WO2010072109A1 - A sustained release system for tumor treating medicament - Google Patents

Abstract

A sustained release system for tumor treating medicament is disclosed. Said system contains degradable macromolecule vehicle, tumor treating agent and amifostine, in which the tumor treating agent comprises chemotherapy agent and one or more chemosensitizer, tumor targeting agent or lymph node tracer. Preferably, the weight ratio of chemotherapy agent to amifostine is 1: 0.001-20000. The sustained release system of present invention can be used for any tumor by changing different treating agent. The system of present invention is a new platform for any agent not only the current drugs but also the new drugs in the future.

Description

 Slow release system for tumor therapeutic drugs

 This application claims priority to Chinese Patent Application No. 200810207703.6, entitled "Degradable Polymer Tumor Therapeutic Drugs and Normal Cell Protectant Sustained Release Drugs", filed on December 25, 2008, all of which are filed on December 25, 2008. The content is incorporated herein by reference. Technical field

 The present invention relates to a medicament for treating a tumor, and more particularly to a sustained release system for a tumor therapeutic drug. Background technique

 At present, the existing tumor chemotherapy drugs are the most important mode of administration by intravenous administration, followed by oral administration, and other administration methods are very few. In the case of intravenous chemotherapy, the drug is distributed throughout the body, and the concentration of the drug in the tumor tissue is unlikely to be high, while the normal tissues and organs are greatly damaged by the chemotherapy drugs in the blood. Oral chemotherapy can cause gastrointestinal damage and changes in the efficacy of the drug due to the first-pass effect of the liver, and the concentration of the drug in the tumor tissue is not likely to be high. Moreover, the in vivo drug concentration of the above two administration methods is distributed in a wave pattern over time, so that the tumor cells are cultivated at a low concentration of the drug.

 The above two problems can be solved by the mode of administration of the locally implanted sustained release drug. Topical administration can greatly increase the concentration of the drug in the tumor tissue (or surrounding tissue), and also avoid damage to the normal tissue at the distal end. The sustained release method can keep the local high-concentration drug at all times.

Although new anti-tumor drugs are emerging, the five-year survival rate of malignant tumors (especially advanced) remains low. Tumor patients often need to make a dilemma when receiving chemotherapy: Large doses of drugs can kill tumor cells (which remain after surgery) to the greatest extent, but the side effects of systemic chemotherapy are unbearable; reducing the dose may reach Less than killing (residual) tumor cells, patients who have long been afflicted with diseases are often beaten with chemotherapy drugs. Therefore, the urgent problem to be solved in the treatment of cancer is to maximize the fight against tumor cells and to maximize the safety of the patient itself. In addition, in general, the general medication used in tumor treatment is pulsed administration (such as intravenous chemotherapy), and the interval between the two chemotherapy can make the patient get proper recovery, but unfortunately the tumor Cells also rehabilitate in this process, so the effect of pulsed chemotherapy is often less than ideal.

 Summary of the invention

 It is an object of the present invention to provide a sustained release system for a tumor therapeutic drug, which employs the following technical solutions:

 A sustained release system for a tumor therapeutic drug comprising a degradable polymer carrier, a tumor therapeutic drug and amifostine.

 The tumor therapeutic agent comprises a chemotherapeutic drug and optionally comprises one or more of a chemotherapy sensitizer, a tumor target drug, and a lymph node tracer drug.

 The chemotherapeutic drug of the present invention is a drug which acts on different stages of tumor cell growth and reproduction, and inhibits or kills tumors, which is also called a fine drug.

 The sustained release system of the present invention preferably further comprises a filler, a porogen, an excipient, a dispersant, an isotonic agent, a preservative, a release retarder, a solubilizer, an absorption enhancer, a film former, and a gelling agent. One or more of a crosslinking agent and an acid-base regulator.

 The weight ratio between the chemotherapeutic drug and the amifostine in the sustained release system is preferably 1:0. 001-20000.

 The sustained release system is classified according to use:

 (1) Implanted drug delivery system in and around the tumor tissue; (2) Lymphatic absorbable nano drug sustained release system containing lymph node inducing drug; (3) Nano drug sustained release system in blood or body fluid; (4) a nano drug sustained release system in a specific tissue; the specific tissue is liver, spleen, lung or bone marrow;

 The drug sustained release system in and around the tumor tissue comprises one or more of a degradable polymer compound polylactic acid, a chemotherapeutic drug oxaliplatin, gemcitabine, a tumor targeting drug sorafenib or erlotinib. Or arsenic trioxide and a release retardant glyceryl tristearate; preferably platinum oxalate, gemcitabine, sorafenib or erlotinib, the weight ratio between arsenic trioxide is 1: 0.001-35: 0.001-20: 0.001-2 .

The intralymphatic absorbable nano drug sustained release system comprises a degradable polymer compound polylactic acid/polyglycolic acid, one or more of the chemotherapy drugs fludarabine, cytosine, and bleomycin, and the tumor target To the drug arsenic trioxide, the chemotherapy sensitizer R- verapamil and the pan cell cytoprotective agent amifostine, the lymph node tracer drug methylene blue, isosulfo blue, patent blue, fluorescein, blush, indigo, One of chlorophyll; among them, fludarabine, cytarabine, bleomycin, arsenic trioxide,

The weight ratio between R- verapamil is 1 : 0.001-2.5: 0.001-15: 0.001-5: 0.001-500.

 The nano drug sustained release system in the specific tissue comprises a degradable polymer compound polylactic acid, one or more of the chemotherapy drugs oxalic acid platinum, gemcitabine, a hepatocellular carcinoma targeting drug sorafenib and arsenic trioxide and pan cell protection. The agent amifostine; wherein the weight ratio of platinum oxalate, gemcitabine, sorafenib, and arsenic trioxide is 1: 0.001-85: 0.001-20: 0.001-1.

 The above sustained release drug can be used in the preparation of a medicament for treating malignant tumors. The malignant tumor is preferably, but not limited to, hepatocellular carcinoma, lung cancer, renal cell carcinoma, gastrointestinal stromal tumor, prostate cancer, malignant lymphoma, and acute myeloid leukemia.

 The blood or body fluid nano drug sustained release system comprises a degradable polymer compound methoxy-terminated polyethylene glycol/polylactic acid/polyglycolic acid copolymer, a chemotherapeutic drug cytarabine and aclaramicin. One or more, apoptosis inducer arsenic trioxide, chemotherapy sensitizer R- verapamil and pan cell cytoprotective agent amifostine; among them, cytarabine, aclarithromycin, arsenic trioxide, R-dimensional The weight ratio between lapami is 1: 0.001-15: 0.001-12.5: 0.001-75.

The above sustained release drug can be used in the preparation of a medicament for treating acute myeloid leukemia. When using (1) implanted drug delivery system in and around the tumor tissue to treat solid tumors, it can be implanted in the periphery after surgical resection of most tumors, disseminated or using various forms of endoscopy, endoscopy or percutaneous The puncture method directly places the drug inside (or around) the tumor, avoiding the mode of maximum drug concentration in the blood during intravenous chemotherapy, and of course minimizing bone marrow suppression and damage to vital organs. At the same time, normal cell protectants can be implanted around the tumor tissue in order to form better protection for normal tissues. When using (2) intralymphatic absorbable nano drug delivery system for the treatment of malignant lymphoma, the drug can be directly implanted into the lymph nodes of the patient through various forms of endoscopy, endoscopy or percutaneous puncture. The macrophage engulfs the drug particles and enters the capillary lymphatic vessels. Since the size of the polymer nanocarrier particles does not enter the capillaries, the drug will have the maximum concentration in the local lymphatic vessels. The normal cytoprotective agent used at the same time allows normal cells to be better protected. When the drug-loaded nanoparticles are stained with lymph node inducing dye blue (also available in isosulfan blue, patent blue, fluorescein, blush, indigo, chlorophyll, etc.), they can be used as an indicator in surgery, and existing carbon The black nanoparticle tracer has the advantage of being degradable and has a sustained chemotherapy effect on the tiny lymph nodes that cannot be completely removed by surgery. When using (3) In the blood (body) liquid nano drug sustained-release system, the drug can be injected once in the treatment of blood system tumors, and it is present in the blood for a long time, avoiding the damage of venous blood vessels by daily chemotherapy; when the tumor causes effusion of the chest and abdomen The drug can also be injected at one time, and the drug will be slowly released in the body fluid for a long time. The normal cytoprotective agent used at the same time allows normal cells to be better protected. When a malignant tumor occurs in the liver, spleen, lung, or bone marrow, (4) a nano drug sustained release system in specific tissues such as liver, spleen, lung, and bone marrow. Since the specific size of the drug-loaded particles will be enriched in a particular tissue, the drug injected from the vein will be concentrated in a particular tissue, while the normal cell protectant used will allow the normal cells to be better protected.

 The tumor therapeutic drug sustained-release platform using the degradable polymer as a carrier includes a carrier-biodegradable, biosafety and compatible polymer, which has two major categories, natural and synthetic. Natural polymer materials such as xylitol, chondroitin, hyaluronic acid, collagen, yellow collagen, pectin, gelatin, serum protein, hemoglobin, albumin, vegetable protein, cellulose, starch and its derivatives, alginic acid Salt, chitin, chitosan, etc.; synthetic polymer materials are polylactic acid, hydroxy polylactic acid, polycarboester, polyamino acid, polyvinyl alcohol, polylactic acid-glycolic acid copolymer, poly-cyanoacrylic acid alkyl Ester, lactide glycolide copolymer, polylactic acid polyethylene glycol copolymer, polylactic acid-polyethylene glycol monomethyl ether copolymer, lactide lactide copolymer, polyanhydride copolymer, polylactic acid Polytrimethylene carbonate, polylactic acid-polydicyclohexanone, ethylene vinyl acetate copolymer, di-fatty acid-sweetic acid copolymer, and the like.

 In addition to the degradable polymer support structure, pharmaceutical excipients having different functions such as fillers, porogens, excipients, dispersants, isotonic agents, preservatives, retarders, solubilizers, absorption enhancers may also be selected. , film former, gelling agent, cross-linking agent, acid-base regulator, etc.

 The drug of the sustained release system may be composed of a chemotherapeutic drug, a chemotherapeutic sensitizer, a tumor target drug and a normal cell protectant or a plurality of components thereof.

Alternative chemotherapeutic drugs include drugs that interfere with nucleotide synthesis, interfere with DNA synthesis, interfere with DNA transcription, interfere with protein synthesis, and interfere with microtubule function. Anti-tuberculosis drugs that interfere with nucleotide synthesis: such as guanidine, thioguanine, pentastatin, etc.; anti-pyrimidine drugs: such as fluorouracil, carmofur, deoxyfluorouridine, furan fluorouracil, etc.; Methotrexate, dichloromethazine and the like. Drugs that interfere with the production of deoxynucleotides: such as the nucleoside reductase inhibitor hydroxyurea, hydroxypurine, and the like. Drugs that interfere with DNA production: such as DNA aggregation The enzyme inhibitors are cytarabine, cyclocytidine, fluoxetine, (iso)cyclophosphamide and the like. Drugs that directly destroy DNA include alkylating agents cross-linked with DNA such as nitrogen mustard, chlorambucil, estradiol phosphate, etc.; antibiotics such as mitomycin; metal compounds such as cisplatin, carboplatin, Platinum oxalate or the like; such as antibiotics bleomycin, pingyangmycin, etc., alkaloids such as (hydroxy) camptothecin, etc., which break the DNA strand. Actinomycins that interfere with DNA transcription, anthracyclines such as doxorubicin, pirarubicin, daunorubicin, etc., and mitoxantrone with anthracycline structure. There are <steroidal hormones such as estrogen, progesterone and adrenocortical hormone that interfere with protein synthesis. Methyl benzamidine interferes with the synthesis of DNA, RNA and protein. The drugs that inhibit microtubule function include alkaloids such as vinca (sodium), vinblastine, colchicine, podophyllotoxins such as etoposide, teniposide, paclitaxel and taxotere.

 Alternative chemotherapeutic agents are directed against membrane protein-mediated (P-glycoprotein-mediated, multidrug resistance-mediated, mammary-drug resistance-mediated, lung resistance protein-mediated) MDR ( Multidrug resistance): 4丐 ion channel blockers such as verapamil (R- verapamil), diltiazem, nimodipine, nifedipine, etc.; calmodulin inhibitors such as Yuthiazine derivatives; immunosuppressants such as cyclosporin A and its derivatives; adrenal cortex and its derivatives. For enzyme-mediated MDR, such as glutathione-S-transferase-mediated MDR, the drugs that inhibit glutathione are butyl sulfonamide, nitroimidazole, sodium selenate, selenocysteine. Wait. Topoisomerase II-mediated MDR inhibitors include camptothenic derivatives such as Topotecan, lintelken, 9-aminocamptothecin and the like. MDR inhibitors such as afendimycin, XR11576, etc. mediated by DNA repair-related enzymes (such as DNA polymerase, deoxynucleotide synthetase, and topoisomerase I). MDR inhibitors such as streptozotocin mediated by methylguanine methyltransferase. In addition to enzyme inhibitors related to nucleotide cleavage repair and mismatch repair. There are also inhibitors against MDR caused by dihydrofolate reductase and acid dehydrogenase. Inhibitors of MDR mediated by protein kinase C include stellate spore derivatives N-benzoyl stellate spores and the like. MDR inhibitors mediated by apoptosis-regulating genes include arsenic trioxide, paclitaxel, naturalized powder, astragalus, and hydroxycamptothecin. Traditional Chinese medicines such as curcumin, ligustrazine, ginseng saponins, brucea oil emulsion, elemene, grape seed polyphenols, tea polyphenols, quercetin, tetrandrine, sulphate, etc. And become a chemotherapy sensitizer.

Alternative tumor target drugs are small molecule protein kinase inhibitors, cell cycle regulatory groups Inhibitors, apoptosis-regulating gene inhibitors, cell differentiation and apoptosis inducers, protein farnesyltransferase inhibitors, histone deacetylase inhibitors, matrix metalloproteinase inhibitors, tumor telomerase inhibitors , 5-lipoxygenase inhibitor, heparanase inhibitor and aromatase inhibitor. Protein kinases are highly involved in tumorigenesis and development, and are commonly used as inhibitors of epidermal growth factor receptors, vascular endothelial growth factor receptor inhibitors, and platelet-derived growth factor receptors. Inhibitors, fibroblast growth factor receptor inhibitors, keratinocyte growth factor receptor inhibitors, hepatocyte growth factor receptor inhibitors, fibronectin type III receptor inhibitors, neuronal growth factor receptor inhibitors, etc. . Epidermal growth factor receptor inhibitors are gefitinib, erlotinib; vascular endothelial growth factor receptor inhibitors have nicotinicin derivatives TNP-470, lenalidomide, van der derani, valadatin Platelet-derived growth factor receptor inhibitors include Gleevec, CP-547632, sorafenib, imatinib, sunitinib, capecitabine and the like. In addition to multiple targets that have a better effect than single-targeted kinase inhibitors, there are (fandanitan, valadanib, sunitinib) sorafenib, dasatinib , lapatinib, mitotalin, etc. Cell cycle regulatory gene inhibitors include L86-8275, UCN-01 and the like. Inhibitors of apoptosis regulating genes include gossypol, L86-8275, flavorpiridol, havopiredol and vincristine, and proteosome inhibitor bortezomib. Except for the induction of cell differentiation and apoptosis, there are arsenic such as trioxide to arsenic, tetracycline, etc.; retinoids such as all-trans retinoic acid, 9 ( 13 ) -cis retinoic acid; vitamin D 3 Such as dihydroxyvitamin D 3; butyrate such as sodium butyrate, tributyrin, etc.; selenate such as sodium (sodium) selenate, methyl selenate, etc.; phenylacetate such as styrene Sodium citrate, etc.; phorbol esters and derivatives; polar compounds such as dimethylformamide, hexamethylene formamide, etc.; cyclic adenosine monophosphate (cAMP) such as dibutyryl cAMP, 8-bromo cAMP, etc.; Oxidase-2 inhibitors such as diphenyl aromatic rings such as DuP-697, SC-58125, SC-58635, etc.; methanesulfonanilides such as nimesulide, rofecoxib, celecoxib, NS -398, CGP-28238, L-745337, etc.; di-tert-butyl-substituted phenols such as BF-389, succinimide, etodolac, etc.; plant extracting drug paclitaxel, which acts by inhibiting tubulin Sodexo, vinblastine, etc.; a variety of traditional Chinese medicines can induce differentiation and apoptosis such as ginsenoside, tea polyphenols, quercetin, soy isoflavones, Brucea javanica oil, tanshinone, Lithospermum, Wintergrass, Elemene, Resveratrol, Curcumin, Garlic Extract, etc. Protein farnesyltransferase inhibitors include SCH44342, SCH66336 and R115777. Histone deacetylase inhibitors include SAHA, FK228 and the like. Matrix metal egg The white enzyme inhibitors are marimastat, AG3340, COL-3, AE941, BMS-275291 and the like. The telomerase inhibitors include BSU-1051, PIPER, TMPyP4, azidodeoxythymidine, geldanamycin, novobiocin, pingyangmycin and biguanide maleimide. 5-lipoxygenase inhibitors include zileuton and the like. Heparanase inhibitors include laminarin sulfate, kelp sulfate polysaccharide, xylan sulfate, suramin and the like. Aromatase inhibitors include letrozole, exemestane, and nin.

 A normal cell protectant can be used as a pan cell cytoprotective agent - amifostine. Other protective agents such as mesna can only be used specifically for hemorrhagic cystitis caused by cyclophosphamide, and dexrazoxane can only be used specifically for cardiotoxicity caused by anthracyclines. Therefore, it is not used in the present invention.

 (1) There are various preparation methods for implanting a drug sustained-release system in and around the tumor tissue: a mixed method in which a carrier support and the like are mixed with a drug powder, and the carrier support is melted and the drug is The melt method in which the powder is mixed and cooled, the carrier support or the like is dissolved, the solvent is mixed with the drug powder, the solvent is evaporated, the spray drying method, the freeze-drying method, the degradable polymer material coating method, and the like. The choice of chemotherapeutic drugs for intra-tissue drug delivery system should not use chemotherapy prodrugs that require liver enzyme activation such as: (iso)cyclophosphamide, carmofur, furan fluorouracil, guanidine, thioguanine, etc. Can not be used to greatly stimulate the tissue, such as the occurrence of blister and then tissue necrosis such as (table) doxorubicin, daunorubicin, mitomycin, phosporin, actinomycin D, nitrogen mustard , aniline acridine, maytansine, vinblastine and other drugs.

 The invention has the following advantages:

 The invention is a novel drug use platform, and any new chemotherapeutic drugs, chemotherapy sensitizers, tumor targeting drugs, pan cell protection agents, etc. can be used on this platform in addition to the existing drugs, for the future. Ultimately conquer cancer to play a role. detailed description

 The various systems of the present invention are described in detail below.

(1) There are various preparation methods for implanting a drug sustained-release system in and around the tumor tissue: a mixed method in which a carrier support and the like are mixed with a drug powder, and the carrier support is melted and the drug is a method in which the powder is mixed and cooled, and the carrier support or the like is dissolved, mixed with the drug powder, and the solvent is evaporated, and the spray drying method is performed, and the freeze-drying method can degrade the high score. Submaterial coating method, etc. The choice of chemotherapeutic drugs for intra-tissue drug delivery system should not use chemotherapy prodrugs that require liver enzyme activation such as: (iso)cyclophosphamide, carmofur, furan fluorouracil, guanidine, thioguanine, etc. Can not be used to greatly stimulate the tissue, such as the occurrence of blister and then tissue necrosis such as (table) doxorubicin, daunorubicin, mitomycin, phosporin, actinomycin D, nitrogen mustard , aniline acridine, maytansine, vinblastine and other drugs.

 Example 1

 The early stage of hepatocellular carcinoma is difficult to detect and the late survival period is only about three months. It is still difficult to have a major therapeutic breakthrough. The formulation of the sustained-release implant is composed of the degradable polymer compound polylactic acid, the chemotherapy drug oxalic acid platinum, gemcitabine (Gemcitabine) and the hepatocellular carcinoma targeting drug sorafenib (Nexavar), the apoptosis-inducing agent arsenic trioxide and release. The blocker consists of glyceryl tristearate and the like. The drug particles are sprayed with the antitumor antibiotic pingyangmycin. In addition to the better therapeutic effect on liver cancer, pingyangmycin has an antibacterial effect, which can further prevent bacterial infection during the surgical planting process.

 5.4 g of L-polylactic acid with a molecular weight of 50,000 was dissolved in 25 ml of dichloromethane, 0.2 g of oxalic acid platinum, 1.7 g of gemcitabine, 0.4 g of sorafenib, 20 mg of arsenic trioxide, and glyceryl tristearate 0.4 g. . The hook is mixed and vacuum dried, and then pressed into a bullet-shaped cylinder having a diameter of lmm and a length of 4 mm. After dissolving pingyangmycin in physiological saline, the drug particles were repeatedly sprayed, dried, and sterilized by irradiation with cobalt 60 for use.

 Example 2

 Non-small cell lung cancer accounts for 80% of the total number of lung cancers, and the addition of tumor-targeted and angiogenic factor-inhibiting drugs with conventional chemotherapy drugs will achieve better therapeutic effects. The formulation of the sustained-release implant is composed of a degradable polymer compound polylactic acid/polyglycolic acid, a chemotherapy drug paclitaxel, carboplatin, a tumor-targeting drug gefitinib (Iressa) and an angiogenic factor inhibitor drug lenalidomide. And a release blocker such as glyceryl tristearate. The drug particles are sprayed with an antitumor antibiotic, neomycin, which has an antibacterial effect in addition to the therapeutic effect on lung cancer, and can further prevent bacterial infection during the surgical implantation process.

A 10 g of PLGA having a molecular weight of 50,000 and a polylactic acid/polyglycolic acid ratio of 9:1 was weighed and dissolved in 40 ml of tetrahydrofuran as a coating liquid. Mix 9 g of paclitaxel, 0.5 g of glyceryl tristearate in a micro-coating pot, spray into the coating solution for coating; also coat 9 g of carboplatin, 9 g of gem Tinidil, 9 grams of lenalidomide. The scale was taken from 1 part of lenalidomide, 10 parts of carboplatin, 7.2 parts of paclitaxel and 10 parts of gefitinib. After mixing, it was pressed into a bullet-shaped cylinder with a diameter of 1 mm and a length of 4 mm. After dissolving neomycin with physiological saline, the drug particles were sprayed, dried, and sterilized by irradiation with cobalt 60 for use.

 Example 3

 Pancreatic cancer, commonly known as the king of cancer, is often difficult to detect early and is not sensitive to chemotherapy. In the advanced stage, it will cause great pain to patients. The formulation of the sustained-release implant is composed of a degradable polymer compound polylactic acid/polyglycolic acid, a chemotherapeutic drug, oxalic acid platinum, a molecularly targeted drug erlotinib (Troquet), a chemotherapy sensitizer R-villa Pami and a release blocker such as glyceryl tristearate. The drug is sprayed with a new anticancer antibiotic, the new carcinogen. In addition to the treatment of pancreatic cancer, the new carcinogen has an antibacterial effect, which can further prevent bacterial infection during the surgical implantation process.

 Weighing 50,000 molecular weight, polylactic acid / polyglycolic acid ratio of 9: 1 PLGA 2.3 grams, dissolved in 20 ml of acetone, adding erlotinib 0.3 g, oxalic acid platinum 0.22 g, gemcitabine 1.6 g, tri-hard fat Acid glyceride 0.2 g. After mixing, the spray was freeze-dried, and then pressed into a bullet-shaped cylinder having a diameter of lmm and a length of 4 mm. After dissolving the new carcinogen in physiological saline, the drug particles were repeatedly sprayed, dried, and sterilized by irradiation with cobalt 60 for use.

 Example 4

 Renal cell carcinoma is a tumor with a high proportion of renal cancer. Because of its tissue specificity, it has multi-drug resistance caused by various mechanisms of chemotherapeutic drugs, so it is not sensitive to chemotherapy. The formulation of the sustained-release implant is composed of a degradable polymer compound polylactic acid, a chemotherapy drug methotrexate, cisplatin, a renal cell carcinoma molecular targeted drug sorafenib (Nexaco), a chemotherapy sensitizer R-villa Pami and a release blocker such as glyceryl tristearate. The drug particles are sprayed with an antitumor antibiotic, bleomycin. In addition to the therapeutic effect on kidney cancer, bleomycin has an antibacterial effect, which can further prevent bacterial infection during surgical implantation.

20 g of L-polylactic acid with a molecular weight of 50,000 was dissolved in 50 ml of acetone as a coating liquid, and 19 g of sorafenib and 1 g of glyceryl tristearate were placed in a micro-coating pot and sprayed. The coating liquid was coated; the same coating of methotrexate 4.75 g with glyceryl tristearate powder 0.25 g, cisplatin 4.75 g with glyceryl tristearate powder 0.25 g, R- verapamil 19 g 1 g with glyceryl tristearate powder. Weigh 1 part of methotrexate, 3.3 parts of cisplatin, and 6.7 parts of sorafenib and R- verapamil. After mixing, the mold is pressed into a bullet-shaped cylinder having a diameter of 1 mm and a length of 4 mm. After dissolving bleomycin in physiological saline, the drug particles were repeatedly sprayed, dried, and sterilized by irradiation with cobalt 60 for use. Sterilized by cobalt 60 irradiation for use.

 Example 5

 Gastrointestinal stromal tumors are a kind of surgery. It is difficult to completely remove the tumors that are easy to relapse and easy to metastasize. The effect of chemotherapy alone is not good. The formulation of the sustained-release implant is composed of a degradable polymer compound polylactic acid/polyglycolic acid, a chemotherapeutic drug 5-Fu, cisplatin and a gastrointestinal stromal tumor molecular targeting drug imatinib (Gleevec) and release. The blocker consists of glyceryl tristearate. The drug particles are sprayed with an anti-tumor antibiotic, aclarithromycin, which has an antibacterial effect in addition to a good therapeutic effect on various tumors, and can further prevent bacterial infection during the surgical implantation process.

 Weighing 50,000 of PLGA with a molecular weight of 50,000, polylactic acid/polyglycolic acid ratio of 9:1, dissolved in 10 ml of acetone, adding 5-Ful.6 g, cisplatin 200 mg, and imatinib mesylate 1.2 g , glyceryl tristearate 0.3 g. After mixing and heating, the mold is pressed into a bullet-shaped cylinder having a diameter of lmm and a length of 4 mm. After dissolving the aclarithromycin in physiological saline, the drug particles were repeatedly sprayed, dried, and sterilized by irradiation with cobalt 60 for use.

 Example 6

 Hormone-independent prostate cancer is an inevitable form of prostate cancer progression to the advanced stage, and it is difficult to treat. The formulation of the sustained-release implant is composed of the degradable polymer compound polylactic acid, the chemotherapy drug Taxotere, the prostate cancer-specific drug estradiol phosphate mustard (Ai Shishi) and the release blocker tristearate. composition. The drug particles are sprayed with an anti-tumor antibiotic, paclitaxel. In addition to having a good therapeutic effect on prostate cancer, the anti-bacterial effect of the anti-tumor can further prevent bacterial infection during the surgical implantation process.

 Weighing 50,000 L-polylactic acid with a molecular weight of 50,000. 60 ° heating and melting, adding 2.8 g of estradiol phosphate mustard (Ai Shi), 0.4 g of Taxotere, 0.32 g of tristearic acid. After mixing, the mold is pressed into a bullet-shaped cylinder having a diameter of lmm and a length of 4 mm. The granules were repeatedly sprayed with physiological saline to dissolve the granules, dried, and sterilized by cobalt 60 irradiation for use.

 Example 7

Malignant glioma has the characteristics of invasion and growth, and it is difficult to completely remove the tumor from the operation of the brain. Only postoperative implant chemotherapy can change the situation after poor healing. Sustained release implant Formulated by a degradable polymer compound polylactic acid, a glioma-specific chemotherapy drug temozolomide, cisplatin, an inhibitor of MDR mediated by methylguanine methyltransferase, streptozotocin, a tumor cell apoptosis inducer Arsenic trioxide and a release retardant, glyceryl tristearate. Since the inhibition of MDR must be administered one hour earlier, temozolomide, cisplatin and arsenic trioxide and pharmaceutical excipients are compressed into granules, and the outer layer is sprayed with sufficient amount of streptozotocin. The antibacterial effect of streptozotocin can further prevent surgery. Bacterial infection during planting.

 L-polylactic acid 200 mg with a molecular weight of 50,000 was dissolved in 10 ml of acetone, 60 mg of temozolomide, 100 mg of cisplatin, 30 mg of arsenic trioxide, and 20 mg of tristearate. After mixing, the mixture was freeze-dried, and then pressed into a bullet-shaped cylinder having a diameter of 0.5 mm and a length of 2 mm. After dissolving streptozotocin into a nearly saturated solution with physiological saline, the drug particles were repeatedly sprayed, dried, and sterilized by cobalt 60 irradiation for use.

 Since the pan-cell protectant amifostine cannot pass the blood-brain barrier, planting in normal brain tissue around the tumor becomes an irreplaceable protective measure for intravenous injection. A bullet-shaped cylinder with a diameter of 0.5 mm and a length of 2 mm can be made to reduce mechanical damage during implantation.

 Example 8

 The pan-cell protectant amifostine protects cells by the formation of sulfhydryl compounds in normal tissues, up to 100 times the concentration in tumor tissues. Amifostine is a prodrug that produces cytoprotective active metabolites by alkaline phosphatase in tissues. The alkaline microenvironment will favor the action of alkaline phosphatase and give the drug a greater local concentration. .

 Amifostine should be used at least 15 minutes before chemotherapy to ensure better protection of normal cells.

 The formulation of the normal cell protection sustained release implant is composed of a degradable polymer compound polylactic acid and polyglycolic acid copolymer PLGA, a drug amifostine, a pH regulator sodium hydrogencarbonate, and a release retardant glyceryl tristearate. composition. Since the protective effect of amifostine depends on the pH of the environment, the addition of 10% sodium bicarbonate to the formulation allows the sustained-release carrier to remain at a pH of about 8 during the degradation process without the addition of an acid-base regulator. The pH of the chemotherapeutic drug implants will be greatly reduced when degraded, and this difference is also more conducive to the protection of normal cells. Spraying the drug particles with antibiotics can further prevent bacterial infection during surgical implantation.

Weighing 50,000 molecular weight, polylactic acid / polyglycolic acid ratio of 9: 1 PLGA 4 grams, dissolved in In 30 ml of dichloromethane, 4.5 g of amifostine, 1 g of sodium hydrogencarbonate and 0.5 g of tristearate were mixed, vacuum dried, and pressed into a bullet shape with a diameter of 1 mm and a length of 4 mm. Cylinder. After dissolving the antibiotics in physiological saline, the drug particles were repeatedly sprayed, dried, and sterilized by irradiation with cobalt 60 for use.

 plan 1:

 Each of the degradable chemotherapeutic drug sustained release agents in the above Examples 1 to 7 can be used together with the normal cell protection sustained release agent of Example 8. For those who fail to undergo surgical resection, the normal cell protection slow release agent can be implanted in the normal tissue surrounding the tumor tissue by percutaneous or endoscopy, and the chemotherapy drug sustained release agent is implanted in the tumor; for those who can undergo surgical resection Intraoperative use, and prophylactic chemotherapeutic drug sustained release agent planted in the peripheral surgical field (with tumor resected), in order to eliminate the individual transfer or dissemination of tumor cells while the most effective protection of normal tissues. It is best to implant amifetine in clinical use to achieve the best protection.

 Scenario 2:

 Each of the degradable chemotherapeutic drug sustained release agents in the above examples 1 to 7 was added with amifostine at the time of preparation, and the amifostine solution was sprayed on the surface of the implant, and then sterilized according to conventional sterilization. Amifostine on the surface of the drug helps normal cells to be protected when they are not exposed to chemotherapy. The drug prepared according to this method can be implanted (excised) in the peripheral tissues of the tumor to kill the free tumor cells while protecting the normal tissues.

 (2) There are various preparation methods for lymphatic absorbable nano drug sustained-release system (including lymph node display drugs): such as salting out method, emulsion-solvent diffusion method, nanoprecipitation method, emulsion-solvent evaporation method, solvent- Non-solvent method, phacoemulsification method, spray method, etc.

 Example 9

 Malignant lymphoma is caused by malignant tumors of the reticular system. The types of tissues are diverse, and various organs and parts may be invaded. It is difficult to treat. Previous treatments have been administered intravenously, and patients often fail to achieve the best results due to the side effects of the drug. The formulation of sustained-release implant is composed of degradable polymer compound polylactic acid/polyglycolic acid, chemotherapy drug fludarabine, cytarabine, bleomycin, apoptosis inducer arsenic trioxide, chemotherapy sensitizer R-dimensional Lapami consists of the pan-cell protectant amifostine.

Weighing 50,000 molecular weight, polylactic acid / polyglycolic acid ratio of 9: 1 PLGA 75 mg, fluorine Dalbinbin 2.5 mg, co-dissolved in 5 ml of acetone, and mixed for use (solution A). Prepare another 75 mg of Pluronic F68 (poloxamar) dissolved in 15 ml of room temperature water and mix for use (solution B). The liquid A was poured into the solution B and gently stirred to form nanoparticles. The acetone was evaporated under reduced pressure, and filtered through a nitrocellulose membrane of 1.0 μm to obtain drug-loaded nanoparticles having an average diameter of 160-170 nm, which were dried for use. Similarly, cytarabine, bleomycin, arsenic trioxide, R- verapamil and amifostine nanoparticles were prepared. Weighed 4 parts of fludarabine, 1 part of glucosinolate, 6 parts of bleomycin, 2 parts of arsenic trioxide, 200 parts of R- verapamil and 80 parts of amifotin. After mixing, it was lightly pressed into a mold. A bullet-shaped cylinder of 1 mm in diameter and 4 mm in length is sterilized by irradiation with cobalt 60 for use.

 For patients with malignant lymphoma, the drug can be directly implanted into the lymph nodes of the patient through various forms of endoscopy, endoscopy or percutaneous puncture. Macrophages phagocytose the drug particles and enter the capillary lymphatics. The highest drug concentration is present in the lymph nodes. Continuous chemotherapy can be achieved by the detachment of the drug's nanoparticles from the implant into the capillary lymphatics.

 Example 10

 The above-mentioned methods were used to prepare nano-drug particles of liver, non-small cell lung cancer, pancreatic cancer, renal cancer, gastrointestinal stromal tumor, prostate cancer and the like. Spray and dry with a nearly saturated solution of Methylene chloride or water, and sterilize by irradiation with cobalt 60 for use.

 Different nano-simulators can be used when different solid tumor patients need to perform lymph node dissection. Diluting the Meilan nano drug-loading granules with physiological saline can inject the peripheral tissue of the tumor tissue, and the incomplete cleaning of the lymph nodes of the patient may be greatly eliminated. For the lymph nodes that are inadvertently swept away and the two or three stations that do not need to be cleaned, the escaped tumor cells are also killed by the chemotherapy action of the nanoparticles.

(3) The preparation method of the nano drug sustained-release system in blood (body) liquid is the same as above, except that ordinary nanoparticles enter the blood vessel and are in the phagocytic system of the mononuclear cells in vivo within a few minutes or even seconds. Macrophages are swallowed and cannot be circulated for a long time in blood (body) fluid. Long-circulating nano drug-loaded granules can only be prepared by subjecting the degradable nanoparticles to hydrophilic modification of the surface. Hydrophilic modification can be carried out by modifying the surface of the particles with a hydrophilic polymer, or directly synthesizing a degradable polymer having a hydrophilic segment. Commonly used surface modification materials are: polyethylene glycol, polyoxyethylene, polyoxyethylene ether, polyoxyethylene ester, poloxamer (polyurethane-polyoxygen) Propylene-polyoxyethylene triblock copolymer), poloxamin (polyoxyethylene-polyoxypropylene copolymer ethylenediamine).

 Example 11

 Leukemia is a malignant tumor of the blood system, and many types of acute myeloid leukemia with multiple recurrences are called refractory acute leukemia. The use of long-circulating nanomedicine in the chemotherapy of blood system can keep the therapeutic concentration of the drug in the blood for a long time, greatly reduce the number of intravenous injections, and play a role in vein protection; and the amifostine in the drug group Better protection of normal cells during chemotherapy. The formulation of the sustained-release implant is composed of a degradable polymer compound methoxy-terminated polyethylene glycol/polylactic acid/polyglycolic acid copolymer (mPEG-PLGA) and a chemotherapeutic drug cytarabine, aclarithromycin, cells. The apoptosis-inducing agent arsenic trioxide, the chemotherapy sensitizer R- verapamil and the pan-cell protectant amifostine.

 Weighing a copolymer of polylactic acid/polyglycolic acid with a molecular weight of 10,000 and a methoxy-terminated polyethylene glycol having a molecular weight of 5,000 (the ratio of polylactic acid/polyglycolic acid is 1:1, and the content of polyethylene glycol is 10%) 300 mg, cytarabine 80 mg, aclarin 120 mg, arsenic trioxide 100 mg, R- verapamil 600 mg, amifostine 300 mg, co-dissolved in 10 ml of acetone, mix spare. This solution was quickly added dropwise to 10 ml of water for injection with a rapid magnetic stirring of 0.25% pluronic F68 (poloxamer), stirred for 20 minutes, and then decompressed until the acetone was completely evaporated. 300 mg of amitriptyline was dissolved in physiological saline to prepare a nearly saturated solution, and the drug particles were repeatedly sprayed, thoroughly dried, and sterilized by cobalt 60 irradiation for use. The obtained drug-loaded nanoparticle has an average particle diameter of 90 nm and can be present in the blood for a long period of time.

 Example 12

 The long-circulating nano drug-loading particles of liver, non-small cell lung cancer, pancreatic cancer, renal cancer, gastrointestinal stromal tumor, prostate cancer and the like were prepared by the above methods. Thoracic and abdominal metastases caused by various solid tumors can also be treated with long-circulating nanomedicine for intracavitary chemotherapy, but long-circulating nanomedicines made with targeted chemotherapy drugs should be used separately. This long-circulating drug can minimize the phagocytosis of macrophages and maximize the time present in the cavity.

(4) The preparation method of the nano drug sustained-release system in specific tissues such as liver, spleen, lung and bone marrow is basically the same as above. Its pharmacological mechanism is: The surface properties of nanoparticles affect the enrichment in organs, such as hydrophilic, positively charged nanoparticles are easily enriched in the lungs, hydrophobic, negatively charged Nanoparticles are easily enriched in the liver; in addition, nanoparticles of different sizes are phagocytized by macrophages of different organs and trapped in organs to exert chemotherapy. For example, particles of 100-200 nm will be enriched in the liver, particles of 3-12 microns will be enriched in the lungs, and particles of 50 nm will be enriched in the spleen and bone marrow.

 Example 13

 For the treatment of liver cancer, in addition to the locally implantable degradable sustained release drug, intravenously injected degradable sustained release nanomedicine that can be enriched in the liver can be used. The formulation of sustained-release nanomedicine consists of degradable polymer compound polylactic acid, chemotherapeutic drug oxaliplatin, gemcitabine (Gemcitabine) and hepatocellular carcinoma targeting drug sorafenib (Nexavar), apoptosis inducer arsenic trioxide and pan-cell The protective agent is composed of amifetine.

 540 mg of L-polylactic acid with a molecular weight of 10,000 was dissolved in 15 ml of acetone, 20 mg of oxaliplatin, 170 mg of gemcitabine, 40 mg of sorafenib, 2 mg of arsenic trioxide, 60 mg of amitriptyline, and after mixing. It was added to 15 ml of water for injection containing 0.1% pluronic F68 (poloxamar) under moderate agitation, stirred for 20 minutes, and then decompressed until the acetone was completely evaporated. After thorough drying, it was sterilized by cobalt 60 irradiation for use. The obtained drug-loaded nanometer has an average particle diameter of 100 nm and will be abundant in the liver.

3⁄4 episodes.

 The invention is a novel drug use platform, and any new chemotherapeutic drugs, chemotherapy sensitizers, tumor targeting drugs, pan cell protection agents, etc. can be used on this platform in addition to the existing drugs, for the future. Ultimately conquer cancer to play a role.

 The above description of the degradable polymeric tumor therapeutic drug and the normal cell protective agent sustained-release drug provided by the present invention is described in detail. The principle and embodiment of the present invention are described in the following. The description of the above embodiment is only The method for understanding the present invention and its core idea; at the same time, for those of ordinary skill in the art, according to the idea of the present invention, there will be changes in the specific embodiment and the scope of application. The description should not be construed as limiting the invention.

Claims

Rights request

 A sustained release system for a tumor therapeutic drug comprising a degradable polymer carrier, a tumor therapeutic drug, and amifostine.

 The sustained release system according to claim 1, wherein the tumor therapeutic drug comprises a chemotherapeutic drug and optionally contains one or more of a chemotherapy sensitizer, a tumor targeting drug, and a lymph node tracer drug.

 The sustained release system according to claim 1, wherein the degradable polymer carrier comprises a natural polymer carrier and a synthetic polymer carrier.

 The sustained release system according to claim 2, wherein the weight ratio between the chemotherapeutic drug and the amifostine in the sustained release system is 1:0. 001-20000.

 The sustained release system according to claim 4, further comprising a filler, a porogen, an excipient, a dispersant, an isotonic agent, a preservative, a release retardant, a solubilizer, and an absorption promotion. One or more of a dose, a film former, a gelling agent, a crosslinking agent, and an acid-base regulator.

 The sustained release system according to claim 5, wherein the degradable polymer carrier is polylactic acid, and the chemotherapeutic drug is one or two of platinum oxalate and gemcitabine, and the tumor is targeted. The drug is one or more of sorafenib, erlotinib, arsenic trioxide, the release retardant is glyceryl tristearate; preferably platinum oxalate, gemcitabine, sorafenib or erlotinib 001-35 : 0. 001-20: 0. 001-2. The weight ratio between the two parts is: 1: 0. 001-35: 0. 001-20: 0. 001-2.

 The sustained release system according to claim 5, wherein: the tumor targeting drug is arsenic trioxide, the chemotherapy sensitizer is R- verapamil, and the degradable polymer carrier is polylactic acid. Or polyglycolic acid, the chemotherapeutic drug is one or more of fludarabine, cytosine, bleomycin, the lymph node tracer drug is methylene blue, cross-blue, patent blue, fluorescein , blush, indigo, one of chlorophyll; preferably the ratio of the weight ratio between fludarabine, cytarabine, bleomycin, arsenic trioxide, and R- verapamil is 1: 0. 001- 2. 5: 0. 001-15: 0. 001-5: 0. 001-500.

The sustained release system according to claim 5, wherein: the degradable polymer carrier is polylactic acid, the tumor targeting drug is sorafenib and arsenic trioxide, and the chemotherapeutic drug is platinum oxalate. One or more of gemcitabine; a weight ratio between platinum oxalate, gemcitabine, sorafenib, and oxidized trioxide is preferably 1: 0. 001-85: 0. 001-20: 0. 001-1.

The sustained release system according to claim 5, wherein: the tumor targeting drug is arsenic trioxide, the chemotherapy sensitizer is R- verapamil; and the degradable polymer carrier is methoxy One of a polyethylene glycol, a polylactic acid, a polyglycolic acid copolymer, the chemotherapeutic drug is one or more of cytarabine and aclarin; preferably cytarabine, The weight ratio between clarithromycin, arsenic trioxide, and R- verapamil is 1: 0. 001-15: 0. 001-12. 5: 0. 001-75.

 The use of the sustained release system according to any one of claims 1 to 5 for the preparation of a medicament for treating tumors, characterized in that: the tumor comprises hepatocellular carcinoma, lung cancer, renal cell carcinoma, gastrointestinal interstitial Tumor, prostate cancer, malignant lymphoma and acute myeloid leukemia.