CN102204881A - Gel sustained-release injection containing camptothecin or derivatives thereof, and preparation method thereof - Google Patents
Gel sustained-release injection containing camptothecin or derivatives thereof, and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicaments, and in particular relates to a gel sustained-release injection containing camptothecin or derivatives thereof, and a preparation method thereof. The gel sustained-release injection is composed of amphipathic segmented copolymers, an effective dose of anti-tumor drug and a solvent, wherein the gel material is a mixture composed of two or more polymers, the water system of the gel material is capable of generating thermosensitive gelation when the temperature rises, and the polymers are generally segmented copolymers formed by polyethylene glycol as a hydrophilic segment and degradable polyester as a hydrophobic segment; and the anti-tumor drug is selected from camptothecin or derivatives thereof. The preparation can be administered by injection, and after the preparation is gelated in situ in vivo, the encapsulated drug can be slowly released. The preparation can be injected into or around a tumor, also can be administered in a tumor cavity after an operation, has a passive targeting function, can effectively reduce the systemic toxicity of the drug, and can be used for treating tumors at different stages.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of gel rubber sustained-release injection and preparation method thereof.
Background technology
As everyone knows, cancer is the major disease of harm people of various countries life and health, and operation adds the main means that chemotherapy is the treatment cancer.Clinical practice proves that traditional chemotherapy mode is treated in the neoplastic process, and medicine is actual, and to reach the valid density of tumor locus on the low side, and toxic and side effects is big.Improve the enrichment of medicine, and then the enhancing chemotherapy effect is the focus of studying instantly at tumor locus.Wherein, tumor by local administration artificially passive target makes tumor by local keep high concentration, thereby improves therapeutic effect to tumor locus, reduces general toxicity simultaneously.
Camptothecine and derivant thereof are the inhibitor of topoisomerase I.But topoisomerase I inducing DNA strand reversibility fracture, camptothecine or and derivant can form stable ternary complex with topoisomerase I and DNA, stop the link again of sub-thread chain rupture, thereby make apoptosis.Topoisomerase I exists only in the S phase of fission process, i.e. the DNA synthesis stage.Camptothecine and derivant thereof are the specific drugs of S phase cell cycle.According to reported in literature, the cell of only having an appointment at one time about 10-15% is in the S phase, will more help the raising therapeutic effect so if can realize the long-acting release of camptothecine and derivant thereof.
In recent years, the slow/controlled release drug-supplying system development of medicine is very fast, the slow/controlled release drug-supplying system can be at a fixed time in, discharge medicine according to predetermined direction continuously to whole body or a certain certain organs, and control blood drug level is between minimal effective concentration and poisoning concentration, thereby the increase bioavailability of medicament, the toxic and side effects of minimizing medicine improves the compliance of patient's medication.Wherein, be the key factor that drug-supplying system has specific function as the biomaterial of pharmaceutical carrier, by developing new high performance drug carrier material, will play promoting and guaranteeing role for the slow/controlled release of realizing medicine.Hydrogel is very similar with body tissue because of it, has excellent biological compatibility, also becomes a kind of original slow releasing carrier of medication material simultaneously.The process of reversible its gelation of hydrogel material of particularly injectable heat is a reversible physical change process, does not relate to organic solvent, also need not chemical reaction, so toxicity is low, blandness; Be drug administration by injection simultaneously, have the advantage of Wicresoft again, thereby be subjected to extensive concern.
The aqueous systems of amphipathic copolymer (polylactic acid-polyglycol-polylactic acid, Vicryl Rapide-Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, polyethylene glycol-lactic acid-Polyethylene Glycol or Polyethylene Glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol) can present the characteristic of thermosensitive hydrogel sometimes.But there are the following problems for this based block copolymer of one-component:
(1) exceeds the size of definite composition and/or molecular weight, just be merely able to water-soluble fully or partially or completely become precipitation, thereby lost sol-gel transition, no longer have a performance of relevant heat-sensitive gelization;
(2) in addition, even sensitive characteristic can appear in partial polymer, the also improper human body of its gelling temperature is used;
(3) range of accommodation of its degradation rate and dynamic process have certain limitation, have also limited its medical usage.
Summary of the invention
The object of the present invention is to provide a kind of gel compliance, biocompatibility, degradability good, and have gel combination slow releasing injection of reversible temperature sensitive property and preparation method thereof.
Gel combination slow releasing injection provided by the invention, by being the gel carrier material with the block copolymer, the camptothecine or derivatives thereof is contained medicine, and water is that the disperse medium of main body is a solvent, and the three constitutes jointly.
Among the present invention, described gel carrier material is two or more mixture of polymers, heat-sensitive gelization can take place along with temperature raises in the aqueous systems of this polymeric blends, promptly when temperature is lower than the sol-gel transition temperature, polymeric blends is dissolvable in water water, when temperature is higher than the sol-gel transition temperature, the spontaneous formation gel of the aqueous solution of polymeric blends, and this process is reversible; Comprise in the polymer wherein that be the block copolymer that hydrophobic block constituted by Polyethylene Glycol (PEG) for hydrophilic block, degradable polyester.
Among the present invention, it is a kind of for health, gefitinib for health, Karenitecin, lucky miaow that the contained medicine of gel combination slow releasing injection is selected from camptothecine, 10-hydroxycamptothecine, 9-nitrocamptothecin, 9-aminocamptothecin, 7-ethyl-10-hydroxycamptothecine, topotecan, irinotecan, Rubitecan, Exatecan, shellfish sieve, or wherein several combinations.
Among the present invention, the used solvent of gel combination slow releasing injection is body fluid, tissue culture medium, the cell culture fluid of pure water, water for injection, normal saline, buffer solution, animals and plants or human body, perhaps for other aqueous solution with not based on the medium of organic solvent.
In the polymeric blends of the present invention, there is the aqueous systems of one or more block copolymers not have the character of heat-sensitive gelization separately, though this can be dissolved in the water these one or more block copolymers in 1-50 ℃ of scope, heat-sensitive gelization can not occur separately; Perhaps, one or more block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully, thereby heat-sensitive gelization can not occur separately.
In the polymeric blends of the present invention, one or more block copolymers are arranged, and this all can only be dissolved in the water in 1-50 ℃ of scope, simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully.
In the polymeric blends of the present invention, the aqueous systems of each block copolymer can all not have the character of heat-sensitive gelization yet.
In the polymeric blends of the present invention, the weight percent content of every kind of block copolymer is between 5-95%, and various block copolymer sums are 100%.
Block copolymer of the present invention comprises that containing of 10-90 wt % has the hydrophilic A polymer blocks of Polyethylene Glycol of 400 to 8000 mean molecule quantity and the hydrophobicity B polymer blocks of 90-10 wt %.
Hydrophobicity B polymer blocks of the present invention is the polyester with mean molecule quantity of 500-40000.
Polyester of the present invention is selected from various poly DL-lactides, poly-D-lactide, poly-L-lactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-Wu Neizhi, poly-1,4, any in 8 – trioxa spiral shell [4.6] –, 9 – hendecanones, poly-P-Dioxane ketone, polyesteramide, Merlon, polyacrylate, the polyether ester, the perhaps any type of copolymer of above-mentioned each kind polyester.
Block copolymer of the present invention is the triblock copolymer of ABA, BAB block configuration, perhaps is the diblock copolymer of BA block configuration, perhaps is and A (BA)
n Or B (AB)
n The segmented copolymer of block configuration, wherein
nIt is 2 to 10 integer.
The weight percent content of polymeric blends of the present invention in aqueous solution be between 3-50%, but be preferred with 10-30%, and 15-28% is for most preferably.
The pH value of gel injection of the present invention is between 2.5-8.0.
The percentage by weight of contained medicine of the present invention is between 0.01-40 wt%.
The present invention finds that also when materials such as gel combination slow releasing injection adding salt, Polyethylene Glycol, chitosan, variation to a certain degree can take place for gelling temperature and drug release rate, and this type of material is called regulator.Regulator can be (but being not limited to): a kind of, the perhaps wherein several combination in various sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, mountain plough alcohol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, albumin glue, hyaluronic acid, the Polyethylene Glycol.Regulator also can be other medical dressing, as filler, solubilizing agent, absorption enhancer, film former, gel, porogen, excipient or blocker etc.Regulator at the weight percentage of gel rubber sustained-release injection between 0.01-15%, preferred 1-15%, more preferably 5-15% is because of concrete needs be decided.
In the gel combination slow releasing injection of the present invention, except block copolymer, medicine and solvent, the polymer that can comprise other type is or/and the non-polymer composition.
Gel combination material of the present invention can improve camptothecine or and the closed loop rate of derivant lactonic ring, camptothecine or and the closed loop ratio of derivant in injection reach 15%-95%.
It is one of following that the preparation method of the gel combination slow releasing injection that the present invention proposes is selected from:
(1) at first mix two or more polymer, then at the dissolution in low temperature polymeric blends in solvent; Add medicine at last, become gel injection behind the dissolving mixing ,-20 ℃ or following storing for future use; Injection in redissolution, the body before using;
(2) at first when low temperature, dissolve two or more polymer respectively, mix solution separately then with solvent; Add medicine at last, become gel injection behind the dissolving mixing ,-20 ℃ or following storing for future use; Injection in redissolution, the body before using;
(3) at first have water miscible polymer in solvent, and then add and not have or not exclusively to have water miscible polymer and carry out solubilising at dissolution in low temperature, thus the preparation hydrogel composition; Add medicine at last, become gel injection behind the dissolving mixing ,-20 ℃ or following storing for future use; Injection in redissolution, the body before using;
(4) prepare block copolymer composition aqueous solution and pharmaceutical preparation respectively, packing stores separately, will make gel sustained-release preparation behind block copolymer composition aqueous solution and the abundant mixing of pharmaceutical preparation before the injection;
(5) preparation obtains medicaments injection earlier, is mixed into gel injection with block copolymer composition then ,-20 ℃ or following storing for future use; Injection in redissolution, the body before using;
(6), add solvent then and make gel sustained-release preparation with block copolymer composition and medicament mixed; Be stored in low temperature or freezing state, use the redissolution back of heating up before using.
In the said method, medicine be selected from camptothecine, 10-hydroxycamptothecine, 9-nitrocamptothecin, 9-aminocamptothecin, 7-ethyl-10-hydroxycamptothecine, topotecan, irinotecan, Rubitecan, Exatecan, shellfish sieve for health, Karenitecin, lucky miaow for one of health, gefitinib or its combination.
In the said method, solvent in the gel combination slow releasing injection can be body fluid, tissue culture medium, the cell culture fluid of pure water, water for injection, normal saline, buffer solution, animals and plants or human body, perhaps for other aqueous solution with not based on the medium of organic solvent.
In the said method, low temperature refers to 0 ℃ to room temperature.
In the said method, low temperature refers in particular to refrigerator cold-storage temperature (4 ℃).
In the said method, polymer is for being that hydrophilic block, degradable polyester are the block copolymer that hydrophobic block constituted by Polyethylene Glycol (PEG).
In the said method, block copolymer obtains by thermal condensation or ring-opening polymerisation.
In the said method, the catalyst that ring-opening polymerisation is adopted is stannous iso caprylate, calcium hydride or zinc powder.
In the said method, there is the aqueous systems of one or more block copolymers not have the character of heat-sensitive gelization separately in the mixture, though this can be dissolved in the water these one or more block copolymers in 1-50 ℃ of scope, heat-sensitive gelization can not occur separately; Perhaps, one or more block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully thereby heat-sensitive gelization can not occur separately.
In the said method, this can only be dissolved in the water one or more block copolymers in the mixture in 1-50 ℃ of scope, and simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully.
In the said method, the aqueous systems of each block copolymer in the mixture does not have the character of heat-sensitive gelization separately.
In the said method, the weight percent content of every kind of block copolymer in the mixture is between 5-95%.
In the said method, block copolymer comprises:
A) the hydrophilic A polymer blocks that contains Polyethylene Glycol of 10-90 wt % with mean molecule quantity of 400 to 8000;
B) the hydrophobicity B polymer blocks of 90-10 wt %.
In the said method, hydrophobicity B polymer blocks is the polyester with mean molecule quantity of 500-40000.
In the said method, polyester is selected from various poly DL-lactides, poly-D-lactide, poly-L-lactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-Wu Neizhi, poly-1, the any type of copolymer of any and above-mentioned each kind polyester in 4,8 – trioxa spiral shell [4.6] –, 9 – hendecanones, poly-P-Dioxane ketone, polyesteramide, Merlon, polyacrylate, the polyether ester.
In the said method, block copolymer is the triblock copolymer of ABA, BAB block configuration, the diblock copolymer or the A (BA) of BA block configuration
n Or B (AB)
n The segmented copolymer of block configuration, wherein
nIt is 2 to 10 integer.
In the said method, the weight percentage of polymeric blends in aqueous solution be between 3-50%, but be preferred with 10-30%, and 15-28% is for most preferably.
In the said method, the pH value of gel injection is between 2.5-8.0.
In the said method, the percentage by weight of medicine is between 0.01-40 wt%.
In the said method, can add regulator in the gel combination slow releasing injection, its weight percentage in aqueous systems is between 0.01-15%, because of specifically needing to decide; Regulator can be selected from a kind of or its combination in sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, mountain plough alcohol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, albumin glue, hyaluronic acid, the Polyethylene Glycol.Regulator also can be other medical dressing, as filler, solubilizing agent, absorption enhancer, film former, gel, porogen, excipient or blocker etc.
In the said method, can in gel rubber sustained-release injection, further mix the polymer even the non-polymer composition of other types, with the appearance that promotes physical gel or be adjusted in the sol-gel transition temperature in the solution, the parameters such as degradation rate of material.
In the said method, the gel combination material can improve camptothecine or and the closed loop rate of derivant lactonic ring, camptothecine or and the closed loop ratio of derivant in injection reach 15%-95%.
In the said method, the ratio of block copolymer can be regulated, thereby obtains needed sol-gel transition temperature and degradation rate etc.
Gel combination slow releasing injection of the present invention is injected in subcutaneous, intracavity, abdominal cavity, thoracic cavity, canalis spinalis, in the tumor, in tumor week, tremulous pulse, lymph node and the bone marrow.
Gel combination slow releasing injection of the present invention can be used for the treatment of the tumor of former of the cerebral tumor, hepatocarcinoma, oral cancer, carcinoma of gallbladder, skin carcinoma, hemangioma, osteocarcinoma, lymphatic cancer, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, incidence cancer etc. or secondary.
The invention has the advantages that:
The gel combination slow releasing injection that the present invention proposes has reversible temperature sensitive property, when can or being lower than room temperature at room temperature, it shows water solublity, and under the warm-blooded animal physiological condition (promptly pH value be about 7 and 37 ℃ under) can carry out heat-convertible gelization, thereby make that the preparation process of preparation is simple and practical, practical operation and application are very convenient.
The gel combination slow releasing injection that the present invention proposes can pass through the injection system administration, preparation is in vivo after the gelatinizing-in-situ, the medicine of parcel not only can slowly discharge also can keep higher drug level, and can increase the sensitivity of medicine, the release cycle can be regulated and control from a few hours to several weeks.This load have camptothecine or and the syringeability temperature-sensitive hydrogel preparation of derivant tumor intracavitary administration after surgery, thereby effectively remove postoperative residual tumor cell in the irregular tumor chamber that can effectively cover behind the tumor resection, and postoperative hemostasis and prophylaxis of tumours cellular invasion are also had preventive effect preferably; Also can or inject in tumor week in tumor, have the function of passive target, can effectively reduce the general toxicity of medicine, can be used for the oncotherapy of different phase.
Simultaneously, the gel combination material that the present invention proposes has the compliance of excellent biological compatibility, degradability and gel, and this material can be degraded to nontoxic α-alkyd and other corresponding monomer fully in preset time.
Description of drawings
Fig. 1. for its viscosity in aqueous solution of block copolymer mixture that obtains according to the Different Weight mixed varies with temperature figure.Measure with dynamic rheometer.
Fig. 2. topotecan is release profiles from gel.
Fig. 3. hydroxy camptothecin is release profiles from gel.
The specific embodiment
Further describe the present invention below by example, but be not limited to these embodiment.
In 250 ml there-necked flasks, add PEG(1500), oil bath is heated to 150 ℃, vacuum filtration is three hours under stirring, to remove residual moisture among the PEG, adding mol ratio then is DL-lactide and the Acetic acid, hydroxy-, bimol. cyclic ester of 4:1, and heating makes after its complete fusion under the vacuum, adds 120 μ l stannous octoates, oil bath is warmed up to 160 ℃, continues reaction 24 hours under argon gas atmosphere.Reaction finishes, and vacuum filtration two hours is to remove responseless monomer and lower boiling product.Head product is dissolved in the dichloromethane solution, ether sedimentation, productive rate is about 80%.By chromatograph of gel permeation (GPC) (adopt polystyrene as standard specimen) measure described BAB block copolymer (PLGA-PEG-PLGA, number average Copolymer-1) and weight average molecular weight (
M n ,
M w ) be respectively 5510 and 6390, the molecular weight distribution coefficient (
M w /
M n ) be 1.16.This does not have the performance of heat-sensitive gelization this copolymer in water.
In 250 ml there-necked flasks, add single-ended methoxy poly (ethylene glycol) MPEG(550), oil bath is heated to 150 ℃, vacuum filtration is three hours under stirring, to remove residual moisture among the MPEG, adding mol ratio then is DL-lactide and the Acetic acid, hydroxy-, bimol. cyclic ester of 3:1, and heating makes after its complete fusion under the vacuum, adds 120 μ l stannous octoates, oil bath is warmed up to 160 ℃, continues reaction 24 hours under argon gas atmosphere.Reaction finishes, and vacuum filtration two hours is to remove responseless monomer and lower boiling product.Head product is dissolved in the dichloromethane solution, ether sedimentation, productive rate is about 85%.By chromatograph of gel permeation (GPC) (adopt polystyrene as standard specimen) measure described AB block copolymer (MPEG-PLGA, number average Copolymer-14) and weight average molecular weight (
M n ,
M w ) be respectively 3550 and 4620, the molecular weight distribution coefficient (
M w /
M n ) be 1.30.This does not have the performance of heat-sensitive gelization this copolymer in water.
In 250 ml there-necked flasks, add Polyethylene Glycol (1000) and PLGA(
M n 4750,
M w 6020, mixture LA/GA=1/1), heating makes after its complete fusion under the vacuum, and oil bath is warmed up to 160 ℃ of condensation reactions 18 hours.Reaction finishes, and head product is dissolved in the dichloromethane solution, uses a large amount of ether sedimentations, and productive rate is about 85%.By chromatograph of gel permeation (GPC) (adopt polystyrene as standard specimen) measure the number average of described BAB block copolymer and weight average molecular weight (
M n ,
M w ) be respectively 6520 and 8340(PLGA-PEG-PLGA, Copolymer-15), the molecular weight distribution coefficient (
M w /
M n ) be 1.28.This does not have the performance of heat-sensitive gelization this copolymer in water.
According to the basic step that embodiment 1 provides, synthesize other block copolymer with the PEG of different molecular weight and different monomers.The performance of these copolymers is listed in the table below:
Table 1
Table 2:
Table 3:
The block copolymer of table 1 and table 2 does not all have the performance of heat-sensitive gelization, and the block copolymer of its invading the exterior 1 just can dissolve in water, and the block copolymer of table 2 can not be dissolved in water or can not be dissolved in water fully; And the block copolymer of table 3 itself just has the performance of heat-sensitive gelization.One or more block copolymers can be from table 3, chosen and water can be when temperature is lower than gel transition temperature, be dissolved in the mixture that the certain proportion mixing obtains with from table 1 and/or table 2, choosing one or more block copolymers, when temperature is higher than gel transition temperature, the aqueous solution of polymeric blends forms gel, and this process is reversible; Also can from table 1, choose one or more block copolymers and mix the performance that the mixture that obtains also has heat-sensitive gelization with certain proportion with from table 2, choosing one or more block copolymers.
At first obtain corresponding mixture with block copolymer C opolymer-1 in 1/1 the mixed table 1 and the block copolymer C opolymer-9 in the table 2, add a certain amount of aqueous solution then, be mixed with weight percent concentration and be 20% sample, pass through magnetic agitation in refrigerator cold-storage temperature (4 ℃) at last, make polymeric blends that the corresponding aqueous solution of dissolving preparation take place.The polymeric blends aqueous solution of preparation can spontaneous formation gel when temperature is higher than the sol-gel transition temperature.
It at first is the aqueous solution of 10% block copolymer C opolymer-1 in room temperature preparation weight percent concentration, and then in above-mentioned aqueous solution, add the block copolymer C opolymer-9 of same percentage by weight, pass through magnetic agitation in room temperature at last, make block copolymer C opolymer-9 solubilising enter solution, prepare corresponding weight percent concentration and be 20% aqueous solution.The aqueous solution of polymeric blends of preparation can spontaneous formation gel when temperature is higher than the sol-gel transition temperature; And gelling performance is identical with the sample of preparation among the embodiment 5.
At first be the aqueous solution of the block copolymer C opolymer-16 of the aqueous solution of 20% block copolymer C opolymer-1 and same weight percent concentration, then with the aqueous solution of 1/1 the above-mentioned formulations prepared from solutions corresponding polymer of ratio uniform mixing mixture in refrigerator cold-storage temperature (4 ℃) preparation weight percent concentration.When temperature was higher than the sol-gel transition temperature, the aqueous solution of the polymeric blends of preparation can spontaneous formation gel.
Studied the gelation behavior of the triblock copolymer mixture aqueous solution that block copolymer C opolymer-1 and Copolymer-9 obtain according to the Different Weight mixed.The mixture aqueous solution that has prepared blended 20% percent concentration of 1/2,1/1,2/1 part by weight has been measured the variation of its viscosity with temperature between 15 ℃ to 45 ℃.Fig. 1 is the variation diagram that Copolymer-1 and Copolymer-9 Different Weight mixed obtain its viscosity with temperature of sample, the transition process of sol-gel has been reacted in the rapid increase of figure medium viscosity, through determining that phase transition temperature is respectively 28 ℃, 34 ℃ and 41 ℃.
The concentration of block copolymer C opolymer-16 in the table 3 is that sol-gel transition takes place in the time of 13 ℃ 20% aqueous solution, forms hydrogel; 20% aqueous solution of Copolymer-1 does not have the performance of heat-sensitive gelization; Mix above-mentioned two kinds of samples that solution obtains with different part by weight, its sol-gel transition temperature can be regulated between 13～37 ℃.
Get hydrogel composition 10 g in embodiment 5 or 6, average mark installs in the container of 5 topotecan that fill 100,20,2 mg respectively then, make the hydrogel composition slow releasing injection that contains 5%, 1% and 0.1% topotecan, and measure its gelation transition temperature and be respectively 33 ℃, 34 ℃ and 34 ℃.
Embodiment 11
It is 2% PEG(2000 that hydrogel composition slow releasing injection in embodiment 10 adds percentage by weight) during polymer, significant change does not take place in its gel strength, and its sol-gel transition temperature has descended 2 ℃ respectively.
Embodiment 12
Get and make each 1 g of hydrogel composition slow releasing injection that contains 5%, 1% and 0.1% topotecan among the embodiment 10, place bag filter respectively, be immersed in the buffer (300 mL) of pH 7.4.The closed loop rate that recorded the medicine lactonic ring in 72 hours after the balance is respectively 80%, 75% and 83%.
Embodiment 13
Get hydrogel composition 10 g in embodiment 5 or 6, average mark installs in the container of 5 hydroxy camptothecins that fill 100,20,2 mg respectively then, make the hydrogel composition slow releasing injection that contains 5%, 1% and 0.1% hydroxy camptothecin, and measure its gelation transition temperature and be respectively 25 ℃, 30 ℃ and 32 ℃.
Embodiment 14
20% aqueous solution, 10 g according to 1/1 part by weight mixed C opolymer-1 and Copolymer-9 preparation obtain add 10 mg topotecan, transfer pH to subacidity topotecan to be dissolved fully, and the back transfers pH to neutral.Get the above-mentioned medicine carrying gel of 1 g and be written in the test tube, add 10 mL release medium.Regularly get a survey absorbance.The gained release profiles as shown in Figure 2.
Altogether be dissolved in chloroform according to 1/1 part by weight mixed C opolymer-1 and Copolymer-9 copolymer mixture material 5 mg hydroxy camptothecins and 1 g, the outstanding film forming of doing, add aqueous medium 4 g again and disperse, obtaining polymer concentration is 20 wt%, and drug loading is the solution of 1 mg/g.Get 1 g solution and place test tube, be incubated 10 min, become gel in 37 ° of C.Add the phosphate buffer that 7 mL are preheating to 37 ° of C above, press the setting-up time sampling, survey its absorbance, the gained release profiles as shown in Figure 3.
Embodiment 16
Get well-grown 7-11 days S180 tumor kind, tumor tissue is made 1-2 * 10
7/ ml cell suspension, right side of mice armpit subcutaneous vaccination 0.2 mL/ are only.Inoculate and divide cage at random after 24 hours, topotecan gel group and simple topotecan tumor-side injection administration in the 1st, 6 days 2 times, each every Mus 0.1 mL.TPT intravenous injection group the 1st, 3,5,7,9 day intravenously administrable 5 times behind tumor inoculation, each every Mus 0.1 mL.
Put to death animal on the 11 day, claim that the heavy ﹑ tumor of body is heavy, it is heavy that average tumor is respectively organized in calculating, obtains tumor control rate and carry out the t check by following formula.
The therapeutic evaluation standard: tumor control rate＜40% is invalid; Tumor control rate 〉=40, and processing p＜0.05 is effective by statistics.Gained the results are shown in Table 4.As seen under the Isodose, gel pack medicine treatment group is better than simple medicine subcutaneous injection and simple medicine intravenous injection therapeutic effect.
Table 4. tumor-side injection is to the experimental therapy effect of mice S180 sarcoma
Claims (14)
1. gel rubber sustained-release injection that contains the camptothecine or derivatives thereof, it is characterized in that: being the gel carrier material with the block copolymer mixture, is contained medicine with the camptothecine or derivatives thereof, is solvent based on the disperse medium of water, the three constitutes jointly; Wherein:
Described block copolymer mixture is made up of two or more polymer mixed, its aqueous systems can be along with the temperature spontaneous generation physical gelization that raises: when temperature is lower than the sol-gel transition temperature, polymeric blends is dissolvable in water water, when temperature was higher than the sol-gel transition temperature, the aqueous solution of polymeric blends formed gel; Comprise by Polyethylene Glycol being that hydrophilic block, degradable polyester are the block copolymer that hydrophobic block constituted in the polymer wherein;
It is a kind of for health, gefitinib for health, Karenitecin, lucky miaow that described medicine is selected from camptothecine, 10-hydroxycamptothecine, 9-nitrocamptothecin, 9-aminocamptothecin, 7-ethyl-10-hydroxycamptothecine, topotecan, irinotecan, Rubitecan, Exatecan, shellfish sieve, or wherein several combinations;
Described solvent is selected from body fluid, tissue culture medium, the cell culture fluid of pure water, water for injection, normal saline, buffer solution, animals and plants or human body, perhaps for other aqueous solution with not based on the medium of organic solvent.
2. gel rubber sustained-release injection according to claim 1 is characterized in that, has the aqueous systems of one or more block copolymers not have the character of heat-sensitive gelization separately in the described polymeric blends; Though this can be dissolved in the water these one or more block copolymers in 1-50 ℃ of scope, but separately heat-sensitive gelization can not appear, perhaps these one or more block copolymers itself can not be water-soluble or can not be dissolved in the water fully, thereby heat-sensitive gelization can not occur separately.
3. gel rubber sustained-release injection according to claim 1, it is characterized in that, in the described polymeric blends, this can only be dissolved in the water one or more block copolymers in 1-50 ℃ of scope, simultaneously, another or more than one block copolymers can not be water-soluble in 1-50 ℃ of scope or can not be dissolved in the water fully.
4. gel rubber sustained-release injection according to claim 1 is characterized in that, the aqueous systems of each block copolymer in the described polymeric blends does not have the character of heat-sensitive gelization separately.
5. according to the described gel rubber sustained-release injection of one of claim 1-4, it is characterized in that the weight percent content of every kind of block copolymer in the described polymeric blends is 5-95%, various block copolymer sums are 100%.
6. gel rubber sustained-release injection according to claim 1 is characterized in that, described block copolymer comprises:
A) the hydrophilic A polymer blocks that contains Polyethylene Glycol of 10-90 wt % with mean molecule quantity of 400 to 8000;
B) the hydrophobicity B polymer blocks of 90-10 wt %, this hydrophobicity B polymer blocks is the polyester with mean molecule quantity of 500-40000.
7. gel rubber sustained-release injection according to claim 6, it is characterized in that, described polyester is selected from poly DL-lactide, poly-D-lactide, poly-L-lactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-Wu Neizhi, poly-1,4, any in 8 – trioxa spiral shell [4.6] –, 9 – hendecanones, poly-P-Dioxane ketone, polyesteramide, Merlon, polyacrylate, the polyether ester, the perhaps any type of copolymer of above-mentioned each kind polyester.
8. gel rubber sustained-release injection according to claim 1 is characterized in that described block copolymer is the triblock copolymer of ABA, BAB block configuration, perhaps is the diblock copolymer of BA block configuration, perhaps is A (BA)
n Or B (AB)
n The segmented copolymer of block configuration, wherein
nIt is 2 to 10 integer.
9. gel rubber sustained-release injection according to claim 1 is characterized in that the weight percent content of described polymeric blends in aqueous solution is 3-50%.
10. gel rubber sustained-release injection according to claim 1 is characterized in that the pH value of described injection is between 2.5-8.0.
11. gel rubber sustained-release injection according to claim 1 is characterized in that, contained medicine is the 0.01-40 % of gel rubber sustained-release injection weight.
12. gel rubber sustained-release injection according to claim 1 is characterized in that, this gel rubber sustained-release injection also adds regulator, and the weight percentage of this regulator in aqueous systems is 0.01-15%; Regulator is selected from a kind of in sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, mountain plough alcohol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, albumin glue, hyaluronic acid, the Polyethylene Glycol or wherein several combinations.
13. the preparation method as the described gel rubber sustained-release injection of one of claim 1-12 is characterized in that being selected from one of following:
(1) at first mix two or more polymer, then at the dissolution in low temperature polymeric blends in solvent; Add medicine at last, become gel injection behind the dissolving mixing ,-20 ℃ or following storing for future use; Injection in redissolution, the body before using;
(2) at first when low temperature, dissolve two or more polymer respectively, mix solution separately then with solvent; Add medicine at last, become gel injection behind the dissolving mixing ,-20 ℃ or following storing for future use; Injection in redissolution, the body before using;
(3) at first have water miscible polymer in solvent, and then add and not have or not exclusively to have water miscible polymer and carry out solubilising at dissolution in low temperature, thus the preparation hydrogel composition; Add medicine at last, become gel injection behind the dissolving mixing ,-20 ℃ or following storing for future use; Injection in redissolution, the body before using;
(4) prepare block copolymer composition aqueous solution and pharmaceutical preparation respectively, packing stores separately, will make gel sustained-release preparation behind block copolymer composition aqueous solution and the abundant mixing of pharmaceutical preparation before the injection;
(5) preparation obtains medicaments injection earlier, is mixed into gel injection with block copolymer composition then ,-20 ℃ or following storing for future use; Injection in redissolution, the body before using;
(6), add solvent then and make gel rubber sustained-release injection with block copolymer composition and medicament mixed; Be stored in low temperature or freezing state, use the redissolution back of heating up before using;
The above low temperature refers to be lower than the sol-gel transition temperature of compositions; Prepared gel combination slow releasing injection can hot reversible formation hydrogel when temperature is higher than the sol-gel transition temperature.
14. as the application of the described gel rubber sustained-release injection of one of claim 1-12 in preparation medicine for treating tumor compositions, described tumor is the tumor of the cerebral tumor, hepatocarcinoma, carcinoma of gallbladder, skin carcinoma, oral cancer, hemangioma, osteocarcinoma, lymphatic cancer, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, these former of incidence cancer or secondary.
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Application publication date: 20111005 |