * | 2002-04-23 | 2002-11-06 | 四川大学 | Imiquimod or its derivative liposome for local skin and its preparing method and use |
| CN1593437A (en) * | 2004-06-29 | 2005-03-16 | 常州太平洋药物研究所有限公司 | Adriacin or adriacin hydrochloride liposome injection and its preparing process |
| WO2005070465A2 (en) * | 2004-01-14 | 2005-08-04 | Gilead Sciences, Inc. | Lipid-based dispersions useful for drug delivery |
| CN102697705A (en) * | 2012-01-18 | 2012-10-03 | 广东药学院 | Liposome gel preparation and preparation method and application thereof |
-
2017
- 2017-05-25 CN CN201710377078.9A patent/CN107137345A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1377648A (en) * | 2002-04-23 | 2002-11-06 | 四川大学 | Imiquimod or its derivative liposome for local skin and its preparing method and use |
| WO2005070465A2 (en) * | 2004-01-14 | 2005-08-04 | Gilead Sciences, Inc. | Lipid-based dispersions useful for drug delivery |
| CN1593437A (en) * | 2004-06-29 | 2005-03-16 | 常州太平洋药物研究所有限公司 | Adriacin or adriacin hydrochloride liposome injection and its preparing process |
| CN102697705A (en) * | 2012-01-18 | 2012-10-03 | 广东药学院 | Liposome gel preparation and preparation method and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| BARNIER-QUER，等: "Adjuvant effect of cationic liposomes for subunit influenza vaccine: influence of antigen loading method, cholesterol and immune modulators.", 《PHARMACEUTICS》 * |
| 孟胜男，等: "《药剂学》", 31 January 2016, 中国医药科技出版社 * |
| 安红，等: "《磷脂化学及应用技术》", 30 June 2006, 中国计量出版社 * |
| 时军，等: "咪喹莫特油水分配系数及其与透皮吸收速率常数的相关性研究", 《广东药学院学报》 * |
| 郑杭生，等: "全缘千里光碱脂质体凝胶剂制备工艺的研究", 《第二届中药现代化新剂型新技术国际学术会议》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108635330A (en) * | 2018-04-17 | 2018-10-12 | 胡柳嘉 | A kind of long-acting slow-release progesterone gel agent composition |
| CN108635330B (en) * | 2018-04-17 | 2021-11-30 | 上海普特生物科技有限公司 | Long-acting sustained-release progesterone gel composition |
| CN111956602A (en) * | 2020-08-31 | 2020-11-20 | 药大制药有限公司 | Preparation method of tranilast liposome cream with scar hyperplasia inhibition effect |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106420610A (en) | Ionic liquid microemulsion and application thereof | |
| Firthouse et al. | Formulation and evaluation of miconazole niosomes | |
| CN102697705B (en) | Liposome gel preparation and preparation method and application thereof | |
| CN103768024B (en) | Ginsenoside Rh2's albumin compound nano-particle and preparation method thereof | |
| CN106361703A (en) | Finasteride nano-liposome, gel and preparation method thereof | |
| CN105708801A (en) | Preparation method and application of 20 (R)-ginsenoside Rg3/soya bean lecithin/cholesterol/folic acid lipidosome medicine | |
| CN101879137B (en) | Method for preparing stealth liposome | |
| CN108578356B (en) | Artemether oral microemulsion in-situ gel and preparation method thereof | |
| CN110025593A (en) | Cell microcapsule, the cell microcapsule for being loaded with anticancer drug, preparation method and application | |
| CN107137345A (en) | A kind of liposome gel formulation and its preparation and use for suppressing scar proliferation | |
| Shailendrakumar et al. | Improved oral pharmacokinetics of pentoxifylline with palm oil and capmul® mcm containing self-nano-emulsifying drug delivery system | |
| CN103690483A (en) | Dl-praeruptorin A microemulsion and preparation method thereof | |
| CN101961426B (en) | Puerh tea extract and extraction method | |
| CN104826118A (en) | Application of lipid-modified substance of chlorogenic acid and derivative thereof | |
| CN109718228A (en) | The antitumor Lymph Node Metastasis of mitoxantrone acts on and its pharmaceutical preparation | |
| Chen et al. | Preparation of triptolide ethosomes | |
| CN100998592B (en) | Microemulsion containing matrine | |
| CN109568297A (en) | A kind of dihydromyricetin solid lipid nano granule and preparation method | |
| CN104983684B (en) | Oleanolic acid multivesicular liposome, preparation method and applications | |
| CN112057425A (en) | Rapamycin preparation and preparation method thereof | |
| CN108743534B (en) | Tripterine or tripterine derivative vesicle and preparation method thereof | |
| CN106265519A (en) | A kind of scutellarin genin Liposomal formulation and preparation method thereof | |
| CN104958257A (en) | Cryptotanshinone skin cutin liposomal preparation and preparing method thereof | |
| Verma et al. | Formulation, development and evaluation of invasomes loaded gel for fungal treatment | |
| Vijeta et al. | Ultra Deformable Nanotransethosomes: A Novel Tool to Intensify Transdermal Drug Delivery a Review |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170908 |