CN104688721A - Anti-rheumatoid arthritis drug gel containing paclitaxel liposome and preparation method of gel - Google Patents
Anti-rheumatoid arthritis drug gel containing paclitaxel liposome and preparation method of gel Download PDFInfo
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Abstract
The invention relates to anti-rheumatoid arthritis drug gel containing paclitaxel liposome and a preparation method of the gel. The gel is prepared from main drugs and blank gel, wherein the main drugs comprise paclitaxel liposome and lidocaine hydrochloride; the mass volume ratio of the paclitaxel liposome to lidocaine hydrochloride is 5:100-20:100; and the mass volume ratio of lidocaine hydrochloride to the blank gel is 1:100-5:100. According to the requirements of evidence-based medicine, a drug paclitaxel for treating RA and lidocaine are compatible with each other, the paclitaxel is coated by utilizing a liposome technology, the bioavailability is improved, and the prepared gel suitable for directed use at an affected part is adopted. The gel achieves a treatment effect aiming at the pathogenesis of RA, and pain of a patient suffering from RA can be rapidly relieved. A novel therapy approach is provided for vast patients suffering from RA.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly relate to a kind of resisting rheumatoid arthritis medicament gelling agent containing Paclitaxel liposome and preparation method thereof.
Background technology
Rheumatoid arthritis (RA) is a kind of pathogenesis and indefinite autoimmune disease, with chronic progressive external destruction of joint for feature, main manifestations is the increment of synovial membrane stave cell height, interstitial massive inflammatory cells infiltrated, and the formation of microvascular new life and pannus.It is characterized in that the multi-joint of brothers' Minor articulus, symmetry, aggressive arthritis, and can internal organs be involved.
For rheumatoid arthritis, not yet have specific medicament at present, existing treatment means can only be symptomatic treatment, to improve the state of an illness, as alleviated the inflammatory reaction in joint, suppresses the function of the development of the state of an illness and maximum Saving cortilage and muscle.Medicine has glucocorticoid, NSAID (non-steroidal anti-inflammatory drug), antirheumatic (DMARDs) and plant amedica.The therapeutic alliance of DMARDs is the Main Means for the treatment of RA at present, such medicine mainly contains methotrexate, ciclosporin, leflunomide, Radix Paeoniae Alba total glucosides etc., wherein methotrexate, cyclophosphamide etc. are the earliest for antineoplastic agent, life-time service toxic and side effects is larger, peptic ulcer, bone marrow depression and lung, liver, kidney equivalent damage can be caused, and affect the treatment of RA, even the toxic and side effects of medicine has become the direct cause of death of patient.Therefore, researching and developing a kind for the treatment of RA medicine of efficient, low toxicity, convenient drug administration, will be the R&D direction of rheumatoid arthritis from now on.Gel, as a kind of Novel external administering mode, is widely used in slow release, controlled release and Pulsed drug delivery system, has good biocompatibility after topical, easily absorb.This has bright advantage for needing the disease of long-term prescription as RA and so on compared with oral formulations; Medicine directly contacts with affected part simultaneously, rapidly through skin and soft tissue, forms high blood drug level rapidly in local, plays drug effect.
Paclitaxel is the compound extracted from yew bark, is a kind of inhibitor of cell mitogen, is mainly used at present treating various cancer.The people such as brahn, kurose in 1994 confirm in CIA rat model, and paclitaxel can lead the apoptosis of synoviocytes of increment phase by selectivity, on normal synovial cell and chondrocyte without impact, significantly can improve the occurring degree of CIA.Therefore, treatment paclitaxel being used for CA is feasible.The report of the animal model of external existing paclitaxel prevention, treatment rheumatoid arthritis.Paclitaxel dissolubility in water very little (1 μ g/mL), ethanol and polyoxyethylene castor oil is adopted to increase the water solublity of paclitaxel as cosolvent clinically, but the latter can produce many untoward reaction, as Cardiovascular Toxicity, anaphylaxis, nephrotoxicity and nervous system toxicity etc., make the clinical practice of paclitaxel be greatly limited.
Liposome is a kind of miniature vesicle drug encapsulation formed in lipoids bilayer, and take phospholipid bilayer as main component, with cholesterol, lecithin is main additives.As a kind of new formulation technology, water soluble drug both can enough be encapsulated in hydrophilic group interlayer by liposome, fat-soluble medicine can be scattered in hydrophobic group interlayer again.Using liposome as taxol drug carrier, significantly can improve the solvent degree of paclitaxel, while increase curative effect of medication, significantly reduce the untoward reaction of medicine.But the less stable of liposome property, easily condenses in storage process, merge and cause the leakage of entrapped drug, long-term preserve more difficult.Medicine is made liposome gel, liposome gel is as liposome on the one hand, skin corium can be reached through horny layer, increase the accumulation of medicine at skin, be conducive to medicine and reach higher drug level in local, improve bioavailability, simultaneously because gel is mainly local absorption, enter blood circulation fewer, significantly can reduce the untoward reaction of medicine.Medicine is made the mobility that gel can also reduce phospholipid bilayer, have suspending effect to liposome and increase the stability of medicine.
Summary of the invention
The object of the present invention is to provide the resisting rheumatoid arthritis medicament gelling agent that a kind of stability is high, dissolubility good, local absorption is good, bioavailability is high.
Another object of the present invention is to provide a kind of preparation method of resisting rheumatoid arthritis medicament gelling agent.
In order to realize foregoing invention object, the present invention adopts following technical scheme:
Containing the resisting rheumatoid arthritis medicament gelling agent of Paclitaxel liposome, comprise principal agent and Blank gel prepares; Described principal agent comprises Paclitaxel liposome and lidocaine hydrochloride, wherein the mass volume ratio of Paclitaxel liposome and Blank gel is 5: 100 ~ 20: 100, and the mass volume ratio of (W/V), hydrochloric acid benefit card and Blank gel is 1: 100 ~ 5: 100 (W/V);
In described Paclitaxel liposome gross weight for 100.00%, described liposome composition: paclitaxel 0.50% ~ 1.50%, phosphatidase 1 5.00% ~ 58.00%, cholesterol 1.00% ~ 8.00%, antioxidant 0.00% ~ 2.50%, proppant 30.00% ~ 70.00%;
In described Blank gel gross weight for 100%, described Blank gel composition: host material 0.50% ~ 5.00%, wetting agent 5.00% ~ 25.00%, transdermal enhancer 0.00% ~ 4.00%, antiseptic 0.01% ~ 1.00%, nertralizer 0.50% ~ 5.00%, remaining as water.
Described Paclitaxel liposome its preparation method comprises the steps: first to be dissolved in chloroform by phospholipid, paclitaxel, cholesterol and antioxidant, be placed in pear shape bottle, 45 DEG C of slow circumvolve reduction vaporizations on Rotary Evaporators, pass into nitrogen removing machine solvent, make lipid membrane shape be uniformly distributed on flask; Frozen-dried supporting agent solution and film are fully mixed aquation 30 minutes, and sonic oscillation, obtains white suspension, carries out circulation shear process, obtain paclitaxel nano lipid liquid solution with high pressure microjet nano-dispersed instrument.Pre-freeze, lyophilization obtains paclitaxel nano lipid soma powder;
Described phospholipid is one or more mixture in soybean lecithin, egg yolk ovum Oletum Trogopterori, hydrogenated soy phosphatidyl choline, PHOSPHATIDYL ETHANOLAMINE, dipalmitoyl phosphatidyl choline, PEG flower phospholipid, distearoyl phosphatidylcholine, DLPC, sphingomyelin, DOPC, phosphatidylinositols, two Semen Myristicae phosphatidylcholines;
Described antioxidant is one or more mixture in vitamin E, vitamin C, propyl gallate, malic acid, ditertbutylparacresol, butylated hydroxyarisol and beta-carotene;
Described proppant is one or more mixture in mannitol, sucrose, trehalose, lactose, maltose, glucose, mannitol, sorbitol;
The described power carrying out the high pressure microjet nano-dispersed instrument of Paclitaxel liposome dispersion is 6-12Kpsi, and pressure is 15K, cycle-index 3 times.
The invention also discloses the preparation method of resisting rheumatoid disease arthritis drug gel, comprise the steps:
Take the gel-type vehicle of recipe quantity, add wetting agent and penetration enhancer, in mortar, grinding is fine and smooth, adds a small amount of distilled water, swellingly spends the night; Take Paclitaxel liposome and lidocaine hydrochloride, use distilled water dissolved dilution, shake up, in mixed-matrix, add antiseptic, dripping nertralizer adjustment pH is 6.0-6.5, and grinding evenly, obtains gel.
Wherein said gel-type vehicle is one or more mixing in Carbopol 941, Acritamer 940, carbomer 934, carbomer U21, carbomer U20, poloxamer F127, poloxamer F68.
Described transdermal enhancer is one or more mixing in laurocapram, dimethyl sulfoxide, decyl methyl sulfoxide, sodium tetradecyl sulfate, propylene glycol, glycerol, Polyethylene Glycol, Oleum menthae, Mentholum, eucalyptus oil, Oleum Terebinthinae, oleic acid, linoleic acid, lauryl alcohol, carbamide, salicylic acid, pyrrolidone, Camphora, citric acid.
Described nertralizer is triethanolamine, sodium carbonate, sodium bicarbonate or sodium hydroxide.
Described antioxidant is sodium sulfite, sodium sulfite or sodium thiosulfate.
Described antiseptic is sorbic acid, hydroxypropyl butyl ester, ethyl hydroxybenzoate, benzoic acid, benzalkonium bromide.
The present invention, according to evidence-based medicine EBM requirement, will treat RA drug taxol and lignocaine compatibility, utilize liposome technology wrap up paclitaxel improve bioavailability, and adopt make be suitable for affected part orientation use gel.Both the pathogeny for RA plays therapeutical effect, can alleviate rapidly again the pain of RA patient.For numerous RA patient provides new therapy approach.
Accompanying drawing explanation
Fig. 1: gel releasing medicine through skin penetration curve;
Fig. 2: two kinds of gel release profiles comparison diagrams.
Detailed description of the invention
Embodiment 1: the preparation of Paclitaxel liposome:
Prescription:
Technique: by paclitaxel 0.15g, soybean lecithin 1.8g, cholesterol 0.8g, vitamin E is dissolved in chloroform in right amount according to a certain percentage, is placed in pear shape bottle, 45 DEG C of slow circumvolve reduction vaporizations on Rotary Evaporators, pass into nitrogen removing machine solvent, lipid membrane shape is uniformly distributed on flask.Sucrose solution 20mL is fully mixed aquation 30 minutes with film, and sonic oscillation, obtains white suspension, carries out shearing process to obtain paclitaxel nano lipid liquid solution for 4 times with the high pressure microjet nano-dispersed instrument that power is 9Kpsi.Pre-freeze 5h, lyophilization.
Embodiment 2: the preparation of Paclitaxel liposome:
Prescription:
Technique: by paclitaxel 0.1g, soybean lecithin 5.7g, cholesterol 0.5g, vitamin E is dissolved in chloroform in right amount according to a certain percentage, is placed in pear shape bottle, 45 DEG C of slow circumvolve reduction vaporizations on Rotary Evaporators, pass into nitrogen removing machine solvent, lipid membrane shape is uniformly distributed on flask.Sucrose solution 20mL is fully mixed aquation 30 minutes with film, and sonic oscillation, obtains white suspension, carries out shearing process to obtain paclitaxel nano lipid liquid solution for 4 times with the high pressure microjet nano-dispersed instrument that power is 9Kpsi.Pre-freeze 5h, lyophilization.
Embodiment 3: the preparation of Paclitaxel liposome:
Prescription:
Technique: by paclitaxel 0.06g, soybean lecithin 4.5g, cholesterol 0.5g, vitamin E is dissolved in chloroform in right amount according to a certain percentage, is placed in pear shape bottle, 45 DEG C of slow circumvolve reduction vaporizations on Rotary Evaporators, pass into nitrogen removing machine solvent, lipid membrane shape is uniformly distributed on flask.Sucrose solution 20mL is fully mixed aquation 30 minutes with film, and sonic oscillation, obtains white suspension, carries out shearing process to obtain paclitaxel nano lipid liquid solution for 4 times with the high pressure microjet nano-dispersed instrument that power is 9Kpsi.Pre-freeze 5h, lyophilization.
Embodiment 4: prepared by low doses of paclitaxel liposome composition gel
Prescription:
Add appropriate purified water to 10mL
Technique: take a certain amount of carbomer 0.30g, adds glycerol 0.5g and laurocapram 0.3g, and in mortar, grinding is fine and smooth, adds a small amount of distilled water, swellingly spends the night.Take Paclitaxel liposome 0.05g and each 0.2g of lidocaine hydrochloride, use distilled water dissolved dilution, shake up, in mixed-matrix, add sorbic acid 0.03g, dripping triethanolamine adjustment pH is 6.0-6.5, and grinding evenly, obtains milk white gel.
Embodiment 5: middle dosage Paclitaxel liposome composition gels agent preparation
Prescription:
Add appropriate purified water to 10mL
Technique: take a certain amount of poloxamer F680.25g, adds ketopyrrolidine 0.80g and azone 0.30g, and in mortar, grinding is fine and smooth, adds a small amount of distilled water, swellingly spends the night.Take Paclitaxel liposome 5.00g and lidocaine hydrochloride 0.20g, use distilled water dissolved dilution, shake up, in mixed-matrix, add benzoic acid 0.10g, dripping sodium carbonate adjustment pH is 6.0-6.5, and grinding evenly, obtains milk white gel.
Embodiment 6: prepared by the agent of high dose Paclitaxel liposome composition gels
Prescription:
Add appropriate purified water to 10mL
Technique: take a certain amount of hydroxypropyl emthylcellulose 0.50g, adds Polyethylene Glycol 2.50g and dimethyl sulfoxide 0.40g, and in mortar, grinding is fine and smooth, adds a small amount of distilled water, swellingly spends the night.Take Paclitaxel liposome 8.00g and lidocaine hydrochloride 0.20g, use distilled water dissolved dilution, shake up, in mixed-matrix, add ethyl hydroxybenzoate 0.05g, dripping sodium bicarbonate adjustment pH is 6.0-6.5, and grinding evenly, obtains milk white gel.
Embodiment: 7: different high pressure microjet nano-dispersed instrument power is on the impact of taxusol-lipid weight
1, the detection of liposome quality
1) mensuration of liposome encapsulation
Precision pipettes liposome turbid liquor 0.1ml, is placed in 1ml volumetric flask.The QULA ketone alcoholic solution 0.2ml adding 2% carries out abundant breakdown of emulsion, is settled to scale with dehydrated alcohol, and HPLC measures, and obtains the total content of liposome solutions Chinese medicine.Another precision pipettes the liposome solutions of 0.1mL in conical centrifuge tube, is diluted to 1.1mL with the phosphate buffer of pH7.4, after being mixed under the rotating speed of 1000r/min centrifugal 10min, precipitate not encapsulated paclitaxel crystalline aggregate as far as possible.Then, the liposome supernatant getting 1.0mL after phosphate buffer dilution under 50000r/min centrifugal 30min.Remove supernatant, wash twice with the phosphate buffer of pH7.4.In the end add the QULA ketone alcoholic solution of 2% in centrifugal gained liposomal pellets, concussion, make the abundant breakdown of emulsion of Paclitaxel liposome, dehydrated alcohol is diluted to scale, and HPLC measures, and determines the amount of liposomal encapsulated paclitaxel, by following formulae discovery envelop rate.
2) form and particles size and distribution measure
Take a morsel Ramulus et folium taxi cuspidatae alcohol ester room plastid suspension, distilled water diluting 20 times under room temperature condition,, with the particle diameter of laser nano particle size analyzer determination Paclitaxel liposome suspension (volume warp) size and particle size distribution (carrying software analysis), to differentiate the quality of Paclitaxel liposome.
2, different high pressure microjet nano-dispersed instrument power is on the impact of taxusol-lipid weight
Take paclitaxel 40mg, lecithin 1.20g, cholesterol 150mg, V
e7.5mg, prepares Paclitaxel liposome 40mL, 0Kpsi, 6Kpsi, 9Kpsi, 12Kpsi, 15K circulated under pressure 3 times, investigates microjet nano-dispersed instrument power to the impact of envelop rate, size and distribution, determines best power.
Table 1 high pressure microjet power single factor exploration
Learnt by table 1, along with the increase of high pressure microjet nano-dispersed instrument power, particle diameter is reduced to 76nm gradually by 203nm, and particle size distribution reduces gradually, is reduced to 0.239 by 0.449, but HPLC records envelop rate reduces gradually.Consider, choosing high pressure microjet nano-dispersed instrument power is 9Kpsi.
Embodiment 8: different high pressure microjet nano-dispersed instrument cycle-index is on the impact of taxusol-lipid weight
Prepare experience and embodiment 7 experimental result according to early stage, fixing high pressure microjet nano-dispersed instrument power is 9Ksi, paclitaxel 60mg, lecithin 1.80g, cholesterol 225mg, V
e11.25mg, prepares Paclitaxel liposome 60mL, and setting high pressure microjet nano-dispersed instrument circulates 0,1,2,3,4,5 time respectively, investigates the impact of different cycle-index on envelop rate, size and distribution, determines optimum cycle number of times.
Table 2 high pressure microjet cycle-index single factor exploration
Learnt by table 2, along with the increase of high pressure microjet nano-dispersed instrument cycle-index, Paclitaxel liposome particle diameter diminishes gradually, 90.3nm is reduced to gradually by 234nm, particle size distribution reduces gradually, is reduced to 0.277 by 0.374, and envelop rate is also along with the rising of cycle-index reduces gradually.Consider, the cycle-index choosing high pressure microjet nano-dispersed instrument is 4 times.
Embodiment 9: different phosphate lipid concentration is on the impact of taxusol-lipid weight
Investigate variable concentrations phospholipid consumption to the impact of Paclitaxel liposome.Experience and experimental result is prepared according to early stage, fixing high pressure microjet nano-dispersed instrument power is 9Ksi, and the cycle-index of high pressure microjet nano-dispersed instrument is 4 times, and setting phospholipid concentration is respectively 1%, 2%, 3%, 4%, 5%, paclitaxel and phospholipid ratio are 1: 30, cholesterol and phospholipid ratio are 1: 8, VE consumption be 0.6%, Vc of lecithin consumption is 0.125%.According to the impact of variable concentrations phospholipid on liposome encapsulation, particle diameter and particle size distribution, determine best phospholipid consumption.
The single factor exploration of table 3 phospholipid consumption
Learnt by table 3, along with phospholipid concentration increases, Paclitaxel liposome particle diameter becomes large gradually, be increased to 135nm gradually by 89.4nm, particle size distribution also in trend gradually, is reduced to 0.248 by 0.358, envelop rate also becomes large along with the rising of phospholipid concentration, is increased to 62.8% by 58.1%.Consider, phospholipid concentration is 3% is best.
Embodiment 10: the impact of different medicine fat comparison taxusol-lipid weight
The impact that the mass ratio investigating drug level and phospholipid is prepared Paclitaxel liposome.According to previous experiments result, fixing high pressure microjet nano-dispersed instrument power is 9Ksi, and the cycle-index of high pressure microjet nano-dispersed instrument is 4 times, and lecithin concentration is 3%, and cholesterol and phospholipid ratio are 1: 8, V
econsumption is 0.6%, Vc of lecithin consumption is 0.125%.Setting paclitaxel and phospholipid are respectively than being 1: 10,1: 20, and 1: 30,1: 40,1: 50, according to the impact of variable concentrations paclitaxel on liposome encapsulation, particle diameter and particle size distribution, determine optimum medicine concentration.
The single factor exploration of table 4 medicine fat ratio
Learnt by table 4, along with phospholipid and taxol drug are with it than increasing gradually, Paclitaxel liposome particle diameter first reduces rear increase, and when phospholipid is 20: 1 with the ratio of taxol drug, particle diameter is minimum, when phospholipid is 30: 1 with the ratio of taxol drug, envelop rate is maximum, is 70.9%, except 10: 1 groups of envelop rates are lower, other are organized relatively, between 67% to 69%.Comprehensive analysis, phospholipid and taxol drug with it than for being optimum at 30: 1.
Embodiment 11: various biliary sterin consumption is on the impact of taxusol-lipid weight
The impact that investigation drug level and phospholipid consumption are prepared Paclitaxel liposome.According to previous experiments result, fixing high pressure microjet nano-dispersed instrument power is 9Ksi, and the cycle-index of high pressure microjet nano-dispersed instrument is 4 times, and lecithin concentration is 3%, V
econsumption is 0.6%, Vc of lecithin consumption is 0.125%.Setting lecithin and the ratio of cholesterol be respectively 16: 1,10: 1,8: 1,6: 1, every batch prepare 35 milliliters, according to the cholesterol of different proportion on the impact of liposome encapsulation, particle diameter and particle size distribution, determine the ratio of best phospholipid and cholesterol.
The single factor exploration of table 5 cholesterol consumption
Learnt by table 5, along with the reduction of phospholipid and cholesterol ratio, Paclitaxel liposome particle diameter first reduces rear increase, when lecithin is 8: 1 with the ratio of cholesterol, particle diameter is minimum, is 89.2nm, along with the reduction of phospholipid and cholesterol ratio, the envelop rate of drug taxol reduces gradually, when phospholipid is 16: 1 with the ratio of cholesterol, envelop rate is maximum, is 80.8%, comprehensive analysis, lecithin and cholesterol with it than for being optimum at 10: 1.
Embodiment 12: different vitamin E consumption is on the impact of taxusol-lipid weight
Investigate various concentrations of vitamin E consumption to the impact of Paclitaxel liposome.According to forward part experimental result, fixing high pressure microjet nano-dispersed instrument power is 9Ksi, the cycle-index of high pressure microjet nano-dispersed instrument is 4 times, lecithin concentration is 3%, paclitaxel and phospholipid ratio are 1: 30, cholesterol and phospholipid ratio are 1: 10, Vc is 0.125%, and phosphate buffer pH value is 6.5.Setting V
eit is 0%, 0.3%, 0.6%, 1.2%, 2.4% of lecithin consumption that consumption is respectively.According to the vitamin E consumption of variable concentrations on the impact of liposome encapsulation, particle diameter and particle size distribution, determine best vitamin E consumption.
The single factor exploration of table 6 vitamin E consumption
Learnt by table 6, along with the rising of Vitamin E levels, Paclitaxel liposome particle diameter, particle size distribution also has envelop rate to there is no evident regularity.Consider that vitamin E is main in liposome turbid liquor and play antioxidation, may be relevant with the stability of liposome, therefore the content of vitamin E has no significant effect Paclitaxel liposome particle diameter and envelop rate.Experimentally result, when vitamin E and lecithin mass ratio are 0.6%, envelop rate is the highest.Comprehensive analysis, V
econsumption is 0.6% of lecithin consumption is the best.
Embodiment 13: different frozen-dried supporting agent is on the impact of Paclitaxel liposome envelop rate
Investigate different frozen-dried supporting agent proportioning to the impact of Paclitaxel liposome.According to forward part experimental result, fixing high pressure microjet nano-dispersed instrument power is 9Ksi, and the cycle-index of high pressure microjet nano-dispersed instrument is 4 times, and lecithin concentration is 2%, and paclitaxel and phospholipid ratio are 1: 30, and cholesterol and phospholipid ratio are 1: 10, V
econsumption is 0.6% of lecithin consumption.Set three groups of frozen-dried supporting agents and be respectively mannitol (sugar ester ratio is 1.5), sucrose (sugar ester ratio is 2.5), mannitol trehalose combination (sugar ester ratio is 1.5 and 1.0).Prepare pre-freeze and drying process after liposome turbid liquor identical, after redissolution, according to different frozen-dried supporting agent kind on the impact of liposome encapsulation, particle diameter and particle size distribution, determine best frozen-dried supporting agent kind.
The single factor exploration of table 7 frozen-dried supporting agent kind
Learnt by table 7, liposome turbid liquor lyophilizing redissolve after its envelop rate generally drop to about 60%, several lyophilized preparation there was no significant difference.But its particle diameter and particle size distribution change greatly before and after lyophilizing; obviously there are two groups of broad peaks when measuring particle diameter; one group of mean diameter is at below 100nm; one group between 1000 ~ 2000; the following proportion of 100nm particle diameter has difference, and this may be relevant from the frozen-dried protective mechanism of different lyophilized formulations, and experimental result is all not ideal; comprehensive analysis, choosing sucrose is best freeze drying protectant.
Embodiment 14: the selection of different gel-type vehicle
1, carbomer is substrate
Take 0.1g carbomer and be spread across 0.5g glycerol surface, add distilled water 5mL after fully moistening to dissolve, swellingly to spend the night, drip distilled water to 10g, stir evenly, dripping triethylamine adjustment pH is 6.0 ~ 6.5, observes the form of gel, preparation gel uniform and smooth, transparent, bubble is few, moderate viscosity, stretchability is good.
2, gelatin is substrate
Taking 0.1g gelatin, to add distilled water 5mL fully swelling, slowly stirs, and add 0.5g glycerol and appropriate distilled water to 10g, stir evenly, dripping triethylamine adjustment pH is 6.0 ~ 6.5, and the gel formed after stirring is transparent, micro-yellow.Mobility is less, evenly not easy to apply.
3, polyvinyl alcohol is substrate
Take sodium carboxymethyl cellulose 0.1g, be scattered in distilled water 10mL surface, after fully swelling, bath is heated to 80 DEG C and makes it dissolve completely, adds 0.5g glycerol and appropriate distilled water to 10g.Ambient temperatare is cold, slowly stirs and drip triethylamine adjustment pH to be 6.0 ~ 6.5 and to get final product, and observes the form of gel.The gel viscosity formed is moderate, but mobility is comparatively large, is not suitable for joint and smears.
4, hydroxypropyl emthylcellulose is substrate
Take hydroxypropyl emthylcellulose 0.1g, be scattered in 80 DEG C of 10mL distilled water, be cooled to room temperature gradually, add 0.5g glycerol and slowly stir, hold over night.The gel colorless and odorless obtained, even, transparent, fine and smooth, but the viscosity of gel is not high, is not suitable for joint and smears.
Carbomer is defined as according to above experimental result determination optimum substrate.
Embodiment 15: Paclitaxel liposome composition gels percutaneous penetration investigates optimum prescription
Determine that lipidosome gel substrate is carbomer according to embodiment 9.Adopt orthogonal test to be optimized gel prescription on this basis, carbomer is divided into 1%, 3%, 5% 3 level, and glycerol is divided into 5%, 15%, 25% 3 level, and transdermal penetration agent is respectively 3% Oleum menthae, 3% azone, eucalyptus oil.After making gel, with 48h Percutaneous permeability Q (μ gcm
-2) be inspection target, determine best prescription technique, each factor level is in table 8.
Table 8 orthogonal experiment factor level table
1, the preparation of isolated skin
Get Kunming mouse (SPF), with Veet depilatory cream removing back wool, wash, after 24 hours, disconnected neck is put to death, and peels off skin of back immediately, removes fat and subcutaneous tissue, cleans ,-20 DEG C of Refrigerator stores with normal saline.
2, percutaneous penetration
From refrigerator, take out the mouse carotid butt that will handle well, be put in 37 DEG C of normal saline and thaw.Corium Mus is cut into suitable size (circle of radius 1cm).The Corium Mus sheared is fixed on Franz diffusion cell place, stratum corneum side is to supply pool.Add gel in supply pool, reception tank is all full of receiving liquid (normal saline), and ensures that receiving liquid fully contacts with the large Corium Mus handled well, bubble-free.Arranging bath temperature is 37 DEG C, and magnetic agitation is 300r/min, in 1,2,4,6,8,10,24,48h to take out in receiving chamber all receiving liquids, adds isopyknic blank absorbing liquid simultaneously.HPLC measures the peak area of paclitaxel, calculates accumulative transit dose Q (μ gcm
-2).
Table 9 Orthogonal experiment results
Orthogonal experiment results shows that No. 5 results are best, and under this experiment condition, Percutaneous permeability Q can reach 490.51 μ gcm
-2.From extreme difference angle analysis, wetting agent influence factor is maximum, and be secondly promoter, minimum is substrate, and extreme difference angle analysis optimum combination is A
2b
1c
3, i.e. carbomer 3%, glycerol 5%, transdermal penetration agent 3% azone.Verify with this understanding, in triplicate, Percutaneous permeability Q is respectively 445.26 μ gcm
-2, 451.18 μ gcm
-2, 455.12 μ gcm
-2.Each time point t that samples averages (as table 10), carries out matching with Origin software, and obtain gel releasing medicine through skin penetration curve as Fig. 1, penetration kinetics meets first _ order kinetics equation, i.e. Paclitaxel liposome gel:
ln(1-Q/484.31819)＝0.06114t R
2＝0.9925
Table 10 optimised process composition gels agent transdermal release degree
Embodiment 16: the agent of Paclitaxel liposome composition gels and paclitaxel gel releasing medicine through skin penetration contrast
1, the preparation of paclitaxel gel
Take a certain amount of carbomer 3.0g, add glycerol 5.0g and laurocapram 3.0g, in mortar, grinding is fine and smooth, adds a small amount of distilled water, swellingly spends the night.Take paclitaxel 10g and lidocaine hydrochloride 2.0g, with distilled water dissolved dilution 100mL, shake up, in mixed-matrix, add sorbic acid 0.3g, dripping triethylamine adjustment pH is 6.0-6.5, and grinding evenly, obtains milk white gel.
2, percutaneous penetration carries out the releasing medicine through skin penetration test of two kinds of gels with reference to embodiment 15 method, and makes transdermal release curve with the accumulative transit dose meansigma methods that sample time, t surveyed and contrast.Paclitaxel gel Percutaneous permeability after 10h reaches stable state substantially, and the sustained release and composition gels agent paclitaxel after 10h remains unchanged, penetration kinetics meets first _ order kinetics equation.Show that composition gels agent paclitaxel transdermal release degree is obviously better than paclitaxel gel.As table 11, Fig. 2.
Table 11 two kinds of gel transdermal release degree
Embodiment 17: the agent of Paclitaxel liposome composition gels is to arthritic experimental therapy effect
3.1 gel on Carrageenan cause the impact of rat foot claw swelling
Get SD rat 30, ♂, body weight 180 ~ 220g, be divided into 3 groups at random, often organize 10.1st group is animal pattern matched group, and the 2nd group is compositions lipidosome gel group (2.5mg/kg), and the 3rd group is Paclitaxel liposome gel group (2.5mg/kg).Take be coated with administration method, every day is administered once, successive administration three days.After administration, 1h is stretching by rat hindlimb, partly sterilised, and toes aponeurosis (aponeuroses) subcutaneous injection 1% carrageenin 0.1ml causes inflammation, respectively at cause scorching before and cause scorching after 1h, 2h, 3h, 4h, 5h slide gauge survey rat model foot pawl swelling thickness.Show in table 12, administration group is the swelling of energy significance inhibition rat foot claw all, and wherein during 3h, compositions group, compared with matched group, all has significant difference (P < 0.05); During 4h, Paclitaxel liposome is compared with matched group, has significant difference (P < 0.05).Paclitaxel liposome gel group also present certain inhibitory action to the swelling of rat model foot pawl, but acts on not remarkable after 5h.So composition gels is faster than the Paclitaxel liposome gelatification time, and action effective is longer, suppresses sufficient pawl swelling effect more strong.
Table 12 carrageenin causes rat foot claw swelling experimental result
Note: compare with matched group,
☆p < 0.05
3.2 composition gels survey the inhibitory action of pain test to formaldehyde in mice
Get ICR mice 30, ♂, be divided into 3 groups at random, often organize 10.1st group is animal pattern matched group, and the 2nd group is composition gels group (2.5mg/kg), and the 3rd group is paclitaxel gel group (2.5mg/kg).Every day is administered once, successive administration three days, and after administration, 1h is at side, mice labelling pawl vola subcutaneous injection 5% formalin 50 μ L, is put in glass box immediately by mice, and respectively with stopwatch record mice 10-30min, in 30-60min, two phases lick sufficient number of times.Table 13 experimental result shows, administration group compares with matched group, all have significance analgesic effect (P < 0.05), compositions group comparatively paclitaxel group licks sufficient number of times less, has significant difference (P < 0.05).
Table 13 formaldehyde in mice surveys pain result of the test
Note: compare with matched group,
☆p < 0.05.Contrast with Paclitaxel liposome,
◆p < 0.05.
Claims (7)
1., containing the resisting rheumatoid arthritis medicament gelling agent of Paclitaxel liposome, it is characterized in that comprising principal agent and Blank gel prepares; Described principal agent comprises Paclitaxel liposome and lidocaine hydrochloride, wherein the mass volume ratio of Paclitaxel liposome and Blank gel is 5: 100 ~ 20: 100, and the mass volume ratio of (W/V), hydrochloric acid benefit card and Blank gel is 1: 100 ~ 5: 100 (W/V);
In described Paclitaxel liposome gross weight for 100.00%, described liposome composition: paclitaxel 0.50% ~ 1.50%, phosphatidase 1 5.00% ~ 58.00%, cholesterol 1.00% ~ 8.00%, antioxidant 0.00% ~ 2.50%, proppant 30.00% ~ 70.00%;
In described Blank gel gross weight for 100%, described Blank gel composition: host material 0.50% ~ 5.00%, wetting agent 5.00% ~ 25.00%, transdermal enhancer 0.00% ~ 4.00%, antiseptic 0.01% ~ 1.00%, nertralizer 0.50% ~ 5.00%, remaining as water.
2. resisting rheumatoid disease arthritis drug gel according to claim 1, it is characterized in that described Paclitaxel liposome its preparation method comprises the steps: first to be dissolved in chloroform by phospholipid, paclitaxel, cholesterol and antioxidant, be placed in pear shape bottle, 45 DEG C of slow circumvolve reduction vaporizations on Rotary Evaporators, pass into nitrogen removing machine solvent, make lipid membrane shape be uniformly distributed on flask; Frozen-dried supporting agent solution and film are fully mixed aquation 30 minutes, and sonic oscillation, obtains white suspension, carries out circulation shear process, obtain paclitaxel nano lipid liquid solution with high pressure microjet nano-dispersed instrument.Pre-freeze, lyophilization obtains paclitaxel nano lipid soma powder;
Described phospholipid is one or more mixture in soybean lecithin, egg yolk ovum Oletum Trogopterori, hydrogenated soy phosphatidyl choline, PHOSPHATIDYL ETHANOLAMINE, dipalmitoyl phosphatidyl choline, PEG flower phospholipid, distearoyl phosphatidylcholine, DLPC, sphingomyelin, DOPC, phosphatidylinositols, two Semen Myristicae phosphatidylcholines;
Described antioxidant is one or more mixture in vitamin E, vitamin C, propyl gallate, malic acid, ditertbutylparacresol, butylated hydroxyarisol and beta-carotene;
Described proppant is one or more mixture in mannitol, sucrose, trehalose, lactose, maltose, glucose, mannitol, sorbitol;
The described power carrying out the high pressure microjet nano-dispersed instrument of Paclitaxel liposome dispersion is 6-12Kpsi, and pressure is 15K, cycle-index 3 times.
3. resisting rheumatoid disease arthritis drug gel according to claim 1, is characterized in that described host material is one or more mixing in Carbopol 941, Acritamer 940, carbomer 934, carbomer U21, carbomer U20, poloxamer F127, poloxamer F68.
4. resisting rheumatoid disease arthritis drug gel according to claim 1, is characterized in that described transdermal enhancer is one or more mixing in laurocapram, dimethyl sulfoxide, decyl methyl sulfoxide, sodium tetradecyl sulfate, propylene glycol, glycerol, Polyethylene Glycol, Oleum menthae, Mentholum, eucalyptus oil, Oleum Terebinthinae, oleic acid, linoleic acid, lauryl alcohol, carbamide, salicylic acid, pyrrolidone, Camphora, citric acid.
5. resisting rheumatoid disease arthritis drug gel according to claim 1, is characterized in that described nertralizer is triethanolamine, sodium carbonate, sodium bicarbonate or sodium hydroxide.
6. resisting rheumatoid disease arthritis drug gel according to claim 1, is characterized in that described antioxidant is sodium sulfite, sodium sulfite or sodium thiosulfate.
7. the preparation method of resisting rheumatoid disease arthritis drug gel according to claims 1 to 6, is characterized in that comprising the steps:
Take the gel-type vehicle of recipe quantity, add wetting agent and penetration enhancer, in mortar, grinding is fine and smooth, adds a small amount of distilled water, swellingly spends the night; Take Paclitaxel liposome and lidocaine hydrochloride, use distilled water dissolved dilution, shake up, in mixed-matrix, add antiseptic, dripping nertralizer adjustment pH is 6.0-6.5, and grinding evenly, obtains gel.
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