WO2010072109A1 - Système à libération prolongée pour médicament antitumoral - Google Patents

Système à libération prolongée pour médicament antitumoral Download PDF

Info

Publication number
WO2010072109A1
WO2010072109A1 PCT/CN2009/075008 CN2009075008W WO2010072109A1 WO 2010072109 A1 WO2010072109 A1 WO 2010072109A1 CN 2009075008 W CN2009075008 W CN 2009075008W WO 2010072109 A1 WO2010072109 A1 WO 2010072109A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
tumor
sustained release
release system
chemotherapy
Prior art date
Application number
PCT/CN2009/075008
Other languages
English (en)
Chinese (zh)
Inventor
盛小禹
Original Assignee
Sheng Xiaoyu
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sheng Xiaoyu filed Critical Sheng Xiaoyu
Publication of WO2010072109A1 publication Critical patent/WO2010072109A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a filler 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.
  • 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:
  • 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.
  • a degradable polymer compound polylactic acid a chemotherapeutic drug oxaliplatin, gemcitabine, a tumor targeting drug sorafenib or erlotinib.
  • 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
  • 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 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.
  • 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.
  • 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.
  • normal cell protectants can be implanted around the tumor tissue in order to form better protection for normal tissues.
  • the drug 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.
  • lymph node inducing dye blue also available in isosulfan blue, patent blue, fluorescein, blush, indigo, chlorophyll, etc.
  • lymph node inducing dye blue also available in isosulfan blue, patent blue, fluorescein, blush, indigo, chlorophyll, etc.
  • 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.
  • 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.
  • 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
  • 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.
  • anthracyclines such as doxorubicin, pirarubicin, daunorubicin, etc.
  • mitoxantrone with anthracycline structure.
  • anthracyclines such as doxorubicin, pirarubicin, daunorubicin, etc.
  • mitoxantrone with anthracycline structure.
  • ⁇ 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.
  • 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 ⁇ 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.
  • 4 ⁇ 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 4 ⁇ ion channel blockers
  • 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.
  • 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.
  • fibroblast growth factor receptor inhibitors include 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • tissue necrosis such as (table) doxorubicin, daunorubicin, mitomycin, phosporin, actinomycin D, nitrogen mustard , aniline acridine, maytansine, vinblastine and other drugs.
  • 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
  • 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.
  • 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 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.
  • 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.
  • 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.
  • the scale was taken from 1 part of lenalidomide, 10 parts of carboplatin, 7.2 parts of paclitaxel and 10 parts of gefitinib.
  • 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.
  • the new carcinogen has an antibacterial effect, which can further prevent bacterial infection during the surgical implantation process.
  • 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.
  • 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.
  • 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.
  • the anti-bacterial effect of the anti-tumor can further prevent bacterial infection during the surgical implantation process.
  • 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.
  • streptozotocin 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • lymphatic absorbable nano drug sustained-release system including lymph node display drugs
  • salting out method emulsion-solvent diffusion method, nanoprecipitation method, emulsion-solvent evaporation method, solvent- Non-solvent method, phacoemulsification method, spray method, etc.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • sustained-release nanomedicine 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un système à libération prolongée pour un médicament antitumoral. Ledit système contient un véhicule de type macromolécule dégradable, un agent antitumoral et de l'amifostine, l'agent antitumoral comprenant un agent de chimiothérapie et un ou plusieurs chimiosensibilisateurs, agents de ciblage de la tumeur ou traceurs des ganglions lymphatiques. De préférence, le rapport en poids de l'agent de chimiothérapie à l'amifostine est de 1:0,001-20 000. On peut utiliser le système à libération prolongée de la présente invention pour n'importe quelle tumeur en changeant d'agent de traitement. Le système de la présente invention est une nouvelle plateforme pour n'importe quel agent, non seulement les médicaments actuels mais également les nouveaux médicaments dans le futur.
PCT/CN2009/075008 2008-12-25 2009-11-18 Système à libération prolongée pour médicament antitumoral WO2010072109A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200810207703.6 2008-12-25
CNA2008102077036A CN101444625A (zh) 2008-12-25 2008-12-25 可降解高分子肿瘤治疗药物以及正常细胞保护剂缓释药物

Publications (1)

Publication Number Publication Date
WO2010072109A1 true WO2010072109A1 (fr) 2010-07-01

Family

ID=40740697

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2009/075008 WO2010072109A1 (fr) 2008-12-25 2009-11-18 Système à libération prolongée pour médicament antitumoral

Country Status (2)

Country Link
CN (1) CN101444625A (fr)
WO (1) WO2010072109A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101444625A (zh) * 2008-12-25 2009-06-03 盛小禹 可降解高分子肿瘤治疗药物以及正常细胞保护剂缓释药物
CN111840255B (zh) * 2020-07-31 2022-03-01 北京丰帆生物医药科技有限公司 一种维拉帕米温敏缓释制剂及其制备方法和应用
CN112843052B (zh) * 2021-03-26 2022-07-15 湖南师范大学 表观遗传因子抑制剂2800z在制备抗肝癌药物增敏剂中的应用
CN114507714B (zh) * 2022-04-20 2022-07-05 华中科技大学 一种基于miRNA检测的二维材料半导体传感器制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000056299A2 (fr) * 1999-03-19 2000-09-28 Arch Development Corporation Procede de protection contre les metastases tumorales
US20030096797A1 (en) * 1999-06-15 2003-05-22 Medimmune Oncology Novel pharmaceutical formulations comprising aminoalkyl phosphorothioates
US20030203030A1 (en) * 2002-01-18 2003-10-30 Control Delivery Systems, Inc. Polymeric gel delivery system for pharmaceuticals
US20070190102A1 (en) * 2000-06-30 2007-08-16 Ping Luo Method of preparing hydroxyapatite based drug delivery implant for infection and cancer treatment
CN101444625A (zh) * 2008-12-25 2009-06-03 盛小禹 可降解高分子肿瘤治疗药物以及正常细胞保护剂缓释药物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000056299A2 (fr) * 1999-03-19 2000-09-28 Arch Development Corporation Procede de protection contre les metastases tumorales
US20030096797A1 (en) * 1999-06-15 2003-05-22 Medimmune Oncology Novel pharmaceutical formulations comprising aminoalkyl phosphorothioates
US20070190102A1 (en) * 2000-06-30 2007-08-16 Ping Luo Method of preparing hydroxyapatite based drug delivery implant for infection and cancer treatment
US20030203030A1 (en) * 2002-01-18 2003-10-30 Control Delivery Systems, Inc. Polymeric gel delivery system for pharmaceuticals
CN101444625A (zh) * 2008-12-25 2009-06-03 盛小禹 可降解高分子肿瘤治疗药物以及正常细胞保护剂缓释药物

Also Published As

Publication number Publication date
CN101444625A (zh) 2009-06-03

Similar Documents

Publication Publication Date Title
Wolinsky et al. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers
Abdelmoneem et al. Dual-targeted casein micelles as green nanomedicine for synergistic phytotherapy of hepatocellular carcinoma
Song et al. Endothelial growth factor receptor-targeted and reactive oxygen species-responsive lung cancer therapy by docetaxel and resveratrol encapsulated lipid-polymer hybrid nanoparticles
Jin et al. Cytotoxicity of paclitaxel incorporated in PLGA nanoparticles on hypoxic human tumor cells
EP1922094B1 (fr) Dispositifs permettant le ciblage lymphatique
Tang et al. Honokiol nanoparticles based on epigallocatechin gallate functionalized chitin to enhance therapeutic effects against liver cancer
Martín-Saldaña et al. Polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate to prevent cisplatin-induced ototoxicity
Poláková et al. Electrospun nanofibers for local anticancer therapy: Review of in vivo activity
Martín-Saldaña et al. pH-sensitive polymeric nanoparticles with antioxidant and anti-inflammatory properties against cisplatin-induced hearing loss
JP6938462B2 (ja) 治療用化合物の脳への一方向送達のためのインプラント組成物
US9814734B2 (en) Bufalin liposome, preparation method therefor and application thereof
Dai et al. Preparation of camptothecin-loaded PCEC microspheres for the treatment of colorectal peritoneal carcinomatosis and tumor growth in mice
Gao et al. Dual or multiple drug loaded nanoparticles to target breast cancer stem cells
CA2520475A1 (fr) Particules a charge medicamenteuse ciblant les tumeurs
Bhatnagar et al. Hyaluronic acid grafted PLGA copolymer nanoparticles enhance the targeted delivery of Bromelain in Ehrlich’s Ascites Carcinoma
KR20040058199A (ko) 폴리 양이온성 폴리머 및 음전하를 띠는 약리학적 활성화합물을 포함하는 제어 방출 약물 전달 조성물
Fan et al. Dual drug loaded biodegradable nanofibrous microsphere for improving anti-colon cancer activity
Hao et al. 3D printing‐based drug-loaded implanted prosthesis to prevent breast cancer recurrence post‐conserving surgery
KR20200036815A (ko) 화학색전제
CN106729737A (zh) 一种“脱壳”式智能纳米药物复合物及其制备方法
CN1969816A (zh) 一种含埃坡霉素的抗癌缓释剂
WO2021057007A1 (fr) Agent à libération prolongée à l'échelle nanométrique de rapamycine et son procédé de préparation
Sun et al. A tissue-engineered therapeutic device inhibits tumor growth in vitro and in vivo
WO2010072109A1 (fr) Système à libération prolongée pour médicament antitumoral
WO2018156866A1 (fr) Nanoparticules pour administration de principes actifs dans le traitement des cancers du cerveau

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09834062

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 13131168

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 31/08/2011)

122 Ep: pct application non-entry in european phase

Ref document number: 09834062

Country of ref document: EP

Kind code of ref document: A1