Lipid gel pharmaceutical preparation in situ and its production and use
Technical field
The present invention relates to lipid gel pharmaceutical preparation in situ and its production and use.
Background technology
Situ-gel is gel in place, is that after one kind is administered with solution state, phase in version can occur immediately in agents area,
The preparation for forming non-chemical crosslinking semi-solid gel is converted by liquid.Breast that is homogeneous, being suspended can be made with gel rubber material in medicine
Glue glop or semisolid gel.Gel has good histocompatbility, is grown in the medicine-feeding part holdup time;Together
When can play storage medicine, prevent medicine it is affected by environment wait effect.
According to the difference of Forming Mechanism, situ-gel can be divided into responsive to temperature type, pH responsive types and ion-sensitive
Type etc..In-situ gel is widely used in the novel medicine feeding such as slow-release controlled-release and pulse release system as a kind of new pharmaceutical dosage form
System, situ-gel can be applied to the administration of the number of ways such as skin, eye, nasal cavity, oral cavity, vagina, rectum.
Local anesthetic, it is a kind of medicine that can occur and transmit in the blocking sensory nerve impulsion of medication local reversible
Product, referred to as " local anaesthetics ".In the case where keeping Consciousness, reversible causes local organization analgesis.In general, local anaesthesia
The effect of medicine is confined to medicine-feeding part and spreads and rapidly disappear from medicine-feeding part with medicine.
The local anaesthetics applied earliest is the alkaloid cocaine proposed from South America coca leaf(cocaine), but by
Toxicity is big after absorption, using being restricted.Chemical constitution feature according to cocaine in 1904, artificial synthesized hypotoxicity
Procaine(procaine)Afterwards, use range constantly expands.The lidocaine of nineteen forty-three synthesis(lidocaine)It is then acid amides
The typical case of class local anaesthetics.According to chemical structural type, local anesthetic can be divided into:Paraaminobenzoic acid esters(Procaine,
Benzocainum), amide-type(Lidocaine, Bupivacaine, levobupivacaine, Ropivacaine, mepivacaine, Etidocaine,
Prilocaine etc.), amino ethers and aminoketones(Dyclonine)Deng.
In general, the concentration of local anaesthetics and medicine-feeding part determine the property and scope of nerve block.But such medicine
Vivo biodistribution half-life short, its expansion peripheral vascular effect in addition so that the once daily local anaesthesia duration is short.Mesh
Before, need low dose of frequent drug administration to maintain effective treatment concentration when carrying out clinical local anaesthesia.When dosage is larger, effectively treat dense
The length of holding time of degree, but maximum plasma concentration CmaxBeyond therapeutic window, cause side reaction.
Durative action preparation is developed, effective treatment concentration of medicine can be maintained in a long time, substantially reduces the hair of side effect
It is raw, make patient from the pain of multiple dosing, so as to reduce cost.
The in-situ gel injection agent of Bupivacaine is Hospira companies and DURECT company agreements with the SABER skills of the latter
The preparation of art exploitation.Trade name is drafted as POSIDURTM, is in III phase clinical investigation phase at present.Pharmaceutical adjunct is mainly
Biodegradable sucrose acetate isobutyrate, and organic solvent pyrrolidones.The Bupivacaine of the formula containing free alkali is 660mg/
5ml.Before injection, preparation is regular solution state.After the operative site injection before sewing up a wound, viscosity is contacted with local humor
Increase forms gel, is slowly discharged in local organization, plays the local anaesthesia effect for being for up to 72h, but used sucrose acetate different
Butyrate and pyrrolidinone compounds organic solvent, security have certain risk.
Patent application CN200580025364.4 discloses a kind of non-liposomal composition of injectable, public in embodiment 6
It is 30% (W/W) to have opened hydrogenated soya phosphatide dosage, and propane diols and ethyl oleate dosage are 25% (W/W), bupivacaine HCl
Drugloading rate only have 2% (W/W), and be the paste of not clear, injections difficult.
A kind of phospholipid gel in situ is disclosed in patent application CN 93119112.2, solvent used is essentially insoluble
That in the pharmaceutically acceptable organic solvent of water, embodiment is MCT, and the product should be breast before being injected into vivo
Agent, strong external force is needed during preparation to act on, and uniformity is easily poor, and the control of product is difficult.
HE Warriner et al. are in Science, 16February1996:Reported in Vol.271no.5251pp.969-973
Road adds PEG-DMPE gel, and system viscosity increases with the increase of water content, but it is common simply to have studied blank
Gel, it is not directed to and carries medicine situ-gel.
A kind of lipid gel of injectable is disclosed in patent application CN201110036587.8, uses 20% to 40% phosphorus
Fat forms vesicle type gel(VPG), organic solvent is not contained in the patent formula, is a kind of semisolid gelinite before injection
System, there is the difference of essence with the technical scheme of this patent.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of phospholipid gel pharmaceutical preparation in situ, and said preparation is easy to
Injection, maximum drugloading rate is high, has preferable slow release effect.
Another technical problem to be solved by this invention is to provide a kind of phospholipid gel pharmaceutical preparation in situ, said preparation
It is the solution of homogeneous clarification before injection, good evenness, Quality Control is easy.
A technical problem to be solved by this invention is to provide a kind of preparation side of phospholipid gel pharmaceutical preparation in situ
Method, this method is simple, quick, and can be used for industrialized production.
Another technical problem to be solved by this invention is that providing a kind of in-situ gel preparation is preparing sustained release load medicine
Application in system.
In order to solve the above technical problems, the invention provides a kind of lipid gel pharmaceutical preparation in situ, the lipid in situ
Gel medicine preparation includes phosphatide, the active material and solvent of therapeutically effective amount, contains organic solvent in the solvent.
In order to obtain the technique effect that the present invention is pursued, the mobility of the organic solvent selected by the present invention will be similar to
Water, it is high to the solubility of phosphatide, there is certain dissolubility to active material.
The present invention a preferred scheme, organic solvent be absolute ethyl alcohol, phenmethylol, the tert-butyl alcohol, one kind in glycerine or
It is a variety of, particularly preferably absolute ethyl alcohol.
Phosphatide dosage in situ-gel is relatively large, in order to guarantee to be formed clarification, homogeneous, transparent solution, institute
The phosphatide of selection should be the relatively low phosphatide of phase transition temperature.
Phosphatide of the present invention refers to natural or synthetic phosphatide, preferably one in soybean lecithin, egg yolk lecithin
Kind is several, more preferably soybean lecithin.
Compared with egg yolk lecithin, soybean lecithin stability itself is more preferable, and relevant material is lower, and it is advantageous to soybean phosphorus
Fat, but the state of gel is similar.
In the preferred scheme of the present invention, described active material is water soluble drug.
In another preferred scheme of the present invention, described active material is local anesthetic, preferably amide-type office
Portion's arcotic, the amide-type local anesthetic can be lidocaine, Bupivacaine, levobupivacaine, Ropivacaine,
Mepivacaine, Etidocaine, prilocaine etc., preferably Bupivacaine, levobupivacaine, Ropivacaine, lidocaine
Or its pharmaceutically useful salt, particularly preferably Bupivacaine, levobupivacaine or its pharmaceutically useful salt.
Consider active material solubility in organic solvent and the dosage used, Bupivacaine is especially left-handed
The water soluble salt of Bupivacaine has obvious superiority.
Surprisingly, it has been found that addition of the Bupivacaine as active material, it is steady can to play stable gel formulation storage
Qualitatively act on.
In the preferred scheme of the present invention, water is contained in solvent, contained water can be provided by diversified forms, can be used
Water for injection, the aqueous medium of physiological can also be used, such as sodium-chloride water solution, D/W or phosphate buffer
Deng.
The addition of a small amount of water in solvent, it is possible to increase the solubility of active material, particularly amide-type local anesthetic, enter
And improve the drugloading rate of preparation.
Water can adjust the viscosity of preparation, and in certain scope, with increasing for dampening addition, the viscosity of preparation is gradual
Reduce, the addition of a certain amount of water, the relatively low viscosity of preparation can be ensured so that more convenient when preparation is applied, patient compliance
More preferably, and water can regulate and control release behavior, so in the preparation can be according to required viscosity, drugloading rate and release behavior
To determine the addition of water.
In another preferred scheme of the present invention, the water of the aqueous medium of water or physiological in described solvent accounts for phosphorus
The ratio of the quality sum of fat and organic solvent is 0%~80%.Set in preparation the quality sum of phosphatide and organic solvent as
M, then the quality of the water of the aqueous medium of the water in solvent or physiological and M ratio are 0%~80%;Also can be preferably progressively
0%~60%, 0%~40%, 0%~30%, 0%~15%, 10%~15%.
Add with the unmixing solvent of water, the complexity that can become preparation process, and preparation homogeneity is caused negative
Influence, and the dissolubility of active material may be reduced, although above-mentioned many ask can be caused with the unmixing solvent of water by adding
Topic, but the addition of the solvent unmixing with water has no effect on the solution of technical problem of the present invention on a small quantity, so this hair
The bright addition do not repelled with the unmixing solvent of water.
The phosphatide addition of the present invention is not particularly limited, will according to the viscosity before phospholipid species, cost consideration, injection
Ask, be sustained depending on the release behavior of cycle and needs, it is however generally that, phosphatide dosage is higher, and the viscosity before injection is bigger, release
Cycle is longer.
According to selected phospholipid species, dosage and it is expected that release behavior, to select proper amount of organic solvent, with protect
Card keeps clarification, transparent solution state before the injection.
In the preferred scheme of the present invention, phosphatide and organic solvent described in the lipid gel pharmaceutical preparation in situ
Ratio be 1:7 to 5:1W/W, preferably 1:7 to 2:1W/W, more preferably 1:7 to 1:2 or 1:2 to 2:1 or 1:1.5 to 1:1.
The maximum drugloading rate of lipid gel preparation depends primarily on dissolubility of the active material in gel-type vehicle, active matter
Dissolubility of the matter in gel-type vehicle is higher, and the maximum drugloading rate of lipid gel preparation is higher.If active material is in gel base
Solubility in matter is too low, it may be difficult to reaches the drugloading rate required for sustained release, or the administration of the lipid gel preparation needed
Measure excessive, it is difficult to reach the effect of clinical practice.
The concentration of lipid gel preparation of traditional Chinese medicine active material depends primarily on the drug concentration for playing physiological activity,
The amount of application of the slow-release time of design, internal release behavior and body lipid gel preparation, those skilled in the art can
Relatively easily to determine as needed.
In another preferred scheme of the present invention, with described in total formulation weight gauge in the lipid gel pharmaceutical preparation in situ
The content of active material is 1% to 15%W/W, preferably 1% to 10%W/W, more preferably 4%-10%W/W, most preferably 5%-10%W/
W。
In another preferred scheme of the present invention, cholesterol is not contained in the lipid gel pharmaceutical preparation in situ.
In another preferred scheme of the present invention, do not contained in the lipid gel pharmaceutical preparation in situ in addition to phosphatide
Other Macromolecule glue materials.Other Macromolecule glue materials of the present invention refer to PLA, PLGA or PGA etc..
Another preferred scheme of the present invention, grease is not contained in the lipid gel pharmaceutical preparation in situ.Institute of the present invention
The grease stated refers to soybean oil, safflower oil, cottonseed oil or midchain oil etc..
The preferred scheme of the present invention, the preparation also phosphatide containing PEGylation, the phosphatide of PEGylation is preferably PEGylation
Synthetic phospholipid, more preferably PEGylation phosphatidyl-ethanolamine, particularly preferably DMPE-PEG or DSPE-PEG, be most preferably
DSPE-PEG。
Only DSPE-PEG is more ripe commercially produced product at present, its species mainly include DSPE-PEG2000 and
DSPE-PEG5000, the embodiment of the present invention has used phosphatide of the DSPE-PEG as PEGylation, mainly in view of commercialized side
Just and Cost Problems, the technical problem of the present invention can not be solved by being not intended that the phosphatide of the technically PEGylation of other species.
The addition of a small amount of PEGylation phosphatide, it is unexpected the problem of can improving incomplete release.
Lipid gel pharmaceutical preparation in situ to make this bright reaches more preferably effect, preferably embodiments below:
(1)In the preferred scheme of the present invention, the lipid gel pharmaceutical preparation in situ contains phosphatide, therapeutically effective amount
Active material and organic solvent, using the content of active material described in total formulation weight gauge as 1%-10%W/W, phosphatide and organic molten
The ratio of agent is 1:7 to 1:The water of the aqueous medium of 2W/W, water or physiological accounts for the quality sum weight of phosphatide and organic solvent
Amount is than being 0%~80%;
(2)In another preferred scheme of the present invention, the lipid gel pharmaceutical preparation in situ contains phosphatide, treatment has
The active material and organic solvent of effect amount, using the content of active material described in total formulation weight gauge as 1%-10%W/W, phosphatide and have
The ratio of solvent is 1:2 to 1:The water of the aqueous medium of 1.5W/W, water or physiological accounts for the quality of phosphatide and organic solvent
Sum weight ratio is 0%~80%, preferably 0%~60%;
(3)In another preferred scheme of the present invention, the lipid gel pharmaceutical preparation in situ contains phosphatide, treatment effectively
The active material and organic solvent of amount, using the content of active material described in total formulation weight gauge as 1%-10%W/W, phosphatide and organic
The ratio of solvent is 1:1.5 to 1:The water of the aqueous medium of 1W/W, water or physiological account for phosphatide and organic solvent quality it
It is 0%~60%, preferably 0%~40% with weight ratio;
(4)In another preferred scheme of the present invention, the lipid gel pharmaceutical preparation in situ contains phosphatide, treatment effectively
The active material and organic solvent of amount, using the content of active material described in total formulation weight gauge as 1%-10%W/W, phosphatide and organic
The ratio of solvent is 1:1 to 2:The water of the aqueous medium of 1W/W, water or physiological accounts for the quality sum of phosphatide and organic solvent
Weight ratio is 0%~40%, preferably 0%~30%;
(5)In another preferred scheme of the present invention, the lipid gel pharmaceutical preparation in situ contains phosphatide, treatment effectively
The active material and organic solvent of amount, using the content of active material described in total formulation weight gauge as 1%-10%W/W, phosphatide and organic
The ratio of solvent is 2:1 to 5:The water of the aqueous medium of 1W/W, water or physiological accounts for the quality sum of phosphatide and organic solvent
Weight ratio is 0%~15%, preferably 0%~10%, most preferably 5%~10%.
Another aspect of the present invention provides a kind of method for preparing above-mentioned lipid gel pharmaceutical preparation in situ, it is characterised in that
This method comprises the following steps:
I. the active material of recipe quantity, phosphatide, solvent and/or other pharmaceutically acceptable auxiliary materials are positioned over sealing
In container;
Ii. above-mentioned solution is heated and mixed, fully dissolving.
Another preferred scheme of the present invention, step ii heating-up temperature is 30-80 degrees Celsius, particularly preferably heating temperature
Spend for 30-50 degrees Celsius.
Mixing described in step ii of the present invention refers to the method for the mixing and emulsification commonly used in laboratory and production, is preferably
Magneton stirring, oar stirring or high speed shear.
The preferred scheme of the present invention, the time of the step ii dissolvings are more than or equal to half an hour, be preferably greater than etc.
In 1 hour, more preferably higher than equal to 2 hours.
The present invention also provides a kind of application of described lipid gel in situ in sustained release drug-loading system is prepared, and is preferably
Application in local anaesthesia medicine sustained release preparation is prepared.
The lipid gel pharmaceutical preparation in situ of the present invention is homogeneous, settled solution in vitro, and into after in vivo, solvent is gradual
Diffusion, gradual be swelled forms gel after gel-type vehicle absorbs body fluid, and active material slowly discharges from gel.
Compared with prior art, beneficial effects of the present invention are:
1st, the present invention is to carry the lipid gel in situ of medicine, and easy to use, syringeability is good, good patient compliance.
2nd, the solvent contamination that the present invention uses is small, and toxicity is low, safe.
3rd, the method that the present invention prepares lipid gel preparation in situ simply, efficiently, easily amplifies production, and can be used in work
Industry metaplasia is produced.
4th, lipid gel preparation drugloading rate in situ of the invention is high, slow release effect continued smooth, and release is complete.
5th, lipid gel preparation in situ of the invention can be uniform solution, and quality control is easy.
Such as without contrary, the abbreviation used in the present invention is with the implication shown in following table:
MCT |
Medium chain triglyceride |
DSPE-PEG |
The 1,2- stearoyl phosphatidyl monoethanolamines of Pegylation |
DMPE-PEG |
The 1,2- myristyl phosphatidyl-ethanolamines of Pegylation |
PEG |
Polyethylene glycol |
PLA |
PLA |
PLGA |
PLGA |
PGA |
Polyglycolic acid |
Embodiment
Describe the present invention in detail by the following examples, but not as limitation of the present invention, such as not plus special instruction, with
Lower ratio is mass ratio.
Embodiment 1
Prescription is weighed according to the ratio of table 1, is prepared into hydrochloric chirocaine 50mg/g(Mg/g refers to the left Bu Bika of hydrochloric acid
Because of weight/total formulation weight, similarly hereinafter)Mixed liquor, and be positioned in sealing container, the above-mentioned degrees Centigrade magneton of solution 50 stirred
Mix 30 minutes, fully dissolving, observed after being cooled to room temperature.
Table 1:Composition, state and viscosity characterize
Note:Viscosity value represents 1:Approached with water flow behavior;2:Wall built-up is obvious when rocking;3:Topple over flowable;4:Can
Injected with syringe;5:Syringe is difficult to inject.
Note:The form of table reclaimed water is water for injection.
It was found from from experimental phenomena, within the specific limits, with the increase of water content, the viscosity of system is progressively to decline
, but after water content exceedes certain limit, viscosity can rise suddenly, and what is showed in the prescription of high lipid content is brighter
It is aobvious, it may be possible to caused by water content nearly forms the critical line of phospholipid gel.
The content for changing Levobupivacaine HCL in each prescription is 100mg/g, and prescription, preparation side are weighed according to the ratio of table one
Method is consistent, is observed after being cooled to room temperature, phenomenon is as shown in table 2:
Table 2:Composition, state and viscosity characterize
Note:Solidification state is different from gelation, and the solution after gelation is translucent, slightly mobility, is due to phosphatide
Caused by phase converts;It is due to that active material input amount is too high to solidify state, more than preparation loading, forms whole preparation solid
Body shape, no mobility.
Note:The form of table reclaimed water is water for injection.
Experimental phenomena shows that, as the ratio rise of soybean lecithin and the ratio of absolute ethyl alcohol reduce, prescription viscosity increases
Add, while Drug loading capacity is remarkably decreased in equal water content.It is sustained and imitates in view of the higher cost of phosphatide, drugloading rate and preparation
The ratio of fruit, soybean lecithin and absolute ethyl alcohol is 1:7~2:When 1, more preferably.
Embodiment 2
Each prescription of 50mg/ml in embodiment 1 is respectively put into dialysis tubule (50KD, Float-A-Lyzer G2)
In, dialysis tubule is put into 100ml water, the preparation in dialysis tubule observed after 1 hour, phenomenon is as shown in table 3.
Table 3:Composition and state
Note:The form of table reclaimed water is water for injection.
The external simulation test can preferably show that gelation of the studied phosphatide situ-gel after being injected in vivo becomes
Gesture.The lipid gel in situ studied, its formation mechenism should be because of local phosphatide in aqueous environments after organic solvent spreads rapidly
Viscosity B coefficent caused by concentration is higher.
Embodiment 3
Using the ratio of soybean lecithin/absolute ethyl alcohol as 2:Based on 1, screen drugloading rate and water and soybean lecithin and
The ratio of absolute ethyl alcohol quality sum.Preparation process is the same as embodiment 1.
Release conditions:Release test is carried out with the paddle method in pharmacopeia, gel preparation is put into dialysis tubule, then will be saturating
Analysis pipe is put into medium, 37 degrees Celsius of medium temperature, and dissolution medium is purified water, medium 900ml, 100 revs/min of rotating speed, is coagulated
Glue preparation is 1.0g.
It is as shown in table 4 to discharge data:
Table 4:Discharge data (soybean lecithin:Absolute ethyl alcohol=2:1)
Note:The form of table reclaimed water is water for injection.
In the case where not containing water, when dosage is 150mg/g, medicine can not be completely dissolved.Discharge data
It has been shown that, what additions of water can be clearly the improve drugloading rate of preparation, but too high medicine input amount, the mistake of preparation can be caused
Fast release, the addition of proper discharge of water(Under existing prescription ratio, water accounts for the ratio of the quality sum of soybean lecithin and absolute ethyl alcohol
Example is 10% and 15%), release time of preparation can be extended, but rate of release is not linear with the addition of water.
When the ratio of soybean lecithin/absolute ethyl alcohol is 1:When 7, watr-proportion maximum can account for phosphatide ethanol combined amount
80%, the release data under equal release conditions are:
Table 5:Discharge data (soybean lecithin:Absolute ethyl alcohol=1:7)
Release in vitro feature is still notable.Equally, the addition of water can improve the drugloading rate of preparation, but too high medicine is thrown
Enter amount, can still cause the too fast release of preparation.
Embodiment 4
With phosphatide in embodiment 3:Ethanol is 2:It is 100mg/g that 1 serial prescription, which fixes drugloading rate, and water content is respectively
10%(Prescription one)With 15%(Prescription two)Prescription carry out animal Pharmacokinetic experiments.
Experimental animal is SD rats, and every group 4, injection system is is subcutaneously injected, dosage 10.0mg/kg, administration
Blood 0.1ml is taken within 0,0.25,0.5,1,2,4,6,12,24,36,48,72 hour afterwards, carries out content detection.Data such as table 6 and table 7
It is shown:
Table 6:The plasma drug concentration data of prescription one (ng/ml)
Table 7:The plasma drug concentration data of prescription two (ng/ml)
Data after processing are as shown in table 8:
Table 8:Animal pharmacokinetics experimental data
Note:The form of table reclaimed water is water for injection.
Two prescriptions achieve preferable slow release effect.Of a relatively high water content, compare from the hydrosphere limit for forming gel
Closely, so forming that gel is rapider, and drug diffusion is slow, so peak time is longer, but when water content is larger, preparation more holds
Easily decompose, so overall half-life period is shorter.
With phosphatide in embodiment 3:Ethanol is 1:It is 100mg/g that 7 serial prescription, which fixes drugloading rate, and water content is respectively
20%(Prescription three)With 80%(Prescription four)Prescription carry out animal Pharmacokinetic experiments.Dosage and operating method are the same as 2:1.
Table 9:The plasma drug concentration data of prescription three (ng/ml)
Table 10:The plasma drug concentration data of prescription four (ng/ml)
Pharmacokinetic experiments data after processing:
Still possesses sustained releasing character in vivo.
Embodiment 5
Prescription is weighed according to the ratio of table 11 and is positioned in sealing container, and the above-mentioned degrees Centigrade oar of solution 80 is stirred 1
Hour, fully dissolving, after being cooled to room temperature, it is observed that product is clarification, homogeneous, good fluidity solution.
Table 11:Composition
Release in vitro is carried out to prescription five, six and seven, for test method with embodiment 3, data are as shown in table 12:
Table 12:Total release percentage data
Group |
1 hour |
4 hours |
6 hours |
Prescription five |
23% |
29% |
37% |
Prescription six |
27% |
36% |
45% |
Prescription seven |
15% |
23% |
29% |
Embodiment 6
Prescription is weighed according to the ratio of table 13 and is positioned in sealing container, and the above-mentioned degrees Centigrade magneton of solution 30 is stirred
2 hours, fully dissolving, after being cooled to room temperature, it is observed that product is clarification, homogeneous, good fluidity solution.
Table 13:Composition
Note:The form of table reclaimed water is water for injection
Release in vitro is carried out to prescription eight, nine and ten, for test method with embodiment 3, data are as shown in table 14:
Table 14:Total release percentage data
Group |
1 hour |
4 hours |
6 hours |
Prescription eight |
29% |
45% |
76% |
Prescription nine |
33% |
55% |
75% |
Prescription ten |
20% |
59% |
80% |
Embodiment 7
Into the prescription of prescription one, the DSPE-PEG2000 of addition 2% and 4%, is respectively designated as prescription 11(2%)And prescription
12(4%), preparation method is the same as embodiment 1.It is observed that after being cooled to room temperature, product is to clarify, be homogeneous, good fluidity molten
Liquid.
Prescription one, prescription 11 and prescription 12 are subjected to extracorporeal releasing test, test method is the same as embodiment 3, detection 96
Cumulative release amount after hour, respectively 85%, 93% and 94%, the addition of PEGylation phosphatide, can effectively it improve not exclusively
The problem of release.
Embodiment 8
By prescription one and the prescription of blank one(Active material is free of, other compositions are consistent)It is positioned over 4 degrees Celsius of ice
In case, observation is taken out after preserving 10 days, it is found that the character of prescription one changes without obvious, the prescription one of blank has obvious layering existing
As.
Embodiment 9
Prescription is weighed according to the ratio of table 15 and is positioned in sealing container, and the above-mentioned degrees Centigrade oar of solution 70 is stirred
0.5 hour, fully dissolving, after being cooled to room temperature, it is observed that product is clarification, homogeneous, good fluidity solution.
Table 15:Composition
Thereto in units of 50 μ L, water for injection is gradually added.
Prescription 13 the water addition of addition reach water/(Soybean lecithin+organic solvent)For 20% when, preparation is effective
Gelation.
Prescription 14 the water addition of addition reach water/(Soybean lecithin+organic solvent)For 30% when, preparation is effective
Gelation.
Prescription 15 the water addition of addition reach water/(Soybean lecithin+organic solvent)For 15% when, preparation is effective
Gelation.