CN104622794A - Gel injection combining molecular targeted drug and cytotoxic drug - Google Patents
Gel injection combining molecular targeted drug and cytotoxic drug Download PDFInfo
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Abstract
The invention relates to a gel injection combining a molecular targeted drug and a cytotoxic drug. The gel injection comprises a small molecular targeted drug, a traditional cytotoxic drug, a temperature-sensitive material, a solvent and pharmaceutical excipients, wherein the temperature-sensitive material is selected from poloxamer, polylacticacid-polyethylene glycol-polylactic acid or polyglycolide lactide-polyethylene glycol-polyglycolide lactide and the like; the solvent is selected from water, brine salt or 5% glucose aqueous solution and the like, the prepared gel injection can be injected intratumorally or peritumorally, the anti-tumor effect is obvious, and the side effects are fewer.
Description
Technical field
The present invention relates to a kind of gel injection of combining molecular targeted agents and cell toxicity medicament, be specifically related to the unitary agent of molecular targeted agents and cell toxicity medicament or combination formulations bag to be loaded in the gel that temperature sensing material formed, in tumor or all injections of tumor, play local therapeutic alliance effect, belong to field of pharmaceutical preparations.
Background technology
The treatment of malignant tumor is a global difficult problem always, and along with Radical resection and chemotherapy is integrated in the proposition of radical correction two concepts in last century, oncotherapy has had and is significantly in progress.After this, after the nineties, the appearance of molecular targeted agents is counted as again the new milestone that mankind resist cancer war, enhances the confidence of people's Therapeutic cancer.The multi-drug resistance phenomenon that common chemotherapeutics produces greatly and thereupon because of poor selectivity, toxicity, thus cause the failure of tumor chemical therapy.By comparison, molecular targeted agents can killing tumor cell exactly, drastically increases therapeutic effect, and decreases untoward reaction, thus extend the survival of patients time, quality of making the life better.
Molecular targeted agents refers to and for tumor cell specific target spot, at enhancing antineoplastic simultaneously, can reduce the toxic and side effects of agents on normal cells.Comprise there is targeting growth factor receptors blocker, for some with propagation associated receptor monoclonal antibody, the medicine of Antineoplastic angiogenesis, medicine, anti-tumor vaccine and the gene therapy medicament etc. for some oncogene and cancer cytogenetics mark.Partial clinical and basic research show molecular targeted agents and traditional cell toxicity medicament to carry out administering drug combinations can play a good medication combined effect, thus provides a new scheme for the treatment of tumor.As the Lapatinib oral tablet of U.S.'s approval in 07 year
its prescription is advised this medicine and is blocked doubly his shore conbined usage, is used for the treatment of the metastatic breast cancer of ErbB-2 (human epidermal growth factor receptor 2, HER2) high expressed.
Tumor by local administration, is different from Formulations for systemic administration, and it can improve the drug level of medicine at tumor locus, reduces the drug accumulation of normal structure, thus improves curative effect of medication and reduce toxic and side effects.Molecular targeted agents and traditional cell toxicity medicament are combined and carry out topical expection and may produce better therapeutic effect, but adopt which kind of dosage administration and effect that how administration can produce, prior art is not reported.
The present inventor is to this has been research, in numerous local delivery strategy, it is unexpected that discovery adopt temperature-sensitive gel to have very excellent therapeutic effect, for this reason, the present inventor is on the basis of the technology of existing thermo-responsive hydro gel, binding molecule targeted drug and cell toxicity medicament, be prepared into thermo-responsive hydro gel local injection preparation, said preparation by Amphipathilic block polymer as temperature sensing material, it has the mobility of liquid when low temperature, when being injected in body, phase in version can be there is under body temperature, form semisolid gel residence in local, good local sustained release therapeutic effect can be realized.
Summary of the invention
The invention provides and a kind ofly combine gel injection of molecular targeted agents and cell toxicity medicament and preparation method thereof.Specifically, that the medicine of two kinds of different anticancer mechanisms (molecular targeted agents and cell toxicity medicament) and relevant dosage form thereof are combined, and under the effect of thermosensitive hydrogel, realize the topical of neoplasm in situ, thus intend reaching better medication effect, and it is xicity related to reduce whole body, improve the compliance issues of patient to a certain extent.
The present invention is achieved through the following technical solutions above-mentioned purpose:
Combine a gel injection for molecular targeted agents and cell toxicity medicament, it is characterized in that, described injection by molecular targeted agents, conventional cell cytotoxic drug, temperature sensing material, adds pharmaceutic adjuvant if desired and is prepared from; Wherein,
Molecular targeted agents is selected from: Herceptin, Cetuximab, handkerchief trastuzumab, Buddhist nun's trastuzumab, bevacizumab, her monoclonal antibody, imatinib, gefitinib, Erlotinib, Lapatinib, Conmana, Sorafenib, Sutent, Fan get Ta Ni, endostatin research, CCI-779, everolimus and celecoxib;
Cell toxicity medicament is selected from: paclitaxel, Docetaxel, cyclophosphamide, carmustine, nimustine, camptothecine, 10-hydroxycamptothecine, Rubitecan, 9-aminocamptothecin, cisplatin, carboplatin, vinblastine, vincristine, block doubly his shore, cantharidin, doxorubicin, epirubicin, daunorubicin, Ao Shali moors, gemcitabine, pemetrexed, temozolomide, teniposide, etoposide, vindesine, vinflunine, vinorelbine, ftorafur, cytosine arabinoside, methotrexate, mitomycin, mitoxantrone, topotecan and irinotecan,
Temperature sensing material is selected from: poloxamer, PLA-PEG-PLA, poly (glycolide-co-lactide)-polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, polyethylene glycol-polylactic acid-Polyethylene Glycol, polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol, PCL-PEG-PCL, NIPA polymer and Chitosan-phospholipid complex a kind of or their mixture;
Solvent is selected from: water, normal saline, 5% D/W, glycerol, Polyethylene Glycol, propylene glycol, ethanol and their mixture.
Wherein poloxamer can be selected from poloxamer188 (also referred to as pluronic F127), PLURONICS F87 (also referred to as Pluronic F68) or their mixture.
The gel injection of associating molecular targeted agents provided by the invention and cell toxicity medicament, wherein, the dosage form of described medicine comprises true solution, nano-emulsion, micelle, liposome, nanoparticle, nanocapsule, suspensoid, Emulsion, microcapsule, microsphere, pressed powder and commodity dosage form etc.
The gel injection of associating molecular targeted agents provided by the invention and cell toxicity medicament, wherein, the drug weight of molecular targeted agents and cell toxicity medicament, than being 1:100-100:1, is wherein preferably 1:10-10:1.
The gel injection of associating molecular targeted agents provided by the invention and cell toxicity medicament, wherein, described temperature sensing material and the weight ratio of solvent are 1:10-1.5:1, are wherein preferably 1:5-3:5.
The gel injection of associating molecular targeted agents provided by the invention and cell toxicity medicament, wherein, the content of described medicine is medicine effective quantity, and is not limited to specific amount, if with Weight computation, the scope that the weight of medicine accounts for the percentage ratio of gel injection is:
The Herceptin of (a) 0.01%-20%, Cetuximab, handkerchief trastuzumab, Buddhist nun's trastuzumab, bevacizumab, her monoclonal antibody, imatinib, gefitinib, Erlotinib, Lapatinib, Conmana, Sorafenib, Sutent, Fan get Ta Ni, endostatin research, CCI-779, everolimus and celecoxib;
And
The paclitaxel of (b) 0.01%-20%, Docetaxel, cyclophosphamide, carmustine, nimustine, camptothecine, 10-hydroxycamptothecine, Rubitecan, 9-aminocamptothecin, cisplatin, carboplatin, vinblastine, vincristine, block doubly his shore, cantharidin, doxorubicin, epirubicin, daunorubicin, Ao Shali moors, gemcitabine, pemetrexed, temozolomide, teniposide, etoposide, vindesine, vinflunine, vinorelbine, ftorafur, cytosine arabinoside, methotrexate, mitomycin, mitoxantrone, topotecan and irinotecan,
Gel injection of the present invention, also can add other pharmaceutic adjuvant, as required as pH adjusting agent, antibacterial, antioxidant, osmotic pressure regulator and additive etc.Additive described here comprises for lactose, glucose, propylene glycol, glycerol, methylcellulose, hydroxypropyl emthylcellulose, polyvinyl alcohol and sodium alginate etc., and these additives can be used for regulating the gelation temperature of gel, viscosity, bioadhesive and rate of releasing drug etc.
The gel injection of associating molecular targeted agents provided by the invention and cell toxicity medicament, can be prepared by following methods:
A. solvent is selected to prepare the single or combination formulations A of molecular targeted agents and cell toxicity medicament
B. by stirring and evenly mixing under A, temperature sensing material and appropriate solvent ice bath, the gel injection of associating molecular targeted agents and cell toxicity medicament is obtained.
Also can be prepared by following methods:
A. solvent is selected to prepare the single or combination formulations A of molecular targeted agents and cell toxicity medicament
B. by stirring and evenly mixing under temperature sensing material and appropriate solvent ice bath, Blank gel B is obtained
C. mix under A and B ice bath, obtain the gel injection of associating molecular targeted agents and cell toxicity medicament.
Preferred preparation method is as follows:
(1) preparation of molecular targeted agents microgranule: get molecular targeted agents and be dissolved in organic solvent, under ultrasound condition, in being intake by injecting liquid drug, suspendible disperses, and namely obtains molecular targeted agents microgranule;
(2) preparation of cell toxicity medicament nanoparticle suspension: get cell toxicity medicament and pluronic F127; add organic solvent dissolution; blown by nitrogen under constant flow velocity and volatilize organic solvent, added by water in above-mentioned thin film, namely ultrasonic hydration obtains cell toxicity medicament nanoparticle suspension.
(3) preparation of gel injection: get pluronic F127, joins in above-mentioned microgranule and nanoparticle suspension, stirs, obtain gel injection.
Or
(1) preparation of Blank gel: take PLA-PEG-PLA, joins in 5% D/W, ice bath magnetic agitation, obtained Blank gel.
(2) preparation of drug powder gel injection: take molecular targeted agents and cell toxicity medicament powder, be dispersed in Blank gel, stirring and evenly mixing under ice bath, obtained molecular targeted agents and cell toxicity medicament powder gel injection.
The gel injection of associating molecular targeted agents provided by the invention and cell toxicity medicament, can be used for treating former or secondary carcinoma of people and animal kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon or rectum.
The gel injection of associating molecular targeted agents provided by the invention and cell toxicity medicament, it can be used for intratumor injection, tumor-side injection, and postoperative tumor intracavity is placed, subcutaneous injection, intramuscular injection, lumbar injection, interventional therapy, dosing eyes and nasal-cavity administration.
The gel injection of associating molecular targeted agents of the present invention and cell toxicity medicament has the following advantages:
1, the present invention selects molecular targeted agents and traditional cell toxicity medicament to carry out administering drug combinations, plays more effective oncotherapy effect under different anticancer mechanism effects.The tumor-killing ability that cell toxicity medicament is stronger can improve the drug effect of molecular targeted agents, and the side effect that its indiscriminate attack simultaneously produces can be made up by molecular targeted agents again to a certain extent.Therefore this two class is medication combined will have good clinical effectiveness and relatively low side effect generation.
2, emphasis of the present invention is loaded in thermosensitive hydrogel by molecular targeted agents and cell toxicity medicament combined packet, therefore bag carries the dosage form of prodrug can have multiple choices, and this be the release of control medicine, the simplification of medicine stability, drug drug interaction, medication combined ratio and preparation method provides more choices.
3, the present invention combines the gel injection of molecular targeted agents and cell toxicity medicament, and the oncotherapy effect that its local injection produces, compared with single medicine gel or medication combined Formulations for systemic administration mode, shows stronger drug effect and lower toxicity.And improving in patient's compliance, the potential ability of inventive gel injection is more obvious.
4, the present invention compared to the prior art, has good stability, and curative effect is high, not pain during injection, and two kinds of medicines synergism that cooperatively interacts is good, the features such as few side effects.The present invention compares with other dosage forms, and therapeutic effect is high, obviously has diversity after contrast, achieves good effect.
Accompanying drawing illustrates:
The other administration of tumor in the molecular targeted agents of Fig. 1 embodiment 1 and conventional cell cytotoxic drug gel injection body, tumor growth curve figure (the * p<0.05vs.Control group of lotus BT474 tumor nude mice, * p<0.01vs.Control group, ^p<0.05vs.P-gel group)
The other administration of tumor in the molecular targeted agents of Fig. 2 embodiment 1 and conventional cell cytotoxic drug gel injection body, the body weight change curve chart of lotus BT474 tumor nude mice
The other administration of tumor in the molecular targeted agents of Fig. 3 embodiment 1 and conventional cell cytotoxic drug gel injection body, the survival rate change curve of lotus BT474 tumor nude mice
The other administration of tumor in the molecular targeted agents of Fig. 4 embodiment 1 and conventional cell cytotoxic drug gel injection body, tumor tissues apoptosis experiment (TUNEL) result of lotus BT474 tumor nude mice
The other administration of tumor in the molecular targeted agents of Fig. 5 embodiment 1 and conventional cell cytotoxic drug gel injection body, the safety experiment (tissue HE dyes) of lotus BT474 tumor nude mice
The other administration of tumor in the molecular targeted agents of Fig. 6 embodiment 1 and conventional cell cytotoxic drug gel injection body, tumor growth curve figure (the * p<0.05vs.Control group of lotus MCF-7/ADR tumor nude mice, * p<0.01vs.Control group, ^p<0.05vs.L-gel group)
The other administration of tumor in the molecular targeted agents of Fig. 7 embodiment 1 and conventional cell cytotoxic drug gel injection body, the body weight change curve chart of lotus MCF-7/ADR tumor nude mice
The other administration of tumor in the molecular targeted agents of Fig. 8 embodiment 1 and conventional cell cytotoxic drug gel injection body, tumor weight and the size of lotus MCF-7/ADR tumor nude mice compare (* p<0.05vs.Control group, * p<0.01vs.Control group, ^p<0.05vs.L-gel group, ^^p<0.01vs.L-gel group)
Detailed description of the invention
Further illustrate by the following examples and explain the present invention, but not as restriction of the present invention
The preparation of embodiment 1, Lapatinib microgranule and effect of nano-paclitaxel gel injection
(1) preparation of Lapatinib micronised suspensions: take 60mg Lapatinib and be dissolved in 1ml DMSO; get 200 μ l; under the condition of Probe Ultrasonic Searching; liquid medicine injection is injected in the distilled water under ice bath; after obtained medicinal liquid sucking filtration; with appropriate distilled water again suspendible (final concentration is 8mg/ml), of short duration Probe Ultrasonic Searching dispersion, namely obtains Lapatinib Nanoparticle Solution
(2) preparation of effect of nano-paclitaxel suspension: take 32mg paclitaxel and 160mg pluronic F127 respectively; add 4ml chloroform; ultrasonicly it is made to dissolve completely; blown by nitrogen under constant flow velocity and volatilize organic solvent; and be placed in 25 DEG C of vacuum drying oven 12h, to remove residual organic solvent.In the paclitaxel deionized water of 8ml being added above-mentioned drying and pluronic F127 thin film, hydration 40min, vortex 10min, ultrasonic 10-15min, namely obtain effect of nano-paclitaxel suspension (final concentration is 4mg/ml).
(3) preparation of hybrid medicine gel injection: take 0.5g pluronic F127; join in 1ml Lapatinib micronised suspensions and 1ml effect of nano-paclitaxel suspension; more than ice bath magnetic agitation 6h, obtains Lapatinib microgranule and effect of nano-paclitaxel gel injection
The preparation of embodiment 2, imatinib liposome and Taxol gel injection
(1) preparation of imatinib liposome: get a certain amount of fat material (EPC:Chol:DSPE-PEG2000=57:38:5, m/m/m) and be dissolved in chloroform, and at 37 DEG C rotary evaporation in vacuo film forming.Add the ammonium sulfate aquation of a certain amount of 300mM afterwards, at 37 DEG C, water bath sonicator 20min, prepares blank liposome.Cross post and remove free ammonium sulfate, then at 37 DEG C, hatch 60min with a certain amount of imatinib (fat material: imatinib=15:1, w/w), the free drug of unentrapped is crossed post and is removed.The final concentration of preparation is 2mg/ml.
(2)
for the commercial preparation of PTX, concentration is 6mg/ml, and solvent is ethanol: polyoxyethylene castor oil=1:1.
(3) preparation of hybrid medicine gel injection: take 0.5g pluronic F127, joins 1ml imatinib liposome solutions, 0.5ml
with in 0.5ml mixed liquor of normal saline, more than ice bath magnetic agitation 6h, obtains imatinib liposome and Taxol gel injection
The preparation of embodiment 3, Lapatinib and camptothecine mixing polyelectrolyte nanocapsule gel injection
(1) preparation of Lapatinib and camptothecine mixing polyelectrolyte nanocapsule: camptothecine (40mg), chitosan (6mg) and ammonium bicarbonate (40mg) join in the distilled water of 30ml, stir 5min, under low temperature, water bath sonicator 45min prepares the mixing nanometer core of camptothecine/chitosan.Add the alginic acid (1mg/ml) of 4ml afterwards, ultrasonic 25min.Repeatedly add chitosan and alginic acid solution 3 times, prepare camptothecine/(chitosan/alginic acid)
3compositions, after this continue ultrasonic under successively add Lapatinib (0.5mg/ml) and the alginic acid solution of 20ml again, prepare camptothecine/(chitosan/alginic acid)
3/-Lapatinib/alginic acid sample, the centrifugal 10min of high speed 10000rpm, removes supernatant, and it is resuspended to suitable concn (camptothecine 4mg/ml, Lapatinib 1mg/ml) to add appropriate solvent.
(2) preparation of hybrid medicine gel injection: take 0.5g pluronic F127, in the above-mentioned Lapatinib joining 2ml and camptothecine mixing polyelectrolyte nanocapsule solution, more than ice bath magnetic agitation 6h, obtains Lapatinib and camptothecine mixing polyelectrolyte nanocapsule gel injection.
The preparation of embodiment 4, Erlotinib and Docetaxel powder gel injection
(1) preparation of Blank gel: take 0.5g PLA-PEG-PLA (PLA-PEG-PLA, the molecular weight of PEG is 800-1200, account for 20% of amphipathic nature block polymer weight), join in 2ml 5% D/W, more than ice bath magnetic agitation 6h, obtained Blank gel.
(2) preparation of Erlotinib and Docetaxel powder gel injection: take the Erlotinib of 2mg and the Docetaxel powder of 2mg, be dispersed in Blank gel, stirring and evenly mixing under ice bath, obtained Erlotinib and Docetaxel powder gel injection.
The other administration of tumor in embodiment 5, molecular targeted agents and conventional cell cytotoxic drug gel injection body, to the antitumous effect of lotus BT474 tumor n μ/n μ nude mice
Lapatinib microgranule in Example 1 and effect of nano-paclitaxel gel injection are studied.
Choose female n μ/n μ nude mice (16-18 week, Beijing dimension tonneau China laboratory animal), in right side axil subcutaneous vaccination 1 × 10
6breast carcinoma BT474 cell, inoculate administration after 13 days, administration component is 6 groups, often organize 7, be respectively: blank group (control), taxol group (Taxol), paclitaxel (PTX) gel group (P-gel), Lapatinib (Lapa) gel group (L-gel), paclitaxel/Lapatinib mixed gel group (PL-gel) and oral group of paclitaxel gel+Lapatinib (P-gel+L-oral), administering mode is as follows:
Control group: unprocessed
Taxol group: after gel delivery the 5th day starts administration, intravenous injection, 100 μ l/ time/4 day, totally three times, accumulated dose: 20mg/kg
P-gel group: tumor-side injection, is administered once, 200 μ l/, dosage: 20mg/kg
L-gel group: tumor-side injection, is administered once, 200 μ l/, dosage: 40mg/kg
PL-gel group: tumor-side injection, is administered once, 200 μ l/, dosage: PTX:20mg/kg, Lapa:40mg/kg
P-gel+L-oral group:
P-gel tumor-side injection, is administered once, 200 μ l/, dosage: 20mg/kg
Lapa is oral, once a day, and dosage: 75mg/kg, totally 19 days.
(1) Tumor growth inhibition: the major diameter (L) and the minor axis (r) that use vernier caliper measurement group nude mouse tumor for after administration every two days, calculate gross tumor volume V (V=[L × (r)
2]/2), draw tumor volume versus time variation diagram (Fig. 1).Measure the body weight change of nude mice simultaneously, draw nude mice body weight-time variation diagram (Fig. 2).
Tumor volume versus time variation diagram shows, and the drug effect of administering drug combinations group is best, and the drug effect of single administration group is taken second place, and the nude mouse tumor volume of blank group increases the fastest.At the end of experiment, gross tumor volume size result is as follows:
P-gel+L-oral≈PL-gel<L-gel,P-gel,Taxol<control
Nude mice body weight-time variation diagram display, in administering drug combinations group, the Weight averages of PL-gel group nude mice is significantly higher than P-gel+L-oral group, and after showing to change the oral Formulations for systemic administration of Lapatinib into topical, its toxicity decreases.Identical trend is also embodied in the comparison of P-gel group and Taxol group, if after the tail vein injection of paclitaxel commercial preparation is changed into local release by result display, nude mice body weight also has appropriate rising.
(2) nude mice survival rate experiment: the survival state of each group of nude mice is observed in administration for 20 days afterwards.The results are shown in Figure 3, in administering drug combinations group, the nude mice survival state of PL-gel group is obviously better than P-gel+L-oral group, identical trend is also embodied in the comparison of P-gel group and Taxol group, after the result that Tumor growth inhibition and survival rate are tested all shows to change the medicine of Formulations for systemic administration into topical, the toxicity of medicine decreases relatively.
(3) tumor tissues apoptosis experiment (T Μ NEL): after administration a period of time, often group picks out a nude mice, tumor is cut and prepares frozen section, other each tissue preparation paraffin sections.Tumor frozen section carries out apoptosis dyeing with reference to T Μ NEL test kit to section, the results are shown in Figure 4.Green fluorescence represents the tumor cell of apoptosis, and phosphor dot is more, shows that the apoptotic cell quantity in tumor tissues is more, also represents that drug effect is better from another one side.The drug effect of result display administering drug combinations group is best, and the drug effect of single administration group is taken second place, and in the nude mouse tumor of blank group, apoptotic cell is minimum.Quantity comparative result is as follows:
P-gel+L-oral,PL-gel>L-gel,P-gel,Taxol>control
(4) toxicity test of preparation: after administration a period of time, often group picks out a nude mice, takes out the heart, liver, spleen, lung and kidney, and the paraffin section of each tissue carries out HE dyeing, observes each group of medicine to the toxicity ratio of tissue comparatively.The results are shown in Figure 5, the toxicity of display administering drug combinations group is better than other each group, and wherein to affect be the heart, liver and lung comparatively significantly.And Lapatinib oral Formulations for systemic administration group (P-gel+L-oral) all shows stronger toxicity in the heart, liver and lung are respectively organized.
The other administration of tumor in embodiment 6, molecular targeted agents and conventional cell cytotoxic drug gel injection body, to the antitumous effect of lotus MCF-7/ADR tumor BALB/c nude mice
Lapatinib microgranule in Example 1 and effect of nano-paclitaxel gel injection are studied.
Choose female BAl BIc/c nude mice (6-8 week, Beijing dimension tonneau China laboratory animal), in right side axil subcutaneous vaccination 1 × 10
6individual breast carcinoma MCF-7/ADR cell, inoculate administration after 15 days, administration component is 6 groups, be respectively: blank group (control), taxol group (Taxol), paclitaxel gel group (P-gel), Lapatinib gel group (L-gel), paclitaxel/Lapatinib mixed gel group (PL-gel) and oral group of paclitaxel gel+Lapatinib (P-gel+L-oral), administering mode following (often organizing 7):
Control group: unprocessed
Taxol group: after gel delivery the 5th day starts administration, intravenous injection, 100 μ l/ time/4 day, totally three times, accumulated dose: 20mg/kg
P-gel group: tumor-side injection, is administered once, 200 μ l/, dosage: 20mg/kg
L-gel group: tumor-side injection, is administered once, 200 μ l/, dosage: 40mg/kg
PL-gel group: tumor-side injection, is administered once, 200 μ l/, dosage: PTX:20mg/kg, Lapa:40mg/kg
P-gel+L-oral group:
P-gel tumor-side injection, is administered once, 200 μ l/, dosage: 20mg/kg
Lapa is oral, once a day, and dosage: 75mg/kg, totally 15 days.
(1) Tumor growth inhibition: use the line of apsides of vernier caliper measurement group nude mouse tumor in after administration every two days, (V=is [long × wide to calculate gross tumor volume V
2]/2), draw tumor volume versus time variation diagram (Fig. 6).Measure the body weight change of nude mice simultaneously, draw nude mice body weight-time variation diagram (Fig. 7).
Tumor volume versus time result of variations shows, and the drug effect of administering drug combinations group is best, and in single administration group, the drug effect of Lapatinib gel group is taken second place, and the nude mouse tumor volume of all the other groups increases all very fast.At the end of experiment, gross tumor volume size result is as follows:
P-gel+L-oral<PL-gel<L-gel<P-gel≈Taxol≈Control
Nude mice body weight-time variations result display, in administering drug combinations group, the Weight averages of PL-gel group nude mice is significantly higher than P-gel+L-oral group nude mice, the result that this result and BT474 tumor bearing nude mice are tested is close, and after showing to change the oral Formulations for systemic administration of Lapatinib into topical, its toxicity decreases.
(2) tumor anharmonic ratio comparatively: each group of nude mice was put to death after 16 days by administration, cut tumor and weighed, direct visual comparison size.The results are shown in Figure 8, in administering drug combinations group, the average tumor weight of P-gel+L-oral group nude mice is minimum, PL-gel group is taken second place, and the average tumor weight of single administration group is relatively bigger than normal, wherein the drug effect of L-gel group is more better, Taxol group and P-gel group then compared with blank Control group difference little.The great little result of average tumor is compared as follows:
P-gel+L-oral<PL-gel<L-gel<P-gel≈Taxol≈Control
Claims (10)
1. combine a gel injection for molecular targeted agents and cell toxicity medicament, it is characterized in that, described injection by molecular targeted agents, conventional cell cytotoxic drug, temperature sensing material, solvent, adds pharmaceutic adjuvant if desired and is prepared from; Wherein,
Molecular targeted agents is selected from: Herceptin, Cetuximab, handkerchief trastuzumab, Buddhist nun's trastuzumab, bevacizumab, her monoclonal antibody, imatinib, gefitinib, Erlotinib, Lapatinib, Conmana, Sorafenib, Sutent, Fan get Ta Ni, endostatin research, CCI-779, everolimus and celecoxib;
Conventional cell cytotoxic drug is selected from: paclitaxel, Docetaxel, cyclophosphamide, carmustine, nimustine, camptothecine, 10-hydroxycamptothecine, Rubitecan, 9-aminocamptothecin, cisplatin, carboplatin, vinblastine, vincristine, block doubly his shore, cantharidin, doxorubicin, epirubicin, daunorubicin, Ao Shali moors, gemcitabine, pemetrexed, temozolomide, teniposide, etoposide, vindesine, vinflunine, vinorelbine, ftorafur, cytosine arabinoside, methotrexate, mitomycin, mitoxantrone, topotecan and irinotecan,
Temperature sensing material is selected from: poloxamer, PLA-PEG-PLA, poly (glycolide-co-lactide)-polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, polyethylene glycol-polylactic acid-Polyethylene Glycol, polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide-Polyethylene Glycol, PCL-PEG-PCL, NIPA polymer and Chitosan-phospholipid complex a kind of or their mixture;
Solvent is selected from: water, normal saline, 5% D/W, glycerol, Polyethylene Glycol, propylene glycol, ethanol and their mixture;
Wherein the weight ratio of molecular targeted agents and conventional cell cytotoxic drug is 1:100-100:1, and the weight ratio of temperature sensing material and solvent is 1:10-1.5:1.
2. gel injection as claimed in claim 1, it is characterized in that, wherein the weight ratio of molecular targeted agents and conventional cell cytotoxic drug is 1:10-10:1, and the weight ratio of temperature sensing material and solvent is 1:5-3:5.
3. gel injection as claimed in claim 1, it is characterized in that, the percentage by weight that described drug weight accounts for gel injection is:
The molecular targeted agents of (a) 0.01%-20%, and
The conventional cell cytotoxic drug of (b) 0.01%-20%.
4. gel injection as claimed in claim 1, it is characterized in that, described injection dosage form is selected from: true solution, nano-emulsion, micelle, liposome, nanoparticle, nanocapsule, suspensoid, Emulsion, microcapsule, microsphere, pressed powder dosage form.
5. gel injection as claimed in claim 1, it is characterized in that, described temperature sensing material is selected from poloxamer188, PLURONICS F87 or their mixture.
6. the preparation method of gel injection according to claim 1, is characterized in that, step is as follows:
A () selects solvent to prepare the single or combination formulations A of molecular targeted agents and conventional cell cytotoxic drug
B (), by stirring and evenly mixing under A, temperature sensing material and appropriate solvent ice bath, obtains the gel injection of associating molecular targeted agents and conventional cell cytotoxic drug.
7. the preparation method of gel injection according to claim 1, is characterized in that, step is as follows:
A () selects solvent to prepare the single or combination formulations A of molecular targeted agents and conventional cell cytotoxic drug
B (), by stirring and evenly mixing under temperature sensing material and appropriate solvent ice bath, obtains Blank gel B
C () mixes under A and B ice bath, obtain the gel injection of associating molecular targeted agents and conventional cell cytotoxic drug.
8. the preparation method as described in claim 6 and 7, it is characterized in that, step is as follows:
(1) preparation of molecular targeted agents microgranule: get molecular targeted agents and be dissolved in organic solvent, under ultrasound condition, in being intake by injecting liquid drug, suspendible disperses, and namely obtains molecular targeted agents microgranule;
(2) preparation of cell toxicity medicament nanoparticle suspension: get cell toxicity medicament and pluronic F127; add organic solvent dissolution; blown by nitrogen under constant flow velocity and volatilize organic solvent, added by water in above-mentioned thin film, namely ultrasonic hydration obtains cell toxicity medicament nanoparticle suspension.
(3) preparation of gel injection: get pluronic F127, joins in above-mentioned microgranule and nanoparticle suspension, stirs, obtain gel injection;
Or
(1) preparation of Blank gel: take PLA-PEG-PLA, joins in 5% D/W, ice bath magnetic agitation, obtained Blank gel.
(2) preparation of drug powder gel injection: take molecular targeted agents and cell toxicity medicament powder, be dispersed in Blank gel, stirring and evenly mixing under ice bath, obtained molecular targeted agents and cell toxicity medicament powder gel injection.
9. preparation method as claimed in claim 6, it is characterized in that, step is as follows:
Lapatinib and paclitaxel are as the preparation of the gel injection of active constituents of medicine:
(1) preparation of Lapatinib micronised suspensions: take 60mg Lapatinib and be dissolved in 1ml DMSO, get 200 μ l, under the condition of Probe Ultrasonic Searching, liquid medicine injection is injected in the distilled water under ice bath, after obtained medicinal liquid sucking filtration, with appropriate distilled water again suspendible, final concentration is 8mg/ml, of short duration Probe Ultrasonic Searching dispersion, namely obtains Lapatinib Nanoparticle Solution;
(2) preparation of effect of nano-paclitaxel suspension: take 32mg paclitaxel and 160mg pluronic F127 respectively; add 4ml chloroform; ultrasonicly it is made to dissolve completely; blown by nitrogen under constant flow velocity and volatilize organic solvent; and be placed in 25 DEG C of vacuum drying oven 12h, to remove residual organic solvent.In the paclitaxel deionized water of 8ml being added to above-mentioned drying and pluronic F127 thin film, hydration 40min, vortex 10min, ultrasonic 10-15min, namely obtain effect of nano-paclitaxel suspension, and final concentration is 4mg/ml;
(3) preparation of hybrid medicine gel injection: take 0.5g pluronic F127; join in 1ml Lapatinib micronised suspensions and 1ml effect of nano-paclitaxel suspension; more than ice bath magnetic agitation 6h, obtains Lapatinib microgranule and effect of nano-paclitaxel gel injection.
10. preparation method as claimed in claim 7, it is characterized in that, step is as follows:
The preparation of Erlotinib and Docetaxel gel injection
(1) preparation of Blank gel: take 0.5g PLA-PEG-PLA, joins in 2ml 5% D/W, more than ice bath magnetic agitation 6h, obtained Blank gel;
(2) preparation of Erlotinib and Docetaxel gel injection: take the Erlotinib of 2mg and the Docetaxel powder of 2mg, be dispersed in Blank gel, stirring and evenly mixing under ice bath, obtained Erlotinib and Docetaxel powder gel injection.
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