CN104784109B - The temperature sensitive sustained release pharmaceutical composition of taxone - Google Patents
The temperature sensitive sustained release pharmaceutical composition of taxone Download PDFInfo
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- CN104784109B CN104784109B CN201410031013.5A CN201410031013A CN104784109B CN 104784109 B CN104784109 B CN 104784109B CN 201410031013 A CN201410031013 A CN 201410031013A CN 104784109 B CN104784109 B CN 104784109B
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Abstract
The present invention relates to the temperature sensitive sustained release pharmaceutical composition of taxone.Specifically, one aspect of the present invention is related to a kind of pharmaceutical composition, wherein including：Taxone, shitosan, β sodium glycero-phosphates, second alcohol and water.Further, the method the present invention relates to prepare the pharmaceutical composition.Pharmaceutical composition of the present invention can be used to prepare the medicine of anticancer；Particularly the cancer therapy drug can be used for the treatment of malignant tumour or Post operation by locating injection approach prevents recurrence, and can be used in combination with radiation, Chinese medicine.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to one kind is used for lesion/cancer disease medicine for treatment compositions, especially
It is related to a kind of temperature sensitive pharmaceutical composition of the sustained release containing taxone composition.The present composition can be by intratumor injection, knurl
The local positioning injection systems such as week injection are administered for the treatment of kinds of tumors, big especially for those drug toxicities or cannot
With conventional chemotherapy, the tumour of radiotherapy, can by being administered in locally injected into tumor after positioning, increase drug concentration and improve and treat
Effect, reduction general toxicity.
Background technology
Cancer is disease that is not normal by control growth and proliferation of cell mechanism and causing.Cancer cell is except can be with infinite multiplication
Outward, normal structure is even transferred to body other parts via body-internal-circulation system or lymphatic system arround also locally invading.
Counted according to the World Health Organization (World Health Organization, WHO), cancer is serious harm human life and health
One of major disease, cause the disease death in the whole world about 13%.The treatment means of tumour mainly include operative treatment, radiation
Property treatment and three kinds of chemotherapy.Wherein, chemotherapy is always in occupation of main status.Nearly more than ten year, the chemotherapy of anti-malignant tumor
In medicine, bearing taxanes are one of most potential medicines.The CDCC of taxone is by suppressing
Microtubule depolymerization is so as to prevent cell differentiation, and many experiments explanation micro-pipe is an important target spot in anticancer research.It is therein
Representative drugs taxol and Docetaxel, are clinically the fiest-tire medications of oophoroma and breast cancer, and can with it is suitable
Platinum drug combination is used to treat non-small cell lung cancer, is also shown in the prostate cancer therapy of hormone resistance in addition important
Effect.Although structure between different taxoid drugs, micro-pipe binding ability is different with Pharmacokinetic Characteristics, but there is class
As side effect, such as dose-dependent immunosuppressive action, the thing followed is exactly Nervous toxicity, mucositis, alopecia and stomach and intestine
React in road.And solubility is relatively low in water due to taxone, so in the injection of commercially available such medicine use more
Nonionic surfactant carries out solubilising, such as using Cremophor EL solubilising, and polyenoid in paclitaxel injection
Using Tween 80 solubilising etc. in paclitaxel injection, and these solvents normally result in hypersensitivity, bring that patient's is very big
Pain.To life quality requirements higher and higher today, how to improve the medication compliance of cancer patient, reducing that poison is secondary to be made
With, improve curative effect, reduce chemotherapy etc., it has also become the important content of Pharmaceutical study.
Sustained release thermo-sensitive gel injection, as a kind of novel Drug Delivery Systems with distinct physiological and pharmacy characteristic,
With ideal performances such as temperature sensitive metamorphosis, sustained and controlled release medicaments.It has the characteristics that (1) can be with surrounding environment temperature
Degree changes and adjusts medicine state (such as discharge, be detained) in vivo to adapt to the timely and effective treatment of the state of an illness；(2) can locally give
Medicine, and can be in close contact with agents area for a long time, there is preferable bioadhesive, so as to improve bioavilability；(3)
, can be bound by contained medicine wherein or in gap, Drug controlled release by tridimensional network highly-hydrophilic；(4) tissue
Compatibility is good, easy to use, etc..Coordinate the current clinical imageology technology for developing rapidly, targeting, positioning in cancer drug
Even in timed delivery, can play an important role.In the treatment especially in the treatment of some solid knurls of tumour, it is directed to
Application of the medicine technology including medicine-feeding technology in arterial embolization technique, knurl etc. is more and more, using the technology and appropriate new system
Agent delivery system is combined, it is possible to achieve the various states such as administration, positioning, stop, release, maintenance, is conducive to the treatment of tumour.
Shitosan (chitosan) is natural cationic polysaccharide, with good biocompatibility, biodegradable, source
The features such as abundant, pharmaceutical carrier and biomedical sector are widely used in, and shitosan/sodium β-glycerophosphate (β-
Glycerophosphate, GP, in the present invention also referred to as sodium glycero-phosphate) hydrogel has Thermo-sensitive, in the system
Beta-glycerophosphate is also generally acknowledged nontoxic biocompatible substance.Shitosan/GP can be mixed into a kind of good injection
With the system of support.Shitosan is liquid condition under room temperature and low-temperature condition with the mixed liquor of GP, in the physiological temp shape of human body
Under the pH environment of state and human body, the mixed liquor will become gel.In recent years it is many to support system on shitosan/GP hydrogels
Research, and application of the hydrogel system on delivery system that develop on a large scale greatly.Shitosan is the deacetylated derivative of chitin, tool
There is good biological degradability and biocompatibility, while shitosan has bio-adhesive performance, Drug controlled release can be played
Effect, with unique property, therefore be widely used in the research of pharmaceutical carrier.
But it is temperature sensitive solidifying that the sustained release prepared as matrix with shitosan/sodium glycero-phosphate is particularly with above-mentioned sustained release thermo-sensitive gel
Application of the glue as drug delivery system in terms of taxone is still what those skilled in the art were expected.
The content of the invention
One of technical problems to be solved by the invention are to provide one kind to be sustained thermo-sensitive gel as drug delivery system
Taxone composition, said composition has the advantages that at least one following aspect：Can be used to site-specific delivery of drugs (be noted in knurl
Penetrate, knurl week injection etc.), improve drug effect, reduce administration number of times, reduce toxic and side effect, improve cancer patient quality of life, storage
It is easy-to-use (for example meet high temperature gelling after be returned at low temperature again when again can be with speed-shifting faster into good fluidity
Liquid).The inventors discovered that the temperature sensitive sustained release pharmaceutical composition of the taxone with special formulation has above-mentioned one
Individual or many aspects advantages, and the purpose of said one or many aspects can be realized.The present invention is able to based on this discovery
Complete.
Therefore, first aspect present invention provides a kind of pharmaceutical composition, wherein including：Taxone, shitosan,
Sodium β-glycerophosphate, second alcohol and water.
Pharmaceutical composition according to a first aspect of the present invention, after it is placed 1 hour at the temperature less than or equal to 28 DEG C
Liquid in a flowable.Pharmaceutical composition according to a first aspect of the present invention, after it is placed 1 hour at 5~28 DEG C of temperature
Liquid in a flowable.Term " flowable liquid " refers to be determined according to fluidity determining method of the present invention and be judged as flowing
Dynamic liquid.
Pharmaceutical composition according to a first aspect of the present invention, after it places 30min at the temperature greater than or equal to 33 DEG C
In not flowable semisolid hydrogel.Pharmaceutical composition according to a first aspect of the present invention, it is at 33~42 DEG C of temperature
It is in not flowable semisolid hydrogel after placement 30min.Term " not flowable semisolid hydrogel " refers to according to this hair
Bright mobility determination method is determined and is judged as not flowable semisolid hydrogel.
In general, various compositions of the invention are placed enough for a long time for example at 20 ± 2 DEG C of temperature at room temperature
For example at more than 2 hours such as more than 5 hours such as more than 10 hours or longer such as more than 24 hours, they
The variable flowable liquid of chemical conversion.So as in the present invention, fluidity determining method is so to determine：
(a) take appropriate tester (such as pharmaceutical composition of the present invention, it can be liquid form in a flowable,
Can also be in not flowable semisolid hydrogel form), it is placed at 20 ± 2 DEG C of temperature (such as 2 hours in good time
Above such as more than 5 hours such as more than 10 hours or it is longer such as more than 24 hours) so that its be liquefied as be in
Flowable liquid；
B () takes the tester 1g of the liquid in a flowable, the tool plug scale test tube bottom for being placed in 10ml (about occupies 1ml
Volume), test tube scale is marked from test tube bottom to opening direction；
C () stands in good time so that the tester is presented it stablizes at this temperature the close plug of test tube at the temperature of regulation
Physical state；
Then d be inverted for test tube by (), it is in good time to stand, and visually observing tester main body branch (has the test of more than 50% amount
Thing, can readily by estimating determination) it is whether dirty flowable to judge whether along test tube wall：
(d1) if tester main body branch at least flows to 5ml graduation marks down, then it is assumed that the tester is in step (c) institute
State liquid in a flowable at set point of temperature；
(d2) if tester main body branch at least flows down no more than 2ml graduation marks, then it is assumed that the tester is in step
It is in not flowable semisolid hydrogel at (c) described set point of temperature.
Pharmaceutical composition according to a first aspect of the present invention, its when with fluidity determining method of the present invention, in step (c)
In, the test tube of close plug is placed at the temperature less than or equal to 28 DEG C 1 hour, 1 is placed particularly at 5~28 DEG C of temperature
Hour, subsequent step is then performed again and is observed.In general, table after the so test of the pharmaceutical composition with feature of present invention
Bright is flowable liquid.
Pharmaceutical composition according to a first aspect of the present invention, its when with fluidity determining method of the present invention, in step (c)
In, make the test tube of close plug that 30min is placed at the temperature greater than or equal to 33 DEG C, placed particularly at 33~42 DEG C of temperature
30min, then performs subsequent step and observes again.In general, after the so test of the pharmaceutical composition with feature of present invention
It is shown to be not flowable semisolid hydrogel.
According to above-mentioned fluidity determining method of the invention, it can also determine pharmaceutical composition of the present invention and exist after simply changing
It is changed into the gelling time of not flowable this process of semisolid hydrogel (at this from flowable liquid under the conditions of set point of temperature
T1 can be designated as in invention), i.e.,：For example, in determination step (c), make composition regulation temperature (T1) (for example higher than or wait
In 33 DEG C of temperature, particularly such as 33~42 DEG C) place's standing regular hour (t1), until composition is in step (d2)
Existing not flowable semisolid hydrogel, the above-mentioned time t1 of record is the gelling time at a temperature of T1.
Pharmaceutical composition according to a first aspect of the present invention, it (particularly for example exists in the temperature greater than or equal to 33 DEG C
At a temperature of 33~42 DEG C, such as at a temperature of 37 DEG C) there is the gelling time of 1~90min, particularly with 5~60min's
Gelling time.
According to above-mentioned fluidity determining method of the invention, it can also determine pharmaceutical composition of the present invention and exist after simply changing
Never flowable semisolid hydrogel is changed into the solution solidifying time of flowable this process of liquid (at this under the conditions of set point of temperature
T2 can be designated as in invention), i.e.,：For example, in determination step (c), first make composition can gelation temperature (be for example greater than or equal to
33 DEG C of temperature, particularly such as 33~42 DEG C) place stand make composition be fully gelled (generally for example stand more than 2 hours i.e.
Enough), composition is then made to be stood at temperature (T2) (normally below or equal to 28 DEG C, particularly 5~28 DEG C) place of regulation
Regular hour (t2), until composition is presented liquid in a flowable in step (d1), the above-mentioned time t2 of record is
The solution solidifying time at a temperature of T2.
Pharmaceutical composition according to a first aspect of the present invention, it is in the temperature less than or equal to 28 DEG C (particularly for example 5
At a temperature of~28 DEG C, such as solidifying time, the particularly solution with 10~60min of the solution with 5~90min at a temperature of 20 DEG C
The solidifying time.
Pharmaceutical composition according to a first aspect of the present invention, wherein described taxone is selected from：Taxol, polyenoid
Taxol, paclitaxel-2'-hydroxy, 10-deacetyl taxol, 7-epi-taxol and combinations thereof.
Pharmaceutical composition according to a first aspect of the present invention, wherein the taxanes medicine comprising 0.05~1% (w/v, similarly hereinafter)
Thing.Pharmaceutical composition according to a first aspect of the present invention, wherein comprising 0.05~0.75% taxone.According to this hair
The pharmaceutical composition of bright first aspect, wherein comprising 0.05~0.5% taxone.
Pharmaceutical composition according to a first aspect of the present invention, wherein the shitosan comprising 0.5-5%.According to the present invention first
The pharmaceutical composition of aspect, wherein the shitosan comprising 0.75-4%.Pharmaceutical composition according to a first aspect of the present invention, wherein
Shitosan comprising 1%-3%.
Pharmaceutical composition according to a first aspect of the present invention, wherein the sodium β-glycerophosphate comprising 2-20%.According to the present invention
The pharmaceutical composition of first aspect, wherein the sodium β-glycerophosphate comprising 3-18%.Drug regimen according to a first aspect of the present invention
Thing, wherein the sodium β-glycerophosphate comprising 5-15%.
Pharmaceutical composition according to a first aspect of the present invention, wherein comprising 0.5-10% ethanol.According to a first aspect of the present invention
Pharmaceutical composition, wherein comprising 0.75-7.5% ethanol.According to the pharmaceutical composition of first aspect present invention, wherein comprising 1-5%
Ethanol.
Pharmaceutical composition according to a first aspect of the present invention, wherein comprising 0.05~1% taxone, 0.5-5%
Shitosan, the sodium β-glycerophosphate of 2-20%, the water (adding to the water of 100% amount) of 0.5-10% ethanol and aequum.
Pharmaceutical composition according to a first aspect of the present invention, wherein comprising 0.05~0.75% taxone,
The water of the shitosan of 0.75-4%, the sodium β-glycerophosphate of 3-18%, 0.75-7.5% ethanol and aequum.
Pharmaceutical composition according to a first aspect of the present invention, wherein comprising 0.05~0.5% taxone, 1%-3%
Shitosan, the sodium β-glycerophosphate of 5-15%, the water of 1-5% ethanol and aequum.
Pharmaceutical composition according to a first aspect of the present invention, wherein also including organic acid or its salt.According to the present invention first
The pharmaceutical composition of aspect, wherein the organic acid is selected from citric acid or tartaric acid.Medicine according to a first aspect of the present invention
Composition, wherein the salt of described organic acid is its sodium salt.Pharmaceutical composition according to a first aspect of the present invention, wherein also including
Citric acid, sodium citrate, tartaric acid, sodium tartrate.Pharmaceutical composition according to a first aspect of the present invention, wherein the organic acid
Or its salt and the mol ratio of the sodium β-glycerophosphate are 0.1~5：100, such as described organic acid or its salt and the β-glycerine
The mol ratio of sodium phosphate is 0.2~2.5：100, such as described organic acid or its salt are with the mol ratio of the sodium β-glycerophosphate
0.5~2：100.It has been unexpectedly discovered that add appropriate organic acid or its salt in pharmaceutical composition of the present invention, can be with
Be conducive to obtaining the composition with feature of present invention, such as when said composition is returned at low temperature again after chance high temperature gelling again
Can with speed-shifting faster into good fluidity liquid, it is to avoid medicine is difficult to be returned to good after high temperature gelling is met by chance
The liquid condition of good mobility simultaneously causes smoothly be got it filled with syringe during subsequent administrations difficulty such as drug administration by injection.
Pharmaceutical composition according to a first aspect of the present invention, it is determined at 20 DEG C and in the state of liquid, and its pH value is
5.5~7.5, such as its pH value is 6.0~7.5, and such as its pH value is 6.5~7.5.It is to obtain the pH value expected, can be must
To appropriate acid-base modifier, preferably NaOH and hydrochloric acid is added in the present composition when wanting, generally with they
The aqueous solution is used, and its amount is to be enough to adjust target ph.
Due to shitosan, solute effect is preferable generally under conditions of slant acidity, therefore when the present composition is prepared,
First shitosan can be dissolved with the reagent of appropriate slant acidity, preferential is the salt of aqueous hydrochloric acid solution such as concentration about 0.1mol/L
Aqueous acetic acid of aqueous acid, aqueous acetic acid such as concentration about 0.1mol/L etc..Acid reagent uses formula that can reach
The amount or slightly higher amount of the shitosan dissolving of amount are used.But because the present composition needs regulation to mesh as herein described
PH value is marked, therefore these acid reagents are finally neutralized.
Pharmaceutical composition according to a first aspect of the present invention, it is the preparation that injectable is used.
Pharmaceutical composition according to a first aspect of the present invention, it is the sterile preparation that injectable is used.
Pharmaceutical composition according to a first aspect of the present invention, it is substantially that method by comprising the following steps is prepared into
Arrive：
A) shitosan is made chitosan solution with the aqueous dissolution of acid reagent；
B) taxone is dissolved in ethanol, then it is slowly added in above-mentioned chitosan solution, hot pressing
Sterilizing, puts and cool down in ice-water bath at least 30min, standby；
C) sodium β-glycerophosphate is dissolved in appropriate water for injection, is made the solution that concentration is 60%, cross 0.22 μm of filter membrane
It is degerming, put and cool down in ice-water bath at least 30min, standby；
D) in ice bath, step c) resulting solutions are slowly added in step b) resulting solutions under agitation, add water
To full dose, it is thoroughly mixed, the pH value of solution is adjusted if necessary to prescribed limit, pack, obtains final product.
Pharmaceutical composition according to a first aspect of the present invention, wherein each step is aseptically operated.It is special
It is not that wherein step d) is aseptically operated.In one embodiment, finally added all in step d)
Material and be stirred for it is uniform after, gained liquid is carried out into 0.22 μm of filter membrane degerming.
Pharmaceutical composition according to a first aspect of the present invention, wherein the aqueous solution of acid reagent is concentration described in step a)
The aqueous acetic acid of 0.1mol/L or the aqueous hydrochloric acid solution of concentration 0.1mol/L.
Pharmaceutical composition according to a first aspect of the present invention, it has formula described in Examples below any one of 1-8.
Pharmaceutical composition according to a first aspect of the present invention, it has formula described in Examples below any one of 1-8 and makes
Method.
Further, second aspect present invention provides the method for preparing pharmaceutical composition, is wrapped in described pharmaceutical composition
Contain：Taxone, shitosan, sodium β-glycerophosphate, second alcohol and water；The described method comprises the following steps：
A) shitosan is made chitosan solution with the aqueous dissolution of acid reagent；
B) taxone is dissolved in ethanol, then it is slowly added in above-mentioned chitosan solution, hot pressing
Sterilizing, puts and cool down in ice-water bath at least 30min, standby；
C) sodium β-glycerophosphate is dissolved in appropriate water for injection, is made the solution that concentration is 60%, cross 0.22 μm of filter membrane
It is degerming, put and cool down in ice-water bath at least 30min, standby；
D) in ice bath, step c) resulting solutions are slowly added in step b) resulting solutions under agitation, add water
To full dose, it is thoroughly mixed, the pH value of solution is adjusted if necessary to prescribed limit, pack, obtains final product.
The water of the acid reagent of the dissolving shitosan in method according to a second aspect of the present invention, wherein step a)
Solution is the aqueous acetic acid of concentration 0.1mol/L or the aqueous hydrochloric acid solution of concentration 0.1mol/L.Acid reagent is made with that can reach
The amount or slightly higher amount for being formulated the shitosan dissolving of consumption are used.But by the present composition needs regulation to this paper institutes
The target ph stated, therefore these acid reagents are finally neutralized.
Method according to a second aspect of the present invention, wherein each step is aseptically operated.Particularly, its
Middle step d) is aseptically operated.In one embodiment, whole materials are finally added simultaneously in step d)
After being stirred for uniformly, gained liquid is carried out into 0.22 μm of filter membrane degerming.
Method according to a second aspect of the present invention, the pharmaceutical composition obtained by it is the preparation that injectable is used.
Method according to a second aspect of the present invention, the pharmaceutical composition obtained by it is the sterile preparation that injectable is used.
Method according to a second aspect of the present invention, the pharmaceutical composition obtained by it is at the temperature less than or equal to 30 DEG C
Liquid in a flowable after placing 1 hour.Method according to a second aspect of the present invention, pharmaceutical composition obtained by it 5~
Liquid in a flowable after being placed 1 hour at 30 DEG C of temperature.
Method according to a second aspect of the present invention, the pharmaceutical composition obtained by it is at the temperature greater than or equal to 35 DEG C
It is in not flowable semisolid hydrogel after placement 30min.Method according to a second aspect of the present invention, the medicine group obtained by it
Compound is in not flowable semisolid hydrogel after placing 30min at 35~42 DEG C of temperature.
Method according to a second aspect of the present invention, wherein described taxone is selected from：Taxol, polyenoid Japanese yew
Alcohol, paclitaxel-2'-hydroxy, 10-deacetyl taxol, 7-epi-taxol and combinations thereof.
Method according to a second aspect of the present invention, includes 0.05~1% (w/v, similarly hereinafter) in the pharmaceutical composition obtained by it
Taxone.Method according to a second aspect of the present invention, includes 0.05~0.6% in the pharmaceutical composition obtained by it
Taxone.Method according to a second aspect of the present invention, includes 0.05~0.5% in the pharmaceutical composition obtained by it
Taxone.
Method according to a second aspect of the present invention, the shitosan comprising 0.5-5% in the pharmaceutical composition obtained by it.Root
According to the method for second aspect present invention, the shitosan comprising 0.75-4% in the pharmaceutical composition obtained by it.According to the present invention the
The method of two aspects, the shitosan comprising 1%-3% in the pharmaceutical composition obtained by it.
Method according to a second aspect of the present invention, the β-phosphoglycerol comprising 2-20% in the pharmaceutical composition obtained by it
Sodium.Method according to a second aspect of the present invention, the sodium β-glycerophosphate comprising 3-18% in the pharmaceutical composition obtained by it.Root
According to the method for second aspect present invention, the sodium β-glycerophosphate comprising 5-15% in the pharmaceutical composition obtained by it.
Method according to a second aspect of the present invention, includes 0.5-10% ethanol in the pharmaceutical composition obtained by it.According to this
The method of invention second aspect, includes 0.75-7.5% ethanol in the pharmaceutical composition obtained by it.According to a second aspect of the present invention
Method, in the pharmaceutical composition obtained by it include 1-5% ethanol.
Method according to a second aspect of the present invention, comprising 0.05~1% taxanes in the pharmaceutical composition obtained by it
The water of medicine, the shitosan of 0.5-5%, the sodium β-glycerophosphate of 2-20%, 0.5-10% ethanol and aequum (adds to 100% amount
Water).
Method according to a second aspect of the present invention, comprising 0.05~0.6% taxane in the pharmaceutical composition obtained by it
The water of class medicine, the shitosan of 0.75-4%, the sodium β-glycerophosphate of 3-18%, 0.75-7.5% ethanol and aequum.
Method according to a second aspect of the present invention, comprising 0.05~0.5% taxane in the pharmaceutical composition obtained by it
The water of class medicine, the shitosan of 1%-3%, the sodium β-glycerophosphate of 5-15%, 1-5% ethanol and aequum.
Method according to a second aspect of the present invention, also includes organic acid or its salt in the pharmaceutical composition obtained by it.Root
According to the method for second aspect present invention, organic acid described in the pharmaceutical composition obtained by it is selected from citric acid or tartaric acid.
Method according to a second aspect of the present invention, the salt of the organic acid described in pharmaceutical composition obtained by it is its sodium salt.According to
The pharmaceutical composition of first aspect present invention, wherein also including citric acid, sodium citrate, tartaric acid, sodium tartrate.According to this hair
The method of bright second aspect, organic acid described in the pharmaceutical composition obtained by it or its salt rub with the sodium β-glycerophosphate
You are than being 0.1~5：100, such as described organic acid or its salt and the mol ratio of the sodium β-glycerophosphate are 0.2~2.5：
100, such as described organic acid or its salt and the mol ratio of the sodium β-glycerophosphate are 0.5~2：100.Unexpectedly
It was found that, appropriate organic acid or its salt is added in pharmaceutical composition of the present invention, can be conducive to obtaining has feature of present invention
Composition, such as said composition meet high temperature gelling after be returned at low temperature again when again can be with speed-shifting faster into stream
The good liquid of dynamic property, it is to avoid medicine is difficult to be returned to the liquid condition of good fluidity and causes after high temperature gelling is met by chance
Cannot smoothly be got it filled with syringe during subsequent administrations difficulty such as drug administration by injection.
Method according to a second aspect of the present invention, the pharmaceutical composition obtained by it is surveyed at 25 DEG C and in the state of liquid
Fixed, its pH value is 5.5~7.5, and such as its pH value is 6.0~7.5.To obtain the pH value expected, can when necessary to this hair
Appropriate acid-base modifier, preferably NaOH and hydrochloric acid are added in bright composition, are generally used with their aqueous solution,
Its amount is to be enough to adjust target ph.
Method according to a second aspect of the present invention, the pharmaceutical composition obtained by it has any reality of first aspect present invention
Apply the feature of scheme.
Yet further, third aspect present invention provides the pharmaceutical composition of first aspect present invention any embodiment
Or purposes of the pharmaceutical composition for preparing of second aspect present invention any one methods described in the medicine for preparing anticancer.
Purposes according to a third aspect of the present invention, wherein the cancer therapy drug locating injection approach is used for controlling for malignant tumour
Treat or Post operation prevents recurrence, and can be used in combination with radiation, Chinese medicine.
Purposes according to a third aspect of the present invention, wherein the cancer therapy drug is by way of tumor-localizing drug administration by injection
Apply.In one embodiment, the mode of the tumor-localizing drug administration by injection is selected from：Intratumor injection, knurl week injection, it is subcutaneous
Injection, (abdominal cavity, thoracic cavity and intraspinal tube) injection in chamber, selective arterial injection, in lymph node and intramedullary injection etc..
Purposes according to a third aspect of the present invention, wherein the malignant tumour is entity tumor.The entity tumor is for example
But it is not limited to oophoroma, stomach cancer, liver cancer, prostate cancer, cancer of pancreas, breast cancer, kidney, non-small cell lung cancer, head and neck cancer, oesophagus
Cancer, cervical carcinoma, colorectal cancer, cutaneum carcinoma, black cancer or other epidermal carcinomas and cancerous ulcer etc..
Purposes according to a third aspect of the present invention, wherein the medicine is used for intratumoral injection oophoroma, stomach cancer, liver
Cancer, prostate cancer, cancer of pancreas, breast cancer, kidney, non-small cell lung cancer, head and neck cancer, the cancer of the esophagus, cervical carcinoma and cancerous ulcer or
Post operation prevents recurrence；Can be used in combination with radiation, Chinese medicine.
Purposes according to a third aspect of the present invention, wherein the medicine is used for knurl week injection treatment oophoroma, breast cancer is non-
ED-SCLC, stomach cancer, liver cancer, prostate cancer, cancer of pancreas or Post operation prevent recurrence；Can be used in combination with radiation, Chinese medicine.
Purposes according to a third aspect of the present invention, wherein the medicine is used for intraperitoneal injection treats oophoroma, stomach cancer, liver
Cancer, prostate cancer, cancer of pancreas, kidney, abdominal cavity malignant lymphoma, cervical carcinoma, colorectal cancer or Post operation prevent recurrence；Can be with
Radiation, Chinese medicine are used in combination.
Purposes according to a third aspect of the present invention, wherein the medicine is used for epidermis external application and hypodermic injection treatment skin
Cancer, black cancer or other epidermal carcinomas or Post operation prevent recurrence；Can be used in combination with radiation, Chinese medicine.
Any embodiment of either side of the invention, can be combined with other embodiments, as long as they are not
Contradiction occurs.Additionally, in any embodiment of either side of the present invention, any technical characteristic goes for other realities
The technical characteristic in scheme is applied, as long as they are not in contradiction.The invention will be further described below.
All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary
Offer expressed implication with it is of the invention inconsistent when, be defined by statement of the invention.Additionally, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase for referring to if any inconsistent with common art-recognized meanings, with institute's table of the present invention
The implication stated is defined.
In general, the present invention relates to a kind of design and preparation of the sustained release thermo-sensitive gel containing taxone, and its
Using.Especially using the conventional antineoplastic such as taxol, Docetaxel as main ingredient, by adjusting shitosan, β-glycerine phosphorus
The species and consumption of sour sodium and similar auxiliary material, the sensitive gel preparation of preparation temperature is allowed to be at room temperature flowable liquid,
And the semi-solid gel of biodegradable absorption can be transformed under physiological temp, realize the slow release of medicine；So as to pass through
The local positioning injection system such as intratumor injection, hypodermic injection is administered for the treatment of kinds of tumors.Japanese yew prepared by the present invention
Alkanes medicament slow release gel, gelling temperature is 33-42 DEG C, is capable of achieving room temperature fluid, the semisolid transformation of body temperature；Release in vitro
Experiment shows that the gel can slowly discharge, and the preparation of 20 days is about 80%；Internal pharmacokinetics experiment shows that the gel exists
The residence time of tumor tissues is more long, and continues slow release, at 21 days still on valid density；Results of pharmacodynamic test shows
Show, the gel can effectively suppress the tumour growth of tumor-bearing mice；Contrast with the regular solution agent of parallel administration shows that this coagulates
Glue preparation can improve curative effect, reduce overall toxic reaction, have obvious advantage in the treatment of tumour.
In addition, it is necessary to be especially envisaged that medicinal clinical applicability, therefore medicine storage after the preparation, transported
It is possible to be exposed under high temperature once in a while in journey, such as at a temperature of up to 35 DEG C, and this short time is exposed to high temperature and can cause
Originally the pharmaceutical preparation being in a liquid state is gelled to form not flowable semisolid.Present inventors have surprisingly discovered that, to the present invention
When adding appropriate specific organic acid or its salt in composition, can cause to be gelled because being exposed to high temperature and be rendered as flowing
Dynamic composition, when disposing at a lower temperature again, can in the short period of time re-form free flowable liquid,
This be for drug administration by injection it is extremely valuable, therefore clinical staff cannot by injecting pathway to patient apply can not
The half of flowing consolidates gel, and only easily returning back to free flowable liquid is only great clinical value.
In the compositions of the present invention, especially pass through using the conventional antineoplastic such as taxol, Docetaxel as main ingredient
The species and consumption of adjustment shitosan, sodium β-glycerophosphate and similar auxiliary material, the sensitive gel preparation of preparation temperature, are allowed in room
It is flowable liquid that temperature is lower, and can be transformed into semi-solid gel under physiological temp, realizes the slow release of medicine；So as to logical
Cross the treatment that the local positioning injection systems such as intratumor injection, the injection of knurl week are administered for kinds of tumors.Belong to new agent technology and
Oncotherapy technical field.New formulation of the invention, the temperature sensitivity energy and excellent physical and chemical stability for having uniqueness,
With medicament slow release performance, tumor-bearing mice experiment shows that said preparation has good antitumor action.
Taxol is the Typical Representative of taxone of the present invention, and its molecular formula is C47H51NO14, molecular weight
853.9, with following chemical structural formula
The present inventor generally provides a kind of novel ts type preparation of taxone, and it is provided simultaneously with delaying
Release performance and temperature sensitivity can (i.e. in the present invention can they be called to be sustained thermo-sensitive gel injection), by site-specific delivery of drugs
(intratumor injection, the injection of knurl week etc.), for the treatment of the malignant tumours such as various liver cancer, cancer of pancreas, to can realize raising drug effect,
Reduce administration number of times, reduce the purposes such as toxic and side effect, the quality of life for improving cancer patient.
Present invention sustained release thermo-sensitive gel injection is by the shitosan with good biocompatibility and biodegradability
As main carriers material, it is prepared from other corresponding auxiliary materials.The hydrogel is at ambient temperature liquid, is taken the photograph in 33-42
Immobilising semisolid hydrogel is can be changed into when family name spends.Extracorporeal releasing test result shows that this thermo-sensitive gel is to cancer therapy drug
There is good slow controlled-release effect.Tumour can be effectively covered after the gel injection, the semi-solid Drug Storage of formation can effectively extend medicine
Release time makes it maintain medicine effective concentration.The sustained release temperature-sensitive hydrogel not only has preparation simple, and drugloading rate is high, stability
Good advantage, can also in-situ injection and degradation in vivo.By the checking that Internal pharmacokinetics are tested, the gel is in tumor tissues
Residence time is more long, and continues slow release, at 21 days still on valid density；Results of pharmacodynamic test displays that this coagulates
Glue can effectively suppress the tumour growth of tumor-bearing mice；Contrast with the regular solution agent of parallel administration shows, the gel preparation
Curative effect can be improved, overall toxic reaction is reduced, there is obvious advantage in the treatment of tumour.
Brief description of the drawings
Fig. 1 shows each group Mouse Weight variation diagram.
Fig. 2 shows each group mouse tumor relative volume variation diagram.
Specific embodiment
The present invention can be conducted further description by the following examples, however, the scope of the present invention is not limited
In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention to used in experiment to material and test method carry out generality
And/or specific description.Although for realize many materials that the object of the invention used and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.In the context of the present invention, Cit represents citric acid, and Cit-Na is represented
Sodium citrate, Tar represents tartaric acid, and Tar-Na represents sodium tartrate；In each example below, when representing their amount, be with
It represents that such as Cit consumptions are 1/100 expression Cit relative to the mol ratio of sodium glycero-phosphate：Sodium glycero-phosphate=1：100
(mol/mol).In example below the present invention, when pH value (measured value under the conditions of 20 DEG C) of regulating liquid medicine is needed, use
The experience regulation as known to preparation formulation art technical staff of 0.1mol/L hydrochloric acid solutions or 0.1mol/L sodium hydroxide solutions
To setting.
A, embodiment part
Embodiment 1：Prepare pharmaceutical composition of the present invention
Formula
| Taxol | 0.2g |
| Shitosan | 2g |
| Sodium β-glycerophosphate | 10g |
| Ethanol | 2.5g |
| Cit | 1/100 |
| Water | In right amount, 100g is added to |
| Final liquid pH value | 7.0 |
Prepare：To prepare the condition of sterile preparation, prepared according to following steps：
A) aqueous solution (0.1M acetic acid) dissolving of shitosan acid reagent is made 2.5% chitosan solution；
B) taxone is dissolved in ethanol, then it is slowly added in above-mentioned chitosan solution, hot pressing
Sterilizing, puts and cool down in ice-water bath at least 30min, standby；
C) sodium β-glycerophosphate is dissolved in appropriate water for injection, is made the solution that concentration is 60%, cross 0.22 μm of filter membrane
It is degerming, put and cool down in ice-water bath at least 30min, standby；
D) in ice bath, step c) resulting solutions are slowly added in step b) resulting solutions under agitation, add water
To full dose, it is thoroughly mixed, the pH value of solution is adjusted if necessary to prescribed limit, pack, obtains final product.
Fluidity determining method measurement result：Gelling time (t1,37 DEG C)=18min, solidifying time (t2,20 DEG C)=43min of solution.
Embodiment 2：Prepare pharmaceutical composition of the present invention
Formula：
| Taxol | 0.05g |
| Shitosan | 3g |
| Sodium β-glycerophosphate | 5g |
| Ethanol | 5g |
| Cit | 0.5/100 |
| Water | In right amount, 100g is added to |
| Final liquid pH value | 6.5 |
Prepare：Carried out with reference to the method for embodiment 1,0.1M dissolving with hydrochloric acid shitosans are used in step a).
Fluidity determining method measurement result：Gelling time (t1,37 DEG C)=7min, solidifying time (t2,20 DEG C)=56min of solution.
Embodiment 3：Prepare pharmaceutical composition of the present invention
Formula：
| Taxol | 0.5g |
| Shitosan | 1g |
| Sodium β-glycerophosphate | 15g |
| Ethanol | 1g |
| Cit | 2/100 |
| Water | In right amount, 100g is added to |
| Final liquid pH value | 7.5 |
Prepare：Carried out with reference to the method for embodiment 1.
Fluidity determining method measurement result：Gelling time (t1,37 DEG C)=57min, solidifying time (t2,20 DEG C)=12min of solution.
Embodiment 4：Prepare pharmaceutical composition of the present invention
Formula：
| Docetaxel | 0.75g |
| Shitosan | 0.75g |
| Sodium β-glycerophosphate | 18g |
| Ethanol | 0.75g |
| Cit-Na | 0.75/100 |
| Water | In right amount, 100g is added to |
| Final liquid pH value | 6.9 |
Prepare：Carried out with reference to the method for embodiment 1,0.1M dissolving with hydrochloric acid shitosans are used in step a).
Fluidity determining method measurement result：Gelling time (t1,37 DEG C)=35min, solidifying time (t2,20 DEG C)=23min of solution.
Embodiment 5：Prepare pharmaceutical composition of the present invention
Formula：
| Docetaxel | 0.05g |
| Shitosan | 4g |
| Sodium β-glycerophosphate | 3g |
| Ethanol | 7.5g |
| Tar | 1.5/100 |
| Water | In right amount, 100g is added to |
| Final liquid pH value | 7.3 |
Prepare：Carried out with reference to the method for embodiment 1.
Fluidity determining method measurement result：Gelling time (t1,37 DEG C)=45min, solidifying time (t2,20 DEG C)=33min of solution.
Embodiment 6：Prepare pharmaceutical composition of the present invention
Formula
| Paclitaxel-2'-hydroxy | 0.2g |
| Shitosan | 2g |
| Sodium β-glycerophosphate | 8g |
| Ethanol | 2.5g |
| Tar-Na | 1.2/100 |
| Water | In right amount, 100g is added to |
| Final liquid pH value | 6.0 |
Prepare：Carried out with reference to the method for embodiment 1.
Fluidity determining method measurement result：Gelling time (t1,37 DEG C)=28min, solidifying time (t2,20 DEG C)=36min of solution.
Embodiment 7：Prepare pharmaceutical composition of the present invention
Formula
| 10-deacetyl taxol | 0.2g |
| Shitosan | 2g |
| Sodium β-glycerophosphate | 8g |
| Ethanol | 2.5g |
| Tar-Na | 1.2/100 |
| Water | In right amount, 100g is added to |
| Final liquid pH value | 6.0 |
Prepare：Carried out with reference to the method for embodiment 1.
Fluidity determining method measurement result：Gelling time (t1,37 DEG C)=14min, solidifying time (t2,20 DEG C)=24min of solution.
Embodiment 8：Prepare pharmaceutical composition of the present invention
Formula
| 7-epi-taxol | 0.2g |
| Shitosan | 2g |
| Sodium β-glycerophosphate | 8g |
| Ethanol | 2.5g |
| Tar-Na | 1.2/100 |
| Water | In right amount, 100g is added to |
| Final liquid pH value | 6.0 |
Prepare：Carried out with reference to the method for embodiment 1.
Fluidity determining method measurement result：Gelling time (t1,37 DEG C)=26min, solidifying time (t2,20 DEG C)=42min of solution.
In addition, the composition that 1~embodiment of the above embodiment of the present invention 8 is provided is determined in 33~42 DEG C of temperature ranges
The gelling time of (being determined at 33 DEG C, 35 DEG C, 39 DEG C, 42 DEG C respectively) is in the range of 5~60min；These compositions 5~
The gelling time for being determined in 28 DEG C of temperature ranges (determined at 5 DEG C, 10 DEG C, 15 DEG C, 28 DEG C respectively) is in 12~60min scopes
It is interior.It can be seen that, there is the composition that 1~embodiment of the embodiment of the present invention 8 is provided good gelling-solution to coagulate performance.
Embodiment 11：Prepare pharmaceutical composition
Formula and preparation method, the difference is that organic acid Cit therein is changed into following different amounts, are obtained with reference to embodiment 1
Following formula/sample：
| Sample C111 | C112 | C113 | C114 | C115 | C116 | C117 | C118 | C119 |
| Cit*0 | 0.05% | 0.2% | 0.5% | 1.5% | 2% | 3% | 4% | 5% |
* Cit consumptions are the molar percentages relative to sodium β-glycerophosphate, similarly hereinafter.
As a result：Tri- Cit consumptions of C111, C112, C113 are less than/are equal to 0.2% sample, although their gelling time
(t1,37 DEG C) is in the range of 5~60min；But, their solution coagulates the time (t2,20 DEG C) in more than 180min, especially
Be the solution solidifying time (t2,20 DEG C) of the sample that C111 is not added with Cit up to more than 14 hours, this is clinically unacceptable.
Tri- Cit consumptions of C114, C115, C116 are 0.5~2% sample, and their gelling time (t1,37 DEG C) is in 5~60min
In the range of, the solution solidifying time (t2,20 DEG C) is in the range of 10~60min.But for tri- Cit of C117, C118, C119
Consumption is too high sample, although their the solution solidifying time (t2,20 DEG C) in the range of 10~60min, goes out completely
What people expected is long gelling time, and gelling time (t1,37 DEG C) reaches more than 230min, and the excessive Cit of display addition can reduce product
The gelatinization results of product.
With reference to above example 11, but active component is changed to Docetaxel, be as a result displayed in the solution solidifying time (t2,
20 DEG C) and the presentation of gelling time (t1,37 DEG C) aspect and C111~C119 each sample identical results.
In addition, according to the method for above example 1, but use other organic acids instead and replace Cit, as a result finding no other has
Machine acid is obtained in that the effect of the solution solidifying time (t2,20 DEG C) less than 60min, for example, be unable to reach using acetic acid, lactic acid etc.
This effect.
Embodiment 12：Prepare pharmaceutical composition
Formula and preparation method with reference to embodiment 1, unlike organic acid Cit therein is changed to Cit-Na, and use with
Lower different amounts, obtain following formula/sample：
| Sample | C121 | C122 | C123 | C124 | C125 | C126 | C127 | C128 | C129 |
| Cit-Na | 0 | 0.05% | 0.2% | 0.5% | 1.5% | 2% | 3% | 4% | 5% |
As a result：Tri- Cit-Na consumptions of C121, C122, C123 are less than/are equal to 0.2% sample, although during their gelling
Between (t1,37 DEG C) in the range of 5~60min；But, their solution coagulates the time (t2,20 DEG C) in more than 160min, special
Be not the solution solidifying time (t2,20 DEG C) of the sample that C121 is not added with Cit-Na up to more than 12 hours, this is clinically unacceptable
's.Tri- Cit-Na consumptions of C124, C125, C126 are 0.5~2% sample, their gelling time (t1,37 DEG C) 5~
In the range of 60min, the solution solidifying time (t2,20 DEG C) is in the range of 10~60min.But for C127, C128, C129 tri-
Individual Cit-Na consumptions are too high sample, although their the solution solidifying time (t2,20 DEG C) is in the range of 10~60min,
It is that it is completely surprising that gelling time is long, gelling time (t1,37 DEG C) reaches more than 205min, the excessive Cit- of display addition
Na can reduce the gelatinization results of product.
Embodiment 13：Prepare pharmaceutical composition
Formula and preparation method with reference to embodiment 1, unlike organic acid Cit therein is changed to Tar, and using it is following not
Same consumption, obtains following formula/sample：
| Sample | C131 | C132 | C133 | C134 | C135 | C136 | C137 | C138 | C139 |
| Tar | 0 | 0.05% | 0.2% | 0.5% | 1.5% | 2% | 3% | 4% | 5% |
As a result：Tri- Tar consumptions of C131, C132, C133 are less than/are equal to 0.2% sample, although their gelling time
(t1,37 DEG C) is in the range of 5~60min；But, their solution coagulates the time (t2,20 DEG C) in more than 195min, especially
Be the solution solidifying time (t2,20 DEG C) of the sample that C131 is not added with Tar up to more than 16 hours, this is clinically unacceptable.
Tri- Tar consumptions of C134, C135, C136 are 0.5~2% sample, and their gelling time (t1,37 DEG C) is in 5~60min
In the range of, the solution solidifying time (t2,20 DEG C) is in the range of 10~60min.But for tri- Tar of C137, C138, C139
Consumption is too high sample, although their the solution solidifying time (t2,20 DEG C) in the range of 10~60min, goes out completely
What people expected is long gelling time, and gelling time (t1,37 DEG C) reaches more than 190min, and the excessive Tar of display addition can reduce product
The gelatinization results of product.
With reference to above example 13, but Tar is changed to Tar-Na, is as a result displayed in solution solidifying time (t2,20 DEG C) and glue
Solidifying time (t1,37 DEG C) aspect is presented and C131~C139 each sample identical results.
B, test example part
Test example 1：Slow release effect is investigated
Embodiment 1 gained combination of the lotus knurl (S180 sarcomas) mouse (n=10) intratumor injection (25mg/kg) containing taxol
Thing, can still be detected in blood plasma after 30 days taxol (>15ng/ml).And with the common commercially available paclitaxel injection of dosage
(An Sutai) just cannot be detected in blood plasma after being administered 2 days (<1ng/L).Illustrate the gel be obviously prolonged taxol
Internal release, and its release in vivo is (external with reference to described in CN102399377A specifications embodiment 2 with release in vitro result
Drug release determination of experimental method) it is consistent.
Test example 2
Embodiment 4 gained of the lotus knurl (S180 sarcomas) mouse (n=10) intratumor injection (25mg/kg) containing Docetaxel
Composition, can still be detected in blood plasma after 21 days Docetaxel (>15ng/ml), and with the common Docetaxel of dosage
Parenteral solution (taxotere) just cannot be detected in blood plasma after being administered 2 days (<1ng/L).Illustrate that the gel has been obviously prolonged polyenoid
The release in vivo of taxol, and its release in vivo and (the reference CN102399377A specification implementations of release in vitro result
Tablets in vitro determination of experimental method described in example 2) it is consistent.
Test example 3
With Kunming kind male ICR small white mouses as subjects, by 2 × 106Individual H22 cancer cell subcutaneous are injected in its right side
Back, treats tumour growth to 200-300mm3, mouse is divided into five groups (tables 1), except physiological saline group injecting normal saline, other
Group is all administered by 20mg/kg.Docetaxol injection is taxotere, Docetaxel gel is the gained combination of embodiment 4
Thing, Blank gel reference implementation example 4 is prepared but is not added with medicine.
Table 1：Packet and administering mode
| Group | Administering mode |
| A groups (blank group) | D7 intratumor injections physiological saline after inoculation |
| B groups (Blank gel i.t.) | D7 intratumor injections Blank gel after inoculation |
| C groups (Docetaxel iv) | D7 intravenous injections Docetaxol injection after inoculation |
| D groups (Docetaxel it) | D7 intratumor injections Docetaxol injection after inoculation |
| E groups (Docetaxel gel it) | D7 intratumor injections Docetaxel gel after inoculation |
Activity, the meal situation of daily observation nude mice after administration, every 3 days measurements Mouse Weight and gross tumor volumes.As a result
Show, Docetaxel gel can significantly inhibit tumour growth and substantially without toxicity.Each group Mouse Weight and gross tumor volume
Situation of change is as shown in Figure 1, 2.
Fig. 1 shows each group Mouse Weight variation diagram, and changes of weight trend is basically identical between showing each group；Each song in figure
Line is represented respectively：A) physiological saline group, b) Blank gel group c) is injected intravenously Docetaxol injection group, d) intratumor injection
Docetaxol injection group, e) intratumor injection Docetaxel gel group.
Fig. 2 shows each group mouse tumor relative volume variation diagram, shows intratumor injection Docetaxel gel of the present invention
The tumour growth rate of group animal is substantially slower than other group animals.Each curve is represented respectively in figure：A) physiological saline group, it is b) empty
White gel group, c) is injected intravenously Docetaxol injection group, d) intratumor injection Docetaxol injection group, e) intratumor injection
Docetaxel gel group.
Claims (13)
1. a kind of pharmaceutical composition, consisting of：0.05 ~ 0.75% taxone, the shitosan of 0.75-4%, 3-18%
Sodium β-glycerophosphate, 0.75-7.5% ethanol, the water of organic acid or its salt and aequum；The organic acid be selected from citric acid or
Tartaric acid, the organic acid or its salt are 0.5 ~ 2 with the mol ratio of the sodium β-glycerophosphate：100.
2. pharmaceutical composition according to claim 1, its placed 1 hour at 5 ~ 28 DEG C of temperature after liquid in a flowable.
3. pharmaceutical composition according to claim 1, its place 30min at 33 ~ 42 DEG C of temperature after in not flowable half
Solid hydrogel.
4. pharmaceutical composition according to claim 1, its gelling time with 5 ~ 60min at a temperature of 37 DEG C.
5. pharmaceutical composition according to claim 1, its solidifying time of solution with 10 ~ 60min at a temperature of 20 DEG C.
6. pharmaceutical composition according to claim 1, wherein described taxone is selected from：Taxol, Docetaxel,
Paclitaxel-2'-hydroxy, 10-deacetyl taxol, 7-epi-taxol and combinations thereof.
7. pharmaceutical composition according to claim 1, it is determined at 20 DEG C and in the state of liquid, and its pH value is 6.0 ~ 7.5.
8. pharmaceutical composition according to claim 1, it is determined at 20 DEG C and in the state of liquid, and its pH value is 6.5 ~ 7.5.
9. pharmaceutical composition according to claim 1, it is the sterile preparation that injectable is used.
10. the pharmaceutical composition of any one of claim 1-9 prepare anticancer medicine in purposes.
The purposes of 11. claims 10, the cancer therapy drug locating injection approach is used for treatment or the operation rear defence of malignant tumour
Only recur.
The purposes of 12. claims 11, the mode of the tumor-localizing drug administration by injection is selected from：Intratumor injection, knurl week injection, it is subcutaneous
Injection, intracavitary administration, selective arterial injection, in lymph node and intramedullary injection.
The purposes of 13. claims 11, the malignant tumour is selected from：Oophoroma, stomach cancer, liver cancer, prostate cancer, cancer of pancreas, breast
Gland cancer, kidney, non-small cell lung cancer, head and neck cancer, the cancer of the esophagus, cervical carcinoma, colorectal cancer, cutaneum carcinoma, black cancer.
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| Title |
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| A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel;Eve Ruel-Gariepy et al.;《European Journal of Pharmaceutics and Biopharmaceutics》;20041231;第57卷;第53-63页 * |
| Cuiyun Li et al.Efficacy, Pharmacokinetics, and Biodistribution of Thermosensitive Chitosan/β-Glycerophosphate Hydrogel Loaded with Docetaxel.《AAPS PharmSciTech》.2014,第15卷(第2期),第417-424页. * |
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