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Compound anticancer sustained-release agent containing Clofarabine

A technology of clofarabine and sustained-release agent, which is applied to medical preparations containing active ingredients, pharmaceutical formulations, antitumor drugs, etc., can solve the problems of complicated surgical operations, cost-effective implementation, restrictions, etc.

Inactive Publication Date: 2008-10-01
JINAN KANGQUAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the excessive expansion and hyperplasia of solid tumors, the interstitial pressure, tissue elastic pressure, fluid pressure and interstitial viscosity are all higher than those of the surrounding normal tissues. Therefore, it is difficult for conventional chemotherapy to form an effective drug concentration in the tumor. See Kong Qingzhong "Intratumoral placement of cisplatin plus systemic carmustine in the treatment of rat brain tumors" "Journal of Surgical Oncology" 69 pages 76-82 (1998) (Kong Q et al., J Surg Oncol.1998 Oct; 69( 2): 76-82), simply increasing the dosage is limited by systemic reactions
Local application of drugs may solve the problem of drug concentration to some extent (Chinese patent), however, surgical operations such as drug implantation are more complicated and traumatic, and in addition to easily leading to various complications such as bleeding, infection, and decreased immunity, It can also cause or accelerate the spread and metastasis of tumors
In addition, the preparation and expensive costs before and after the operation often affect its effective implementation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Put 80 mg of polylactic acid (PLGA) with a peak molecular weight of 35,000 into a container, add 100 ml of dichloromethane, dissolve and mix well, add 10 mg of clofarabine and 10 mg of methotrexate, re-shake, and then vacuum dry to remove the organic solvent . The dried solid composition is shaped immediately, subpackaged and then sterilized by radiation to obtain the anti-cancer sustained release containing 10% clofarabine and 10% methotrexate. All are percentages by weight. The drug release time of the anti-solid tumor pharmaceutical composition in physiological saline in vitro is 15-25 days, and the drug release time in mouse subcutaneous is 25-50 days.

Embodiment 2

[0118] As described in Example 1, the difference is that the anticancer active ingredient and weight percentage are one of the following:

[0119] (1) A combination of 1-40% clofarabine and 1-40% doxorubicin, epirubicin, mitomycin C, actinomycin D or dactinomycin; or

[0120] (2) 1-40% of clofarabine and 1-40% of fluorouridine, deoxyfluorouridine, 5-deoxyfluorouridine, propylthiouracil, fluorouracil, butyl fluorouracil, bisfluridine, 5 -Fluoropyrimidinol, sodium sulfthiopurine, mercaptopurine, mercaptopurine, 6-mercaptopurine, 6-aminopurine hydrochloride, glycinethiopurine, thioguanine, methotrexate, flumethotrexate, Dioxymethotrexate, 10-ethyldeazaminopterate, methotrexate, folic acid, 5,10-dideazatetrahydrofolate, calcium levofolinate, calcium folinate, carmofur, tega Fluorine, Youfudine, Uracil Tegafur, 8-Azaguanine, Uracil, Thimethouracil, Topotecan, Topotecan Hydrochloride, Cytarabine, Cyclocytidine, Hydroxyurea, Hydroxyguanidine The combination.

[0121] The sustained...

Embodiment 3

[0123] Put 80mg of polyphenylpropane (p-carboxyphenylpropane (p-CPP): sebacic acid (SA) at 20:80) copolymer into a container, add 100ml of dichloromethane, dissolve and mix well, then add 10mg of chlorine Farabine and 10 mg fluorouracil were re-shaken and spray-dried to prepare microspheres for injection containing 10% clofarabine and 10% fluorouracil. Then suspend the microspheres in physiological saline containing 15% mannitol to prepare the corresponding suspension-type sustained-release injection with a viscosity of 20cp-300cp (at 20°C-30°C). The drug release time of the slow-release injection in physiological saline in vitro is 15-25 days, and the drug release time in mice subcutaneous is about 30-40 days.

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Abstract

A compound anti-cancer sustained-release injection containing clofarabine is composed of sustained-release microspheres and a solvent, wherein, the sustained-release microspheres comprise anti-cancer effective components and sustained-release excipients, the anti-cancer effective components are composed of the clofarabine and a clofarabine synergist which is selected from anti-tumor antibiotics and / or anti-metabolism drugs, the solvent is the special solvent containing a suspending agent; the sustained-release excipients are selected from polylactic acid / glycolic acid copolymer, monomethyl polyethylene glycol / polylactic acid, polyethylene glycol / polylactic acid, terminal carboxyl polylactic acid, terminal carboxyl polylactic acid / glycolic acid copolymer, EVAc, copolymer of fatty acid and sebacic acid and so on; the viscosity of the suspending agent is 80cp to 3000cp ( at 20 DEG C to 30 DEG C ), and the suspending agent is selected from carboxymethyl cellulose and so on; the sustained-release microspheres can further be made into a sustained-release implant which is injected or arranged in a tumor or the tumor periphery, and the local drug release can approximately last 30 to 50 days. The independent application of the sustained-release injection and the sustained-release implant can effectively inhibit the tumor growth, and the combined application with chemotherapy drugs and / or radiotherapy and other non-surgical therapies, and also can significantly enhance the efficacy.

Description

(1) Technical field [0001] The invention relates to a compound anticancer slow-release agent containing clofarabine, which belongs to the technical field of medicines. Specifically, it is a slow-release preparation against solid tumors, including slow-release injections and slow-release implants. (2) Background technology [0002] Clofarabine, as a new class of chemotherapy drugs, has been widely used in the treatment of childhood acute myeloid leukemia (ALL), relapsed or resistant acute myeloid leukemia (AML), adult leukemia and solid tumors and other malignancies. Tumors, and the effect is more obvious. However, its obvious systemic toxicity greatly limits the application of this drug. [0003] Not only that, blood vessels, connective tissue, matrix proteins, fibrin, and collagen in the tumor stroma not only provide scaffolds and essential nutrients for the growth of tumor cells, but also affect the effect of chemotherapy drugs on the surrounding tumor and tumor tissue. ...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K9/08A61K31/7076A61K31/519A61K47/34A61P35/00A61K47/26
Inventor 高化兰
Owner JINAN KANGQUAN PHARMA TECH
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