CN104116704A - Norcantharidin thermosensitive gel and preparation method and application thereof - Google Patents
Norcantharidin thermosensitive gel and preparation method and application thereof Download PDFInfo
- Publication number
- CN104116704A CN104116704A CN201310152638.2A CN201310152638A CN104116704A CN 104116704 A CN104116704 A CN 104116704A CN 201310152638 A CN201310152638 A CN 201310152638A CN 104116704 A CN104116704 A CN 104116704A
- Authority
- CN
- China
- Prior art keywords
- norcantharidin
- thermo
- agent
- gel
- hydro gel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses norcantharidin thermosensitive gel, comprising the following components by mass percent: 0.05-2% of norcantharidin, 15-20% of poloxamer 407, 0.5-2% of poloxamer 188, 0.25-2% of polysorbate 80, 0.5-2% of ethyl alcohol and the balance of water. The gel is in a liquid state at low temperature, and is rapidly converted into a gel state when being injected into a tumor body, the effects of permanent efficacy, smooth drug release, small toxic and side effects and significant pharmacological effect are achieved, and the norcantharidin thermosensitive gel can be applied to treatment of malignant tumors such as the liver cancer and the like by intratumoral injection of tumors. In addition, a preparation method of the gel is also disclosed.
Description
Technical field
The present invention relates to the agent of a kind of norcantharidin thermo-responsive hydro gel, in addition, the invention still further relates to preparation method and the medical usage thereof of this norcantharidin thermo-responsive hydro gel agent.
Background technology
At present, the malignant tumor including hepatocarcinoma, gastric cancer, pulmonary carcinoma etc. in the world sickness rate presents rapid growth trend, and chemotherapy is one of important means of clinical therapy of tumor.Norcantharidin (formula I) is by the anti-tumor active ingredient cantharidin extracting from Chinese medicine Mylabris at first, through chemical modification and come new antitumoral bioactive molecule, its mechanism of action is: promote the cell death of tumor cell and infection, specificity prevents tumor cell in G
2+ M phase and inhibition tumor cell propagation; Anticancer DNA's is synthetic; Interference cell division, blocks the phase in M; Destruction of cancer cells skeleton and ultrastructure thereof; Improve cancerous cell respiratory control ratio, regulate immunity of organisms.Compared with cantharidin, antitumaous effect gets a promotion, and untoward reaction decreases, and also has the function of leukocyte increasing simultaneously.At present existing injection, tablet listing, clinically for primary hepatocarcinoma, Treating Alimentary Tract Tumor, be also applicable to the treatment of low leukocyte counts disease, hepatitis, liver cirrhosis, hepatitis b virus carrier.Although, use conventional non-slow release norcantharidin injection through hepatocarcinoma intratumor injection, there is certain Graft Versus Tumor, but because most tumors blood vessel is compared with horn of plenty, the medicine injecting in tumor enters body circulation with blood flow very soon, being difficult to has affected curative effect in the part stop effect long period, and single injection amount is when larger, and the toxic and side effects of generation is very obvious.
Poloxamer (Poloxamer) is polyoxyethylene poly-oxygen propylene aether block copolymer, and its general formula is HO(C
2h
4o)
a(C
3h
6o)
b(C
2h
4o)
ch.Wherein a and c are 2-130, and b is 15-67.Be 81.8 ± 1.9% containing polyoxyethylene.Current commercial poloxamer name is called general stream Buddhist nun gram (Pluronic), is the novel macromolecule non-ionic surface active agent of a class, comprises P188, P124, P188, P237, P338, many specifications of P40.Such adjuvant toxicity is little, good biocompatibility, and has reverse hot gelatification, and (4-5 DEG C) is lower to working fluid at low temperatures, under body temperature, becomes gel.Early stage, we adopted poloxamer188 as adjuvant, prepare norcantharidin-poloxamer188 injection slow releasing agent (being called for short: norcantharidin-poloxamer188 slow releasing agent), apply for Chinese patent CN1385154A(title: the slow releasing injection of antitumor norcantharidin), and deliver many sections of scientific papers (1. Li Bai, Ling Changquan, look into long pine. the dynamic change after ultrasound observation poloxamer188 rabbit injection into liver. The 2nd Army Medical College journal, 1998,19 (1): 98; 2. Li Bai, Wu Lili, Lin Wan and, Ling Changquan. the comparative experiments of different dosage form norcantharidin Acute Hepatic nephrotoxicity. Chinese journals of practical medicine, 1998,14 (5): 371-372; 3. Chen Jian, old Zhe, Gao Xiaofeng, Zheng Xiaomei, Jiang Dong, Weng Sanchuan, Ling Changquan. the toxicity of norcantharidin-poloxamer188 slow releasing preparation local injection is observed. Anhui Chinese Medicine College journal, 1999,18 (3): 11-13; 4. Ling Chang is complete, Li Bai, Chen Jian, Wang Wenjian, Zheng Xiaomei, Lin Wan and, Huang Xueqiang, Pan Ruiping. the experimentation of norcantharidin slow releasing preparation toxicity and curative effect. The 2nd Army Medical College journal, 1999,20 (9): 617-620; 5. Li Bai, the salty spring becomes, Zhang Nanzheng, Wang Rongen, Marvin's green grass or young crops. the impact of different factors on dissolution rate of sustained-release preparation of norcantharidin-poloxamer 407 in vitro. and Journal of Chinese Hospital Pharmacy, 1999,19 (9): 517-519; 6. old Zhe, Li Bai, Jiang Dong, Ling Changquan. the hepatocarcinoma intratumor injection curative effect comparison of norcantharidin-poloxamer188 slow releasing agent and dehydrated alcohol. The 2nd Army Medical College journal, 2001,22 (7): 606-608; 7. Li Bai, Zhu Lifeng, Zhang Yani, Gu Wei. the comparison of two kinds of injection type chmice acute toxicity of norcantharidin. Journal of Chinese Integrative Medicine, 2007,5 (1): 74-77).Although, norcantharidin-poloxamer188 slow releasing agent that Chinese patent CN1385154A announces is for liver cancer treatment, in certain degree, obtain the therapeutic effect that is better than conventional non-slow release norcantharidin injection, but this slow releasing agent is still shorter (< 4 hours) of the time of staying in tumor, gelation temperature is still higher, gelling transformation time is still longer, there is the prominent phenomenon of releasing of medicine, bring thus toxic and side effects still aobvious bigger than normal, with long-acting, steadily slow release, still there is very large gap in the clinical application demand of low toxicity, its clinical practice is also subject to severely restricts.
Formula I
Summary of the invention
For the above-mentioned deficiency of prior art, according to embodiments of the invention, wish to propose a kind of norcantharidin thermo-responsive hydro gel agent safe, effective, that side effect is little and be used for the malignant tumor such as intratumor injection for treatment of liver cancer, to both improving the antitumous effect of norcantharidin, alleviate again its toxic and side effects.The malignant tumor such as injection for curing hepatocarcinoma in tumor tumor body, this norcantharidin thermo-responsive hydro gel agent is liquid at low temperatures, in injection enters tumor tumor body after, comparatively fast be converted into gelatinized, realize long-acting, steady release, continue performance antitumor action, and there is less toxic and side effects.
According to embodiment, composition and the quality percentage composition thereof of norcantharidin thermo-responsive hydro gel of the present invention agent are: norcantharidin 0.05%-2%, poloxamer188 15%-20%, PLURONICS F87 0.5%-2%, polyoxyethylene sorbitan monoleate 0.25%-2%, ethanol 0.5%-2%, its surplus is water.Be preferably norcantharidin 0.25%-1%, poloxamer188 17%-19%, PLURONICS F87 0.5%-1%, polyoxyethylene sorbitan monoleate 0.5%-1%, ethanol 0.5%-1%, its surplus is water.Most preferably be norcantharidin 0.5%, poloxamer188 18%, PLURONICS F87 1.2%, polyoxyethylene sorbitan monoleate 0.7%, ethanol 0.7%, its surplus is water.
The preparation method of norcantharidin thermo-responsive hydro gel of the present invention agent comprises the steps: to take norcantharidin, adds suitable quantity of water, is heated to norcantharidin and dissolves, and forms norcantharidin solution; Add poloxamer188, PLURONICS F87 and polyoxyethylene sorbitan monoleate, after stirring low temperature be placed to swelling completely, mix; Add again ethanol and water, sterilizing, subpackage, to obtain final product.
Norcantharidin thermo-responsive hydro gel of the present invention agent is measured through gelation temperature, gelling characteristic, the gel strength of subsequent embodiment, and in experimentatioies such as the liver time of staying, pharmacological action, zest and acute toxicities, show that it has suitable gelation temperature, gelling transforms rapidly, in tumor body, the time of staying is long, without the prominent phenomenon of releasing, pharmacological effect is good, toxic and side effects is little, realize excellent results long-acting, steady release, be significantly better than the disclosed norcantharidin-poloxamer188 of Chinese patent CN1385154A slow releasing agent.Norcantharidin thermo-responsive hydro gel agent preparation method of the present invention is easy, and cost is lower, is applicable to large-scale production application.In view of the Cancer Mortalities such as hepatocarcinoma are high, tumour patient radix is huge, and chemotherapy is as important clinical treatment means, and norcantharidin thermo-responsive hydro gel of the present invention agent has wide market prospect, is containing huge society and economic benefit.
With respect to prior art, the present invention is on the basis of further investigation, the disclosed norcantharidin of Chinese patent CN1385154A-poloxamer188 injection slow releasing agent formula has been carried out to significant improvement, add PLURONICS F87, Polysorbate, ethanol as regulator, through repeatedly optimizing prescription proportioning, build novel norcantharidin thermo-responsive hydro gel agent.Norcantharidin thermo-responsive hydro gel of the present invention agent is liquid at low temperatures, in injection enters tumor tumor body, be converted into rapidly gelatinized, all there is significant improvement at aspects such as gelling characteristic, Release Performance, pharmacological effect, toxic and side effects, really realized long-acting, steady release, gelling transforms rapidly, and toxic and side effects is little, the significant effect of drug effect, the defect that has overcome Chinese patent CN1385154A, has obtained substantial progress.
Brief description of the drawings
Fig. 1 is that the method for recording by Chinese patent CN1385154A embodiment is prepared norcantharidin-poloxamer188 slow releasing agent, and the cumulative release-time plot of the norcantharidin thermo-responsive hydro gel agent of preparing by embodiment of the present invention 1-5 method.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, further set forth the present invention.These embodiment are interpreted as being only not used in and limiting the scope of the invention for the present invention is described.After having read the content of the present invention's record, those skilled in the art can make various changes or modifications the present invention, and these equivalences change and amendment falls into the scope of the claims in the present invention equally.
The preparation of embodiment 1, the agent of norcantharidin thermo-responsive hydro gel
Take 5g norcantharidin, add distilled water 600ml, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 180g, PLURONICS F87 12g, polyoxyethylene sorbitan monoleate 7g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 7ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, norcantharidin final concentration is 0.5%.
Embodiment 2, norcantharidin thermo-responsive hydro gel agent preparation
Take 5g norcantharidin, add distilled water 600ml, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 170g, PLURONICS F87 5g, polyoxyethylene sorbitan monoleate 5g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 5ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, in this norcantharidin thermo-responsive hydro gel agent, norcantharidin final concentration is 0.5%.
Embodiment 3, norcantharidin thermo-responsive hydro gel agent preparation
Take 5g norcantharidin, add distilled water 600ml, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 200g, PLURONICS F87 20g, polyoxyethylene sorbitan monoleate 20g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 20ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, in this norcantharidin thermo-responsive hydro gel agent, norcantharidin final concentration is 0.5%.
Embodiment 4, norcantharidin thermo-responsive hydro gel agent preparation
Take 5g norcantharidin, add distilled water 600ml, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 200g, PLURONICS F87 10g, polyoxyethylene sorbitan monoleate 10g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 20ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, in this norcantharidin thermo-responsive hydro gel agent, norcantharidin final concentration is 0.5%.
Embodiment 5, norcantharidin thermo-responsive hydro gel agent preparation
Take 5g norcantharidin, add distilled water 600ml, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 150g, PLURONICS F87 5g, polyoxyethylene sorbitan monoleate 2.5g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 5ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, in this norcantharidin thermo-responsive hydro gel agent, norcantharidin final concentration is 0.5%.
Embodiment 6, norcantharidin thermo-responsive hydro gel agent preparation
Take 2.5g norcantharidin, add distilled water 600ml distilled water, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 170g, PLURONICS F87 5g, polyoxyethylene sorbitan monoleate 5g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 5ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, in this norcantharidin thermo-responsive hydro gel agent, norcantharidin final concentration is 0.25%.
Embodiment 7, norcantharidin thermo-responsive hydro gel agent preparation
Take 10g norcantharidin, add distilled water 600ml distilled water, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 200g, PLURONICS F87 20g, polyoxyethylene sorbitan monoleate 20g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 20ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, in this norcantharidin thermo-responsive hydro gel agent, norcantharidin final concentration is 1%.
Embodiment 8, norcantharidin thermo-responsive hydro gel agent preparation
Take 0.5g norcantharidin, add distilled water 600ml distilled water, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 180g, PLURONICS F87 12g, polyoxyethylene sorbitan monoleate 7g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 7ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, in this norcantharidin thermo-responsive hydro gel agent, norcantharidin final concentration is 0.05%.
Embodiment 9, norcantharidin thermo-responsive hydro gel agent preparation
Take 20g norcantharidin, add distilled water 600ml distilled water, slightly be heated to norcantharidin and dissolve completely, get recipe quantity poloxamer188 180g, PLURONICS F87 12g, polyoxyethylene sorbitan monoleate 7g, 4 DEG C of placements are spent the night swelling completely to adjuvant, add ethanol 7ml, add distilled water to 1000ml, steam sterilization, subpackage, to obtain final product.After measured, in this norcantharidin thermo-responsive hydro gel agent, norcantharidin final concentration is 2%.
The investigation of embodiment 10, gelation temperature
Press respectively method preparation norcantharidin-poloxamer188 slow releasing agent that Chinese patent CN1385154A embodiment records, and embodiment of the present invention 1-9 method preparation norcantharidin thermo-responsive hydro gel agent, respectively get 20ml, insert precision temperature to mercury ball and be immersed in completely in gel solution.Put it in low temperature (10 DEG C) water-bath rotating speed 300 rmin
-1, keep water-bath to continue slowly to heat up (2 DEG C of min
-1), make temperature that magnetic stir bar stops operating completely for being gelation temperature, the results are shown in Table 1.During due to clinical practice, the agent of norcantharidin thermo-responsive hydro gel is injected in tumor body in low temperature liquid, be converted into gelatinized along with temperature is increased to gelation temperature, norcantharidin thermo-responsive hydro gel of the present invention agent has lower gelation temperature, has gelation rate faster.Gelation rate can better be avoided burst drug release faster, and this is obviously better than the disclosed norcantharidin-poloxamer188 of Chinese patent CN1385154A slow releasing agent.
Table 1. gelation temperature measurement result
Embodiment 11, gelling characteristic are investigated
Press respectively method preparation norcantharidin-poloxamer188 slow releasing agent that Chinese patent CN1385154A embodiment records, and embodiment of the present invention 1-9 method preparation norcantharidin thermo-responsive hydro gel agent, respectively get 200ml, put in 4 DEG C of refrigerators and extremely dissolve completely, measure respectively its gelling characteristic at 20 DEG C, 37 DEG C by embodiment 10 methods.Get 25ml gel suppository and be placed in 50ml graduated cylinder, the disk that records gel strength measuring instrument moves down the required time of 10cm as the index that characterizes gel strength, the results are shown in Table 2.Result shows that norcantharidin thermo-responsive hydro gel agent gel strength characteristic of the present invention is better than the disclosed norcantharidin-poloxamer188 of Chinese patent CN1385154A slow releasing agent, good gel strength can ensure the steady release of gellant, obtain reliable therapeutic effect, avoid burst drug release to cause serious toxicity.
Table 2. gelling characteristic measurement result (n=3)
Note: with the comparison of norcantharidin-poloxamer188 slow releasing agent group
#p<0.05,
##p<0.01;
Embodiment 12, drug release feature are investigated
Press respectively method preparation norcantharidin-poloxamer188 slow releasing agent that Chinese patent CN1385154A embodiment records, and the agent of embodiment of the present invention 1-9 method preparation norcantharidin thermo-responsive hydro gel, respectively get 2ml, put in the bag filter of treated mistake, closely, after sealing, put in a small beaker.The tool plug conical flask that 50ml phosphate buffer (pH7.6) (as release medium) is housed is together put into 37 DEG C of air bath agitator 15min simultaneously, it is become after gel, bag filter is put into conical flask, ensure to be released medium submergence.With 50rmin
-1for velocity fluctuation.Closely draw acceptable solution 1ml in 0,20,40,80,120,180,240,300,360,420,480 min, supplement the fresh buffer of same volume simultaneously in stripping conical flask.The acceptable solution of drawing, through 0.45 μ m filtering with microporous membrane, is got subsequent filtrate for subsequent use, measures the content of norcantharidin through HPLC method, calculates preparation, draws preparation-time graph, the results are shown in Figure 1.Result shows that continuing drug release time by norcantharidin-poloxamer188 slow releasing agent of Chinese patent CN1385154A method preparation is less than 4 hours, and by steadily release 8 hours of the norcantharidin thermo-responsive hydro gel agent of embodiment of the present invention 1-5 method preparation, fully proved that the Release Performance of this new type gel system is significantly better than the disclosed norcantharidin-poloxamer188 of Chinese patent CN1385154A slow releasing agent.
Dynamic change after embodiment 13, rabbit injection into liver
Press respectively method preparation norcantharidin-poloxamer188 slow releasing agent (norcantharidin final concentration 0.5%) that Chinese patent CN1385154A embodiment records, and the embodiment of the present invention 1 method preparation norcantharidin thermo-responsive hydro gel agent.6 of healthy male new zealand rabbits, body weight 3kg, injection in 2% pentobarbital sodium 30mg/kg auricular vein, lies on the back rabbit to be fixed on self-control yoke, abdominal part is shaved hair, expose visual area, B ultrasonic is detected liver, adopts decussation method location, selecting 2cm place under xiphoid-process is point of puncture, inserting needle 2cm, confirms that needle point is positioned at hepatic tissue, injects medicinal liquid.2 rabbit injection into liver norcantharidin-poloxamer188 slow releasing agent 2ml respectively, inject respectively the each 2ml of norcantharidin thermo-responsive hydro gel agent, inject respectively the each 2ml of PBS buffer for all the other 2 for another 2.The each group of continuous Real Time Observation of B ultrasonic in the rear 15min of injection, after this observes 1 time at interval of 15min, records size, echo and the border condition of medicine light group and takes the photograph sheet, until light group echo disappears.Result shows that B ultrasonic observes after visible PBS rabbit injection into liver, is at once washed away by blood flow, can not stay in liver.And after norcantharidin-poloxamer188 slow releasing agent and thermo-responsive hydro gel agent 2ml injection, needle point around, form the strong echo light group of diameter 2cm left and right, and after 30min, medicinal liquid is gradually to surrounding disperse, the slightly increase of light group scope, and echo is slightly weakened.Norcantharidin-poloxamer188 slow releasing agent group is after 2～4 hours, and light group is gradually washed away by blood flow, diminishes thin out to disappearing.And that the thin out speed that diminishes is gradually washed away by blood flow by norcantharidin thermo-responsive hydro gel agent light group is slower, this process continues to 7-8 hour.Show that the time of staying of thermo-responsive hydro gel agent in liver be significantly longer than the disclosed norcantharidin-poloxamer188 of Chinese patent CN1385154A slow releasing agent, be more conducive to the treatment of tumor.
Embodiment 14, antitumor drug effect are observed
Press respectively method preparation norcantharidin-poloxamer188 slow releasing agent (norcantharidin final concentration 0.5%, ratio of adjuvant is constant) that Chinese patent CN1385154A embodiment records, and the embodiment of the present invention 1 method preparation norcantharidin thermo-responsive hydro gel agent.Rat watt gram 256 JEG-3 (Walker256Carcinoma, W256) cancerous cell increase with cellar culture method, reach 1 × 10
8after the cell number of left and right, centrifugal collecting cell, the culture fluid that inclines, D-Hank ' s liquid washes twice, adds D-Hank ' s liquid 2ml, and piping and druming mixes, and makes cell suspension for subsequent use.Get 1 of Healthy female SD rat, body weight 120g, injects rat abdominal cavity by cell suspension under aseptic condition, and after 3 days, rat ascites generates, and as kind of a Mus, then continues to make subcutaneous tumor-bearing rat model.Etherization ascites tumor rat, extracts ascites under aseptic condition for subsequent use, counts tumor cell approximately 2 × 10 under microscope
7/ ml.50 of Healthy female SD rats, body weight 120 ± 20g, injects ascites 0.2ml(approximately containing tumor cell number 4 × 10 respectively at lower-left abdominal subcutaneous
6), be inoculated in ascites and in latter 1 hour, complete in vitro, about approximately 5 days, subcutaneous rat grows the tumor of diameter 0.5～1cm left and right.Choose and inoculate successfully subcutaneous 40 of female sd inbred rats of lotus W256 tumor (diameter of tumor is 0.5～1cm approximately), body weight 120 ± 20g, random packet, every group 10, respectively at swollen intratumor injection norcantharidin-poloxamer188 slow releasing agent 0.2ml/ only/time (containing norcantharidin 0.1mg), and thermo-responsive hydro gel agent 0.2ml//time (containing norcantharidin 0.1mg), mitomycin 0.2ml//time (containing mitomycin 0.1mg) and PBS(phosphate buffer pH7.0) each 0.2ml//time, treats once for every 4 days.Before injection, weigh rat body weight, with vernier caliper measurement tumor size, by formula V=ab
2gross tumor volume (a: the maximum major diameter of tumor, b: with the perpendicular maximum transverse diameter of maximum major diameter) is calculated in π/6, and observes mice with tumor existence situation (table 4) after record treatment.Result shows that mitomycin, slow releasing agent group, gel group tumor growth are relatively slow, and the growth of PBS group is the rapidest.Treat after 2 times, slow releasing agent group and PBS matched group comparing difference are not remarkable, and gel group effect is better than PBS matched group.Treat and respectively organize afterwards effect for 3 times and be all better than PBS matched group, gel group effect is all better than slow releasing agent group simultaneously, and this shows that Novel temperature-sensitive gel effect is better than the disclosed norcantharidin-poloxamer188 of Chinese patent CN1385154A slow releasing agent.
Embodiment 15, normal liver tissue zest is investigated
Press respectively method preparation norcantharidin-poloxamer188 slow releasing agent (norcantharidin final concentration 0.5%, ratio of adjuvant is constant) that Chinese patent CN1385154A embodiment records, and the embodiment of the present invention 1 method preparation norcantharidin thermo-responsive hydro gel agent.18 of healthy male SD rats, body weight 250 ± 20g, be divided at random 3 groups, every group 6,2% pentobarbital sodium 30mg/kg lumbar injection, is fixed on Mus on minor operation platform, along abdominal part median line open abdomen, expose liver, respectively at injecting norcantharidin-poloxamer188 slow releasing agent, thermo-responsive hydro gel agent and PBS(phosphate buffer pH7.0 in leftlobe of liver), after injection, successively close abdominal cavity.Within postoperative the 3rd, 7,14 days, every group of each disconnected neck put to death 2, the liver injection position making Section for light microscopy of drawing materials, and light microscopy, observes morphological change.Get 2 health not medication of the same race rat livers simultaneously and cut into slices, controlled observation.Result shows injection into liver cantharidin-poloxamer188 slow releasing agent, thermo-responsive hydro gel agent and PBS buffer rat, within after injection 3,7,14 days, dissects animal.Perusal is shown in after injection 3,7 days, front 2 groups of rat liver injection positions present yellow necrotic zone, boundary is fuzzy, cantharidin-poloxamer188 slow releasing agent group necrotic zone 0.5cm × 0.5cm left and right, thermo-responsive hydro gel agent group necrotic zone 0.4cm × 0.4cm left and right, PBS buffer group has no obvious necrotic zone.The 14th day, liver injection position was slightly canescence, and scope is obviously dwindled, and obscurity boundary is unclear; PBS group color and luster is normal.Optical microphotograph Microscopic observation, cantharidin-poloxamer188 slow releasing agent group and thermo-responsive hydro gel agent group, in it, be dispersed in neutrophil infiltration, downright bad proliferation of fibroblast around and lymphocyte, plasmocyte infiltrating, adjacent tissue's swelling of liver cell, the relatively inflammatory infiltration situation of slough, thermo-responsive hydro gel agent group is light compared with cantharidin-poloxamer188 slow releasing agent group.Under PBS group light microscopic, except degree of taking a favourable turn swelling of liver cell, have no obvious pathological change.Result shows that thermo-responsive hydro gel agent is lighter than the disclosed norcantharidin-poloxamer188 of Chinese patent CN1385154A slow releasing agent to the zest of normal liver tissue.
Embodiment 16, acute toxicity are investigated
100 of healthy male mouse of kunming, body weight 20 ± 2g, be divided at random 10 groups, every group 10, the method of recording by Chinese patent CN1385154A embodiment is respectively prepared 5 parts of norcantharidin-poloxamer188 slow releasing agents, and (norcantharidin final concentration is respectively 0.25%, 0.5%, 0.75%, 1.25%, 2.5%, ratio of adjuvant is constant), and the embodiment of the present invention 1 method is prepared 5 parts of thermo-responsive hydro gel agent, and (norcantharidin final concentration is respectively 0.25%, 0.5%, 0.75%, 1.25%, 2.5%, ratio of adjuvant is constant), lumbar injection 0.4ml/ only respectively, observe mouse death rate in 3 weeks, calculate LD
50.The LD of result norcantharidin-poloxamer188 slow releasing agent
50for 14.8mg/kg, the LD of thermo-responsive hydro gel agent
50for 17.4mg/kg, the acute toxicity of thermo-responsive hydro gel agent is less than the disclosed norcantharidin-poloxamer188 of Chinese patent CN1385154A slow releasing agent.
Claims (6)
1. the agent of norcantharidin thermo-responsive hydro gel, is characterized in that, the composition of this gel and quality percentage composition thereof are:
2. by norcantharidin thermo-responsive hydro gel claimed in claim 1 agent, it is characterized in that, the composition of this gel and quality percentage composition thereof are:
3. by norcantharidin thermo-responsive hydro gel claimed in claim 1 agent, it is characterized in that, the composition of this gel and quality percentage composition thereof are:
4. the preparation method of the norcantharidin thermo-responsive hydro gel agent of claim 1-3 described in any one, is characterized in that, comprises the steps: to take norcantharidin, adds suitable quantity of water, is heated to norcantharidin and dissolves, and forms norcantharidin solution; Add poloxamer188, PLURONICS F87 and polyoxyethylene sorbitan monoleate, after stirring low temperature be placed to swelling completely, mix; Add again ethanol and water, sterilizing, subpackage, to obtain final product.
The norcantharidin thermo-responsive hydro gel agent of claim 1-3 described in any one in preparation the purposes as injection for curing malignant tumor medicine in tumor tumor body.
The norcantharidin thermo-responsive hydro gel agent of claim 1-3 described in any one in preparation the purposes as injection for curing liver-cancer medicine in tumor tumor body.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310152638.2A CN104116704B (en) | 2013-04-27 | 2013-04-27 | Norcantharidin thermo-responsive hydro gel agent and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310152638.2A CN104116704B (en) | 2013-04-27 | 2013-04-27 | Norcantharidin thermo-responsive hydro gel agent and its production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104116704A true CN104116704A (en) | 2014-10-29 |
| CN104116704B CN104116704B (en) | 2017-06-06 |
Family
ID=51762487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310152638.2A Expired - Fee Related CN104116704B (en) | 2013-04-27 | 2013-04-27 | Norcantharidin thermo-responsive hydro gel agent and its production and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104116704B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2544843B (en) * | 2015-07-14 | 2022-08-03 | Professional Compounding Centers Of America Pcca | Poloxamer-based intralesional injections for the delivery of chemotherapeutic agents |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385154A (en) * | 2001-05-15 | 2002-12-18 | 中国人民解放军第二军医大学 | Slow-releasing injection type demehylcantharidin for antitumor |
| CN102836211A (en) * | 2011-06-23 | 2012-12-26 | 中国中医科学院中药研究所 | Salvia miltiorrhiza-lobed kudzuvine root eyesight improving in-situ gel |
-
2013
- 2013-04-27 CN CN201310152638.2A patent/CN104116704B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385154A (en) * | 2001-05-15 | 2002-12-18 | 中国人民解放军第二军医大学 | Slow-releasing injection type demehylcantharidin for antitumor |
| CN102836211A (en) * | 2011-06-23 | 2012-12-26 | 中国中医科学院中药研究所 | Salvia miltiorrhiza-lobed kudzuvine root eyesight improving in-situ gel |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2544843B (en) * | 2015-07-14 | 2022-08-03 | Professional Compounding Centers Of America Pcca | Poloxamer-based intralesional injections for the delivery of chemotherapeutic agents |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104116704B (en) | 2017-06-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ji et al. | Hybrid membrane camouflaged copper sulfide nanoparticles for photothermal-chemotherapy of hepatocellular carcinoma | |
| Wu et al. | Focused Ultrasound‐Augmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging‐Guided Brain Tumor Treatment | |
| CN103083250B (en) | Tanshinone IIA-polyactic acid/hydroxyacetic acid microsphere and preparation method thereof | |
| CN101214342A (en) | Paris total saponins extract with tumor metastasis resisting action and pharmaceutical formulation thereof | |
| CN1951369A (en) | Coated nanoliposomes of resveratrol and preparation method thereof | |
| CN104042567A (en) | Ampelopsin nano-micelle and application thereof | |
| CN102000051B (en) | Application of 5-caffeoylquinic acid in preparing anti-tumor drugs | |
| CN104971365B (en) | The new application of nano carbon mixed suspension injection | |
| CN105566271B (en) | The purposes of biflavone compound and its drug of preparation treating cancer | |
| CN101965185A (en) | Use of tea polyphenols in preparing medicaments for prevention or treatment of tumors | |
| Qian et al. | Evaluation of cisplatin-hydrogel for improving localized antitumor efficacy in gastric cancer | |
| CN104116704A (en) | Norcantharidin thermosensitive gel and preparation method and application thereof | |
| CN107982535A (en) | A kind of targeting microwave controlled release medicament-carrying nano-microsphere and its preparation method and application | |
| CN106974908A (en) | Pharmaceutical composition and purposes containing hdac inhibitor and IRE1 inhibitor | |
| CN102552137A (en) | Triptolide fat emulsion injection and preparation method thereof | |
| CN103083251B (en) | Application of tanshinone IIA-polyactic acid/hydroxyacetic acid microsphere to preparation of antitumor drugs | |
| CN102793663B (en) | Sustained-release microsphere injection containing antitumor drug (2-methoxyestradiol) | |
| CN102631341B (en) | New application of ampelopsin sodium in treating bladder cancer | |
| CN106924744A (en) | It is a kind of to supply injection or pharmaceutical carrier (or preparation) for oral use | |
| Li et al. | A dual-responsive “Yin-Yang” photothermal delivery system to accelerate Parthenolide anti-tumor efficacy | |
| CN101530408B (en) | Antineoplastic medicine composition and application thereof | |
| CN104337844A (en) | Venenum bufonis extractive and application of preparation of venenum bufonis extractive to preparing medicines for treating melanoma | |
| CN101919818B (en) | Method for preparing tetrandrine lung-targeted controlled-release microspheres | |
| CN105477068B (en) | Preparation method and application of active site of mulberry branch and leaf | |
| WO2017000770A1 (en) | Pharmaceutical composition and preparation method and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170606 Termination date: 20200427 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |