CN1969820A - Anticancer pharmaceutical composition - Google Patents

Anticancer pharmaceutical composition Download PDF

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Publication number
CN1969820A
CN1969820A CNA2006102012776A CN200610201277A CN1969820A CN 1969820 A CN1969820 A CN 1969820A CN A2006102012776 A CNA2006102012776 A CN A2006102012776A CN 200610201277 A CN200610201277 A CN 200610201277A CN 1969820 A CN1969820 A CN 1969820A
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epothilone
acid
release
sustained
anticancer
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刘玉燕
张红军
俞建江
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Jinan Shuaihua Pharmaceutical Technology Co Ltd
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Jinan Shuaihua Pharmaceutical Technology Co Ltd
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Abstract

The invention provides an anti-cancer medicine composition, which is a slow release agent comprising slow release microspheres and dissolvent, wherein the slow release microballoons comprise anti-cancer active constituents and slow release auxiliary materials, the dissolvent being specific dissolvent containing suspension adjuvant. the anticancer active ingredients are selected from Epothilone and its derivatives (BMS-247550, azaepothilone B, furaepothilone D, BMS-310750) with anti-cancer drugs selected from anti-cancer antibiotic drugs and/or antimetabolites. The slow release auxiliary materials are selected from polylactic acid and its copolymer, di-aliphatic acid and sebacylic acid copolymer, poly(erucic aciddipolymer-sebacylic acid), poly(fumaric acid-sebacylic acid), Polifeprosan or their combination, the viscosity of the suspension adjuvant is 80-3000cp. The anticancer active constituents and the slow release microspheres can also be prepared into slow release implanting agent for injection or placement in or around tumor with a release period of about 20 days. The slow release injection and slow release implanting agent can be used independently for effectively suppressing tumor accretion, or used in combination with non-operative methods such as chemotherapy and/or radiotheraphy with the function of improving their treatment effects.

Description

Anticancer medicine composition
(I) technical field
The invention relates to an anticancer pharmaceutical composition, and belongs to the technical field of medicaments. Specifically, the invention provides an anticancer pharmaceutical composition containing epothilone and derivatives thereof, which is mainly a sustained-release injection and a sustained-release implant. The anticancer sustained release agent is applied in or around tumor, which is beneficial to the drug to obtain and maintain the effective drug concentration in solid tumor and can increase the sensitivity of tumor cells to the drug.
(II) background of the invention
The treatment of cancer mainly comprises methods such as surgery, radiotherapy, chemotherapy and the like. Wherein the surgical treatment can not eliminate scattered tumor cells, so that the tumor cells are frequently relapsed or caused to spread and metastasize due to surgical stimulation; radiotherapy and traditional chemotherapy have no selectivity, are difficult to form effective drug concentration or therapeutic dose locally on tumors, have poor effect and high toxicity, and are limited by systemic toxicity reaction when the drug or radiation dose is simply increased. See, e.g., "Intratumoral Placement of cisplatin plus systemic Carmustine in rat brain tumors" J.Takema.69, pp 76-82, 1998 (Kong Q et al, J Surg Oncol.1998 Oct; 69 (2): 76-82).
Low dose anti-cancer drug therapy can not only increase drug tolerance of cancer cells, but also promote invasive growth thereof, see Beam et al, "anti-cancer drug pulsed screening increases drug tolerance and in vitro infiltration capacity of human lung cancer cells with concomitant changes in gene expression" [ International journal of cancer (Liang Y, et al, Int Jcancer. 2004; 111 (4): 484-93) ].
The solid tumor is composed of tumor cells and tumor stroma, wherein blood vessels in the tumor stroma not only provide a scaffold and essential nutrients for the growth of the tumor cells, but also influence the penetration and diffusion of chemotherapeutic drugs around the tumor and in the tumor tissue, see Niti et al, "influence of the condition of extracellular stroma on drug operation in the solid tumor" [ Cancer research ] No. 60, No. 2497 and No. 503, 2000 (Netti PA, Cancer Res.2000, 60 (9): 2497 and No. 503).
The components of fibrin and collagen in blood vessels and connective tissues in tumor stroma and hyperproliferative tumor cells cause high interstitial pressure (interstitial pressure), high interstitial viscosity (interstitial viscosity), high tissue tension coefficient (tissue tension module) and low interstitial fluid conductivity (hydralic con) of solid tumors. These factors greatly limit the effective diffusion of drugs into solid tumors and within tumors, and thus constitute a major obstacle to tumor chemotherapy.
The defects can be better overcome by local injection or placement of the anti-tumor drug, the local drug concentration of the tumor can be obviously improved, and the systemic toxic reaction can be obviously reduced. A number of in vitro and in vivo experiments have shown therapeutic efficacy against solid tumors, see Kongqing et al, "cisplatin placement in tumors plus systemic carmustine for treatment of rat brain tumors", J.Surg Oncol.1998 Oct (Kong Q et al, J.Surg.Oncol.1998 Oct; 69 (2): 76-82) and Kongqing et al, "cisplatin placement in tumors for cure of rat primary brain tumors", J.Surg.Oncol.1997 Oct, 64: 268-273 (1997) (Kong Q et al, J.Surg.Oncol.1997 Oct). See also Chinese patent (ZL 00111093.4; ZL 96115937.5; application Nos. 001111264, 001111272) and U.S. patent Nos. 6,376,525B 1; 5,651,986; 5,626,862).
However, single-drug chemotherapy often results in increased resistance of tumor cells to anticancer drugs, with consequent therapeutic failure.
Disclosure of the invention
Aiming at the defects of the prior art, the invention provides a novel pharmaceutical composition containing epothilone and/or anticancer drugs. More particularly, the sustained-release preparation is a sustained-release preparation for resisting solid tumors, mainly a sustained-release implant and a sustained-release injection. The local application can effectively inhibit or destroy the growth of the tumor and can also increase the sensitivity of the tumor cells to anticancer drugs; the epothilone and/or anticancer drug is prepared into sustained release agent (mainly sustained release injection and sustained release implant), which not only can greatly improve the drug concentration of the local tumor, reduce the drug concentration of the drug in the circulatory system and reduce the toxicity of the drug to the normal tissue, but also can greatly facilitate the drug injection, reduce the complications of the operation and reduce the cost of the patient. The anticancer medicine can inhibit tumor growth and raise the sensitivity of tumor cell to anticancer medicine.
The anti-solid tumor sustained release agent comprises an anti-cancer effective component and a pharmaceutical adjuvant, wherein the anti-cancer effective component is selected from epothilone derivatives, anti-tumor antibiotics and/or antimetabolites, and preferably the combination of the epothilone derivatives and the anti-tumor antibiotics and/or the antimetabolites.
After a great deal of research, the invention discovers that the combined application of the epothilone derivative and the antitumor antibiotic and/or the antimetabolite can mutually enhance the antitumor effect, and the selected sustained-release auxiliary materials are used as carriers to prepare sustained-release implants and sustained-release injections to achieve unexpected effects when the sustained-release implants and the sustained-release injections are locally applied. The above unexpected findings constitute the subject of the present invention.
The compound pharmaceutical composition of the present invention can be prepared into any preparation form, such as, but not limited to, capsules, sustained release preparations, granules, pills, tablets, powders, injections, ointments, patches, implants, sustained release injections, etc. Among them, sustained release preparations are preferable, and sustained release implants and sustained release injections are most preferable.
Aiming at the defects of the prior art, the invention provides a novel sustained-release injection containing epothilone and anticancer drugs.
The slow released epothilone injection consists of slow released microsphere and solvent. Specifically, the anticancer sustained-release injection consists of the following components:
(A) a sustained release microsphere comprising:
0.5-60% of anticancer active ingredient
Sustained release auxiliary materials 40-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active ingredients are epothilone and anticancer drugs, and the anticancer drugs are selected from antitumor antibiotics and/or antimetabolites. The anticancer medicine can inhibit tumor growth and raise the sensitivity of tumor cell to epothilone.
The medicine prepared from the epothilone is mainly administrated through the conventional ways such as oral administration or intravenous injection, the administration mode of the invention is local sustained release administration, and the systemic toxicity effect of the medicine is obviously reduced while the treatment effect of the medicine is obviously enhanced. The slow release system is mainly a slow release auxiliary material. The medicinal auxiliary materials are more than hundreds of medicinal auxiliary materials with slow release function, in particular the medicinal auxiliary materials which can slowly release the selected epothilone in human bodies or animal bodies within a certain time can be obtained through a large number of creative experiments, and the selection of the combination of the specific slow release auxiliary materials and the slow-release medicines can be determined through a large number of creative labor. The related data, particularly the data of the release characteristics in animals, can be obtained through a large number of creative experiments in vivo and in vitro, can not be determined through limited experiments, and is non-obvious.
The above unexpected findings constitute the subject of the present invention.
The viscosity range IV (dl/g) of the sustained-release auxiliary material is 0.1-0.8, and the sustained-release auxiliary material is selected from racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), polifeprosan, difatty fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], poly (FA-sebacic acid) ], and the like, Ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), Polydioxanone (PDO), polytrimethylene carbonate (PTMC), xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer, albumin glue or their combination; the suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
Epothilones are, but are not limited to, epothilones (a-F) and epothilone derivatives, selected from one or a combination of the following: epothilone (Epothilone) or Epothilone derivatives selected from Epothilone A, Epothilone B (EPO-906), Epothilone C (desoxyepothilone ), Epothilone D (EpoD), 12, 13-desoxyepothilone B, dEpoB, KOS-862 or NSC-703147), Epothilone E, Epothilone F, and the like, and derivatives thereof.
Among them, derivatives of epothilone C such as, but not limited to, 4-desmethyl-9-one-epothilone C, 12, 13-dihydro-13-oxoepothilone C (12, 13-dihydro-13-oxoepothilone C);
derivatives of epothilone B such as, but not limited to, epothilone B with amino substitutions at positions 21 and 26, respectively or simultaneously, dehydroepothilone B with hydrogen at positions 9, 10, 11, 26, 27 halogen substituted epothilone B, epothilone B with hydroxyl substitutions at positions 9, 10, 11, 14, 21, 26, respectively, 21-dihydroxy epothilone B, 21-hydroxy 10, 11 dehydroepothilone B, 4-demethyl-9-one-epothilone B, 4-demethyl-9, 10-didehydro epothilone B, 4-demethyl-10, 11-didehydro epothilone B, 6-demethyl-10, 11-didehydro epothilone B, 21-amino epothilone B, 21-hydroxy epothilone B, 21-dehydroepothilone B, 26-hydroxyepothilone B, 26-fluoroepothilone B, 26-aminoepothilone B, 12, 13-cyclopropylepothilone B, 12, 13-cyclobutyl epothilone B, ixabepilone (BMS-247550), Azaepothilone B (Azaepothilone B, the oxygen in the lactone ring is replaced by nitrogen), 26-Trifluoro- (E) -9, 10-dehydro-12, 13-desoxyepothilone B (26-trifluo- (E) -9, 10-dehydro-12, 13-desoxyepothilone B [ Fludulenone (Flu) ]; derivatives of epothilone D such as, but not limited to, epothilone D with amino substitution at positions 21 and 26, dehydroepothilone D with amino substitution at positions 9 and 10, dehydroepothilone D with hydrogen at positions 10, 11, 26, 27, halogen substitution at positions 9, 10, 11, 14, 21, 26, respectively, epothilone D with hydroxy substitution at positions 21, 26, 21-hydroxy-10, 11, dehydroepothilone D, 4-demethyl-9-one-epothilone D, 4-demethyl-9, 10-didehydro epothilone D, 4-demethyl-10, 11-didehydro epothilone D, 6-demethyl-10, 11-didehydro epothilone D, 21-hydroxy epothilone D, 21-aminoepothilone D, and, 26-hydroxyepothilone D, 26-aminoepothilone D, 26-fluoroepothilone D, 6-ethyl, 16-fluoro, 17-pyridinylesoprazole (or isoepothilone), isoepothilone D, 9, 10-dehydroepothilone D, 10, 11-dehydroepothilone D, furaetheromycin D (furano-epothilone D), (E) -9, 10-dehydro-12, 13-desoxyepothilone D), BMS-310705, 6-ethyl, 16-fluoro, 17-pyridinyloxyepothilone (ZK-EPO), 11, 12-dehydro-12, 13-dehydro-13-epothilone D11, 12, 13-dehydro-13-desoxyepothilone D (12, 13-dihydro-13-oxoepothilone D), 9-oxoepothilone D (9-oxoepothilone D), 8-epi-9-oxoepothilone D (8-epi-9-oxoepothilone D),
The epothilone and epothilone derivatives are preferably one or a combination of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, and furan epothilone D, BMS-310705.
The ratio of epothilone and epothilone derivatives in the composition can be, depending on the particular case, from 0.1% to 50%, preferably from 1% to 30%, most preferably from 5% to 20%.
The ratio of epothilone in the composition is from 0.1% to 60%, preferably from 1% to 50%, most preferably from 2% to 40%, depending on the particular situation.
The antitumor antibiotic is mainly selected from adriamycin hydrochloride (adriamycin), triiron adriamycin, epiadriamycin (epiadriamycin), 7-O-methylnogaca-4 '-epiadriamycin (7-O-methylnoganol-4' -epiadriamycin), diethoxyacetoacetoyl adriamycin, Mitomycin (Mitomycin), Mitomycin C (Mitomycin C), Mitomycin, actinomycin D (dactinomycin), actinomycin C and cyclosporine A. Among them, adriamycin, epiadriamycin, mitomycin C, actinomycin D, dactinomycin and actinomycin C are preferable. The above antitumor antibiotic drugs also include salts thereof such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate or maleate salts.
The proportion of the anticancer antibiotic in the sustained-release injection is determined by specific conditions, and can be 0.1-50%, preferably 1-40%, and most preferably 2-30%.
Antimetabolites can prevent DNA synthesis, inhibit cell division and proliferation, and act by affecting cell cycle and DNA synthesis in different links.
The antimetabolite is selected from one or a combination of the following: fluorouracil (fluridine), deoxyfluorouridine (doxifluridine, flutolanil), 5-deoxyfluorouridine, prothiocypyrimidine, fluorouracil (Fluracil, 5-FU), butylfluorouracil, bispyramid, 5-fluoropyrimidine, sodium Mercaptopurine, Mercaptopurine (Mercaptopurine, desmosine, 6-MP), Mercaptopurine, 6-aminopurine hydrochloride, glycothiopurine, thioguanine (thioguanine, 6-TG), methotrexate (methotrexate, MTX), fluoromethameterin, dioxomethotrexate, folic acid, 10-ethyldeazaprinine (aminopenicillin), fluoromethameterin, dioxomethotrexate, 5, 10-dideoxynitrotetrahydrofolic acid, methorphan, Carmofur (Carmofur), gafur (Tegafur, fluoropyradine, FT-207), eugenidine (Tegafur, Uracil), Uracil (UFT, Uracil), fluorouracil (uridine, 5-d-tetrafurin, methotrexate, fludara, a, 8-azaguanine (8-azaguanine), uracil, thiouracil, calcium Levofolinate, calcium folinate (calcium Levofolinate, leucovorin), topotecan hydrochloride, Cytarabine (cytosine arabinoside, Ara-C)), Cytarabine (cyclotide, Cyclocytidine), Cytarabine (cyclotide), hydroxyurea (hydroxyurea), hydroxyguanidine.
Among the above antimetabolites, fluorouracil, deoxyfluorouridine, 5-deoxyfluorouridine, propylthiouracil, fluorouracil, butylfluorouracil, bispyranopyridine, 5-fluoropyrimidinol, sodium sulfhydrylthiopurine, mercaptopurine, 6-aminopurine hydrochloride, glycothiopurine, thioguanine, methotrexate, fluoromethopterin, methotrexate, 10-ethyldeazaprinine, methotrexate, folic acid, 5, 10-dideoxyntrahydrofolic acid, calcium levofolinate, calcium folinate, carmofur, tegafur, tebufenl, uracil tegafur, 8-azaguanine, uracil, mercaptopyrimidine, topotecan hydrochloride, cytarabine, cyclocytidine, hydroxyurea, hydroxyguanidine are preferable. Most preferred is 5-FU, mercaptopurine, 6-mercaptopurine, methotrexate, folic acid, calcium levofolinate, calcium folinate, carmofur, tegafur, efosine, uracil tegafur, topotecan, cytarabine, cyclocytidine, or hydroxyurea.
The weight percentage of the antimetabolite in the sustained-release injection is 0.1 to 50 percent, preferably 1 to 40 percent, and most preferably 2 to 30 percent.
When the anticancer drug in the drug sustained-release microspheres is only epothilone or an anticancer drug, the anticancer sustained-release injection is mainly used for increasing the effect of the epothilone or the anticancer drug applied by other ways or for the synergy of radiotherapy or other therapies. When the anticancer drug in the drug sustained-release microspheres is only epothilone or an anticancer drug, the application and the synergy mode of the anticancer sustained-release injection are as follows:
(1) the slow release injection containing epothilone is injected locally, while the anticancer drug is applied by other ways;
(2) the slow release injection containing the anti-cancer drugs is locally injected, and the epothilone is applied in other ways;
(3) locally injecting a slow release injection containing epothilone and a slow release injection containing anticancer drugs; or
(4) The slow release injection containing epothilone and synergist is used for local injection.
The slow released anticancer injection for local application may be also used in raising the effect of radiotherapy and other treatment. Other routes refer, but are not limited to, arterial, venous, intraperitoneal, subcutaneous, intraluminal administration.
The weight percentage of the anticancer active ingredient epothilone and/or anticancer drug in the drug sustained release microsphere is 0.5-60%, preferably 1-40%, and most preferably 5-30%. The weight ratio of epothilone to anti-cancer drug is 1-19: 1 to 1: 1-19, preferably 1-5: 1 to 1: 1-5.
The anticancer active ingredients in the anticancer drug composition of the invention are the combination of one or a plurality of epothilones and/or one or a plurality of anticancer drugs, but the combination is preferably as follows:
(a) 1% -50% of an epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705 in combination with 2% -40% of doxorubicin, epirubicin, mitomycin C, actinomycin D, dactinomycin or actinomycin C; or
(b) 1% -50% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furaetheromacin D or BMS-310705 in combination with 2% -40% fluorouracil, deoxyfluorouridine, 5-deoxyfluorouridine, propylthiouracil, fluorouracil, butyl fluorouracil, bispyrazole, 5-fluoropyrimidine, sodium mercaptopurine, 6-aminopurine hydrochloride, glycinethiurine, thioguanine, methotrexate, fluoromethameterin, dioxymethotrexate, 10-ethyldeazaprinine, dioxymethotrexate, methotrexate, folic acid, 5, 10-dideoxyntrahydrofolic acid, calcium levofolinate, tretazapine, fluxathioprine, methotrexate, fluxathiopterine, doxiflurin, 10-ethyl deazaprinine, doxycycline, epothilone B, furaetherin, epothilone D, or BMS-310705, A combination of calcium folinate, carmofur, tegafur, eufordine, uracil tegafur, 8-azaguanine, uracil, mercaptomethluropyrimidine, topotecan hydrochloride, cytarabine, cyclocytidine, hydroxyurea, or hydroxyguanidine.
The slow release auxiliary material of the invention can be hydrolyzed or degraded by enzyme, acid and alkali or tissue fluid, and comprises one or the combination of the following components:
(1) biocompatible polymers, including biodegradable or non-biodegradable polymers and mixtures or copolymers thereof;
(2) a water-soluble low-molecular compound; or/and
(3) suitable additives and excipients for realizing injection, sustained release and other drug dosage forms.
The slow release auxiliary material is selected from one or the combination of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid/glycollic acid copolymer, polifeprosan, difatty acid and sebacic acid copolymer, poly (erucic acid dipolymer sebacic acid), poly (fumaric acid-sebacic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid-glycolic acid copolymer, xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin and protein glue.
The most preferable sustained-release auxiliary materials in the sustained-release microspheres and the weight percentage thereof are as follows:
(1) 55-90% PLA;
(2) 50-90% PLGA;
(3) 50-85% of polifeprosan;
(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;
(5) a combination of polifeprosan 30-60% with PLA 30-60% or PLGA 30-60%;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin or albumin glue; or
(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer.
Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of the aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), difatty acid-sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA), and poly (fumaric acid-sebacic acid) [ P (FA-SA) ], and the like. The content of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization is 10-60 wt% and 20-90 wt%, respectively, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
The molecular weight peak of polylactic acid may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and most preferably 5,000-30,000; the molecular weight of polyglycolic acid may be, but is not limited to, 5000-; the polyhydroxy acids can be selected singly or in multiple ways. When selected alone, polylactic acid (PLA) or a copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) is preferred, and the molecular weight of the copolymer may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and is most preferably 30,000-50,000; when more than one choice is selected, the polymer or the composite polymer or copolymer of different polymers is preferred, and the composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weight is most preferred, such as, but not limited to, polylactic acid with molecular weight of 1000 to 30000 mixed with polylactic acid with molecular weight of 20000 to 50000, polylactic acid with molecular weight of 10000 to 30000 mixed with PLGA with molecular weight of 30000 to 80000, polylactic acid with molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with molecular weight of 30000 to 80000 mixed with sebacic acid. The polylactic acid used is preferably L-polylactic acid (L-PLA). The viscosity range IV (dl/g) of the L-polylactic acid (L-PLA) is 0.2-0.8, the glass transition temperature range is 55-65 ℃, and the melting point is 175-185 ℃.
In addition to the above sustained-release excipients, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical excipients" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Roming and Gaoyun). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders
In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. Wherein the sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.; other pharmaceutical adjuvants such as, but not limited to, filler, solubilizer, absorption enhancer, film-forming agent, gelling agent, pore-forming agent, excipient or retarder can also be added
In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an anti-cancer component in injection, the used sustained-release auxiliary material is one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological saline, absolute ethanol or buffers formulated with various salts. The suspending agent is intended to effectively suspend the microspheres containing the drug, thereby facilitating injection. For convenient injection, the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), preferably 1000-3000 cp (at 20-30 deg C), and most preferably 1500-3000 cp (at 20-30 deg C). The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
The content of the suspending agent in the common solvent depends on the characteristics of the suspending agent, and can be 0.1-30% according to the specific situation. Preferably, the suspending agent consists of:
A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80; or
B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
The preparation of the solvent depends on the kind of the solvent, and common solvents are commercially available or self-made, such as distilled water, water for injection, physiological saline, absolute ethanol or buffers prepared from various salts, but the preparation must strictly follow the relevant standards. The special solvent should consider the type and composition of suspending agent, the composition and properties of the drug suspended in the solvent, the sustained release microsphere (or microcapsule) and the required amount thereof, and the preparation method of the injection, for example, sodium carboxymethylcellulose (1.5%) + mannitol and/or sorbitol (15%) and/or tween 80 (0.1%) are dissolved in physiological saline to obtain the corresponding solvent with viscosity of 10-650 cp (at 20-30 deg.C).
The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).
The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.
The method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to form fine powders, liposome-encapsulating, and emulsifying. Among them, a dissolving method (i.e., solvent evaporation method), a drying method, a spray drying method and an emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections, and the method is arbitrary. The microspheres used may have a particle size in the range of 5-400um, preferably 10-300um, most preferably 20-200 um.
The microspheres can also be used for preparing other sustained-release injections, such as gel injections and block copolymer micelle injections. The block copolymer micelle is formed by a hydrophobic-hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be injected around tumor or in tumor. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly.
The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutic adjuvant can be any one or more of the above pharmaceutic adjuvants, but the water-soluble high polymer is selected as the main choice, and the mixture or copolymer of polylactic acid, sebacic acid, and high polymer containing polylactic acid or sebacic acid is selected as the first choice among various high polymers, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, mixture of PLA and PLGA, mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride, fatty acid dimer-sebacic acid [ P (EAD-SA) ], and poly (fumaric acid sebacic acid) [ P (FA-SA) ]. The blending ratio of polylactic acid (PLA) to polyglycolic acid is 10/90 to 90/10 (by weight), preferably 25/75 to 75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The aromatic polyanhydride is represented by p-carboxyphenylpropane (p-CPP), the content of the p-carboxyphenylpropane (p-CPP) and sebacic acid in copolymerization is respectively 10-60% and 20-90% by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
The sustained-release auxiliary materials in the sustained-release implant and the weight percentage thereof are most preferably as follows:
(1) 55-90% PLA;
(2) 50-90% PLGA;
(3) 50-85% of polifeprosan;
(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;
(5) 55-90% EVAc;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin or albumin glue; or
(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer.
Still another form of the anticancer drug sustained-release preparation of the present invention is that the anticancer drug sustained-release preparation is a sustained-release implant. The effective components of the anticancer implant can be uniformly packaged in the whole pharmaceutic adjuvant, and also can be packaged in the center of a carrier support or on the surface of the carrier support; the active principle can be released by direct diffusion and/or by degradation via polymers.
The slow release implant is characterized in that the slow release auxiliary material contains any one or more of the other auxiliary materials besides the high molecular polymer. The added pharmaceutic adjuvants are collectively called as additives. The additives can be classified into fillers, pore-forming agents, excipients, dispersants, isotonic agents, preservatives, retarding agents, solubilizers, absorption enhancers, film-forming agents, gelling agents, etc. according to their functions.
The main components of the sustained-release implant can be prepared into various dosage forms. Such as, but not limited to, capsules, sustained release formulations, implants, sustained release implants, and the like; in various shapes such as, but not limited to, granules, pills, tablets, powders, spheres, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred. It can be in the form of rod of 0.1-5mm (thick) × 1-10mm (long), or in the form of sheet.
The optimal dosage form of the sustained-release implant is biocompatible, degradable and absorbable sustained-release implant, and can be prepared into various shapes and various dosage forms according to different clinical requirements. The packaging method and procedure for its main ingredients are described in detail in US patent (US5651986) and include several methods for preparing sustained release formulations: such as, but not limited to, (i) mixing a carrier support powder with a drug and then compressing into an implant, a so-called mixing process; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melt process; (iii) dissolving the carrier support in a solvent, dissolving or dispersing the drug to be packaged in a polymer solution, and then evaporating the solvent and drying, the so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.
The anticancer active ingredients of the sustained-release implant can refer to a sustained-release injection, but are preferably as follows, and the weight percentages are as follows:
(a) 1% -50% of an epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705 in combination with 2% -40% of doxorubicin, epirubicin, mitomycin C, actinomycin D, dactinomycin or actinomycin C; or
(b) 1% -50% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furaetheromacin D or BMS-310705 in combination with 2% -40% fluorouracil, deoxyfluorouridine, 5-deoxyfluorouridine, propylthiouracil, fluorouracil, butyl fluorouracil, bispyrazole, 5-fluoropyrimidine, sodium mercaptopurine, 6-aminopurine hydrochloride, glycinethiurine, thioguanine, methotrexate, fluoromethameterin, dioxymethotrexate, 10-ethyldeazaprinine, dioxymethotrexate, methotrexate, folic acid, 5, 10-dideoxyntrahydrofolic acid, calcium levofolinate, tretazapine, fluxathioprine, methotrexate, fluxathiopterine, doxiflurin, 10-ethyl deazaprinine, doxycycline, epothilone B, furaetherin, epothilone D, or BMS-310705, A combination of calcium folinate, carmofur, tegafur, eufordine, uracil tegafur, 8-azaguanine, uracil, mercaptomethluropyrimidine, topotecan hydrochloride, cytarabine, cyclocytidine, hydroxyurea, or hydroxyguanidine.
The sustained-release auxiliary material can be various water-soluble or water-insoluble high molecular polymers, and one or the combination of polylactic acid (PLA), polyglycolic acid-glycolic acid copolymer (PLGA), polifeprosan, di-fatty acid-sebacic acid copolymer (PFAD-SA), poly (erucic acid dimmer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ] is preferably selected from various sustained-release auxiliary materials.
(1) 55-90% PLA;
(2) 50-90% PLGA;
(3) 50-85% of polifeprosan;
(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;
(5) a combination of polifeprosan 30-60% with PLA 30-60% or PLGA 30-60%;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin or albumin glue; or
(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer.
The route of administration depends on a variety of factors, and in order to achieve effective concentrations at the site of the primary or metastatic tumor, the drug may be administered by a variety of routes, such as subcutaneous, intraluminal (e.g., intraperitoneal, thoracic, and intravertebral), intratumoral, peritumoral injection or placement, selective arterial injection, intralymph node, and intramedulary injection. Selective arterial injection, intracavitary, intratumoral, peritumoral injection or placement is preferred.
The application and the synergy mode of the sustained-release implant are the same as those of an anticancer sustained-release injection, namely the combination of locally-placed epothilone and a synergist administrated by other routes, the combination of locally-placed anticancer drugs and epothilone administrated by other routes, and the combination of locally-placed anticancer drugs and locally-placed epothilone. Wherein the locally applied anticancer drug and epothilone can be produced, packaged, sold, and used separately or in combination. The package refers to the loading process of the drug for the auxiliary materials and the internal and external package of the drug-containing sustained release agent for transportation and/or storage.
The invention can be used for preparing pharmaceutical preparations for treating various tumors of human and animals, mainly sustained-release injections or sustained-release implants, wherein the tumors comprise primary or metastatic cancers or sarcomas or carcinosarcomas originated from brain, central nervous system, kidney, liver, gall bladder, head and neck, oral cavity, thyroid, skin, mucous membrane, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, mammary gland, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon and rectum.
The sustained-release injection or the sustained-release implant prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic drugs, anticoagulant drugs, hemostatic drugs and the like.
The techniques of the anti-solid tumor compositions of the present invention are further described by the following assays and examples:
the in vivo tumor inhibition effect of the epothilone B and the anticancer drug is tested.
Using white rat as test object, 2X 105Colon cancer tumor cells were injected subcutaneously into the quaternary costal region, and were divided into the following 10 groups 14 days after the tumor growth (see table 1). The first group was a control and groups 2 to 10 were treatment groups, where group 2 was an epothilone and groups 3 to 6 were doxorubicin, epirubicin, mitomycin C, actinomycin D, respectively. Groups 7 to 10 are combinations of epothilone with doxorubicin, epirubicin, mitomycin C, actinomycin D, respectively. Except for the intratumoral placement of epothilones, adriamycin, epirubicin, mitomycin C, actinomycin D were all administered intraperitoneally. 15mg/kg, except for 2.5mg/kg of epothilone. Tumor volume was measured on day 30 after treatment and the treatment effect was compared (see table 1).
TABLE 1
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 58±12
2(6) Epothilone B 46±10 ＜0.05
3(6) Adriamycin 42±8 ＜0.05
4(6) Epirubicin 50±10 ＜0.05
5(6) Mitomycin C 44±10 ＜0.01
6(6) Actinomycin D 38±6 ＜0.01
7(6) Epothilone B + doxorubicin 26±4 ＜0.001
8(6) Epothilone B + epirubicin 28±6 ＜0.001
9(6) Epothilone B + mitomycin C 16±4 ＜0.001
10(6) Epothilone B + actinomycin D 18±4 ＜0.001
Note: adriamycin, epiadriamycin, mitomycin C and actinomycin D are all anticancer antibiotics. The results show that epothilone B (group 2) and the anticancer antibiotics (groups 3 to 6) have a certain anti-tumor effect (P < 0.05) when applied alone, especially when administered topically, compared to the control group. The combination (groups 7 to 10) had a significant synergistic effect (P < 0.001).
And secondly, the in vivo tumor inhibition effect of the epothilone D and the anticancer drugs is tested.
The in vivo tumor inhibition effects of epothilone D and anticancer drugs were determined according to the first test, and the results showed that anticancer drugs such as doxorubicin, epirubicin, mitomycin C, actinomycin D or dactinomycin could significantly enhance the tumor inhibition effect of epothilone D (P < 0.05). Both of them have a certain tumor inhibiting effect (P < 0.05) on pancreatic cancer when applied independently, especially when locally administered, and have obvious synergistic effect (P < 0.001) when applied together.
And thirdly, locally applying antimetabolite anticancer drugs and the tumor inhibition effect of the isoepothilone D.
Using white rat as test object, 2X 105Individual breast cancer cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 2). The first group was a control and groups 2 to 10 were treatment groups, where group 2 was isoepothilone D and groups 3 to 6 were 5-fluorouracil, 6-mercaptopurine, methotrexate and topotecan, respectively. Groups 7 to 10 of epothilone D with 5-fluorouracil, 6-mercaptopurine, methotrexate and topotecan, respectivelyAnd (4) combining. All the drugs were placed intratumorally, except for 5mg/kg of isoepothilone D, the antimetabolite anticancer drugs were 15 mg/kg. Tumor volume was measured on day 30 after treatment and the treatment effect was compared (see table 2).
TABLE 2
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 58±12
2(6) Isoepothilone D 44±10 ＜0.05
3(6) 5-Fluorouracil 38±10 ＜0.01
4(6) 6-mercaptopurine 40±8 ＜0.01
5(6) Methotrexate (MTX) 38±8 ＜0.01
6(6) Topotecan 36±8 ＜0.01
7(6) Isoepothilone D + 5-fluorouracil 16±2.6 ＜0.001
8(6) Isoepothilone D + 6-mercaptopurine 22±4.2 ＜0.001
9(6) Isoepothilone D + methotrexate 18±4 ＜0.001
10(6) Isoepothilone D + topotecan 18±3 ＜0.001
Note: 5-fluorouracil, 6-mercaptopurine, methotrexate and topotecan are all antimetabolites. The results show that, compared with the control group, the isoepothilone D (group 2) and the antimetabolite anticancer drugs (groups 3 to 6) have certain tumor inhibition effect (P is less than 0.05) when being used alone. However, the combination (groups 7 to 10) had a significant synergistic effect (P < 0.001).
And fourthly, the in vivo tumor inhibition effect of the epothilone and antimetabolite anticancer drugs is tested.
The in vivo tumor inhibition effect of the epothilone and antimetabolite anticancer drugs was tested according to the method of test three. The result shows that the epothilone and antimetabolite anticancer drugs selected from fluorouracil, 6-mercaptopurine, methotrexate, dioxy methotrexate, calcium levofolinate, calcium folinate, carmofur, tegafur, eufordine, topotecan, cytarabine, cyclocytidine, hydroxyurea and hydroxyguanidine have obvious tumor inhibition effect (P is less than 0.05) when being singly applied to colon cancer. The combined application has obvious synergistic effect (P is less than 0.001).
And fifthly, the in vivo tumor inhibition effect of the epothilone D and the antimetabolite anticancer drugs is tested.
Using white rat as test object, 2X 105Each ovarian cancer cell was injected subcutaneously into the quaternary costal region and divided into the following 10 groups 14 days after tumor growth (see Table 3). Group 1 is a control and groups 2 to 10 are treatment groups, wherein group 2 is epothilone D; groups 3 to 6 are anti-metabolic anti-cancer drugs, respectively. Groups 7 to 10 are combinations of epothilone D with different antimetabolic anticancer drugs, respectively. Except for epothilone D, which was placed intratumorally, carmofur, tegafur, idodine and topotecan hydrochloride were all administered intraperitoneally. 5mg/kg except for 10mg/kg of epothilone D. Tumor volume was measured on day 30 after treatment and the treatment effect was compared (see table 3).
TABLE 3
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 56±10
2(6) Epothilone D 44±5 ＜0.05
3(6) Carbomonofluoride 44±8 ＜0.01
4(6) Tegafur 42±8 ＜0.01
5(6) Youfuding 42±9 ＜0.01
6(6) Topotecan hydrochloride 42±6 ＜0.01
7(6) Epothilone D + carmofur 28±3.2 ＜0.001
8(6) Epothilone D + tegafur 22±3.2 ＜0.001
9(6) Epothilone D + Youfuding 20±3.0 ＜0.001
10(6) Epothilone D + topotecan hydrochloride 18±3.0 ＜0.001
Note: carmofur, tegafur, eufordine and topotecan hydrochloride are all antimetabolite anticancer drugs.
The in vivo tumor inhibition effect of the aza epothilone B and antimetabolite anticancer drugs is tested.
Using white rat as test object, 2X 105One lung cancer cell was injected subcutaneously into the quaternary costal region, and the tumor was divided into the following 10 groups 14 days after growth (see table 4). Group 1 is a control and groups 2 to 10 are treatment groups, wherein group 2 is azaepothilone B; groups 3 to 6 are antimetabolite anticancer drugs, respectively. Groups 7 to 10 are combinations of azaepothilone B with different antimetabolite anticancer agents, respectively. Except for the intratumoral placement of azaepothilone B, carmofur, tegafur, 8-azaguanine and cytarabine were all administered intraperitoneally. 16mg/kg except 4mg/kg of azaepothilone B. Tumor volume was measured on day 30 after treatment and the effect was compared (see table 4).
TABLE 4
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 62±14
2(6) Azaetheriomycin B 50±10 ＜0.05
3(6) Carbomonofluoride 46±6.3 ＜0.05
4(6) Tegafur 48±6.0 ＜0.05
5(6) 8-azaguanine 42±6.4 ＜0.05
6(6) Cytarabine 40±4.8 ＜0.05
7(6) Azaetheromycin B + carmofur 28±2.8 ＜0.001
8(6) Azaetheromycin B + tegafur 26±3.6 ＜0.001
9(6) Azaetheromycin B + 8-azaguanine 18±2.0 ＜0.001
10(6) Azaetheromycin B + cytarabine 22±2.0 ＜0.001
Note: carmofur, tegafur, 8-azaguanine and cytarabine are all antimetabolites.
In vivo tumor inhibiting effects of seventy percent, epothilone (BMS-247550) and anticancer drugs were tested.
Using white rat as test object, 2X 105One gastric cancer tumor cell was subcutaneously injected into the quaternary costal region, and the tumor was divided into the following 10 groups 14 days after growth (see table 5). The first group was control and groups 2 to 10 were treatment groups, wherein group 2 was BMS-247550 and groups 3 to 6 were doxorubicin, epirubicin, mitomycin C, actinomycin D, respectively. Groups 7 to 10 are BMS-247550 in combination with doxorubicin, epirubicin, mitomycin C, actinomycin D, respectively. Except BMS-247550, which was placed intratumorally, adriamycin, epirubicin, mitomycin C, actinomycin D were all administered intraperitoneally. 15mg/kg except 2.5mg/kg of BMS-247550. Tumor volume size was measured on day 30 post treatmentThe therapeutic effects were compared (see table 5).
TABLE 5
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 56±12
2(6) BMS-247550 38±6 ＜0.05
3(6) Adriamycin 42±8 ＜0.05
4(6) Epirubicin 50±10 ＜0.05
5(6) Mitomycin C 44±10 ＜0.01
6(6) Actinomycin D 38±6 ＜0.01
7(6) BMS-247550+ Adriamycin 24±8 ＜0.001
8(6) BMS-247550+ epirubicin 26±6 ＜0.001
9(6) BMS-247550+ mitomycin C 22±4 ＜0.001
10(6) BMS-247550+ actinomycin D 16±4 ＜0.001
Note: adriamycin, epiadriamycin, mitomycin C and actinomycin D are all anticancer antibiotics. The results show that BMS-247550 (group 2) and anticancer antibiotics (groups 3 to 6) alone have a certain anti-tumor effect (P < 0.05), especially when administered topically, compared to the control group. The combination (groups 7 to 10) had a significant synergistic effect (P < 0.001).
And eighthly, locally applying antimetabolite anticancer drugs and the tumor inhibition effect of the furan epothilone D.
Using white rat as test object, 2X 105Liver cancer cell skinThey were injected into the quaternary costal region and divided into the following 10 groups 14 days after tumor growth (see Table 6). The first group was a control and groups 2 to 10 were treatment groups, where group 2 was furan epothilone D and groups 3 to 6 were 5-fluorouracil, 6-mercaptopurine, methotrexate and topotecan, respectively. Groups 7 to 10 are combinations of furan epothilone D with 5-fluorouracil, 6-mercaptopurine, methotrexate and topotecan, respectively. All the drugs were placed intratumorally, except that furan epothilone D was 2.5mg/kg, the antimetabolite anticancer drugs were 17.5 mg/kg. Tumor volume was measured on day 30 after treatment and the treatment effect was compared (see table 6).
TABLE 6
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 58±12
2(6) Furan epothilone D 28±6 ＜0.05
3(6) 5-Fluorouracil 38±10 ＜0.01
4(6) 6-mercaptopurine 40±8 ＜0.01
5(6) Methotrexate (MTX) 38±8 ＜0.01
6(6) Topotecan 36±8 ＜0.01
7(6) Furan epothilone D + 5-fluorouracil 29±4.6 ＜0.001
8(6) Furan epothilone D + 6-mercaptopurine 20±6.2 ＜0.001
9(6) Furan epothilone D + methotrexate 18±4 ＜0.001
10(6) Furan epothilone D + topotecan 18±6 ＜0.001
Note: 5-fluorouracil, 6-mercaptopurine, methotrexate and topotecan are all antimetabolites. The results show that compared with the control group, the furan epothilone D (group 2) and the antimetabolite anticancer drugs (groups 3 to 6) have certain tumor inhibition effect (P is less than 0.05) when being used alone. However, the combination (groups 7 to 10) had a significant synergistic effect (P < 0.001).
Similar synergy is seen with other epothilones in combination with other antimetabolites, such as: fluorouracil, 6-mercaptopurine, methotrexate, levofolinic acid calcium, folinic acid calcium, carmofur, tegafur, eufosdine, topotecan hydrochloride, cytarabine, cyclocytidine, hydroxyurea or hydroxyguanidine antimetabolite anticancer drugs and BMS-310705, and adriamycin, epirubicin, mitomycin C, actinomycin D or dactinomycin antibiotic anticancer drugs and BMS-310705, epothilone B or epothilone D. The tested tumor cells include brain tumor (CNS-1, C6, 9L), gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), Papillary Adenocarcinoma of Thyroid (PAT), liver cancer, pancreatic cancer, renal cancer, esophageal cancer, etc.
Experiment nine, comparison of in vivo release of epothilone sustained-release implant made of polylactic acid with different molecular weights
Rats were used as test subjects, and divided into groups (3/group) and subcutaneously administered equivalent amounts of epothilone D sustained release implants loaded with polylactic acid (PLA) of different Molecular Weights (MW). Then, the remaining amount of the drug in the implant was measured on days 1, 3, 7, 14, 21, 28 and 35, respectively, to obtain the in vivo release rate (%). The results show that the release with molecular weight 20000 is: 1 day (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90%), 28(94) and 35 (98%). Comparing in vivo release of epothilone D sustained-release implants made with different molecular weights, it was found that the release slowed with increasing molecular weight, and compared to the systemic group, the tumor suppression rate increased with increasing molecular weight of polylactic acid, as exemplified by day 7, in the order of 68% (MW: 5000), 66% (MW: 15000), 54% (MW: 25000), 50% (MW: 40000) and 48 (MW: 60000).
Experiment ten, anti-tumor effect of local application of anti-cancer drug and epothilone B.
Using white rat as test object, 2X 105Individual esophageal cancer cells were injected subcutaneously into the quaternary costal region and divided into the following 10 groups 14 days after tumor growth (see table 7). The first group was control and groups 2 to 10 were treatment groups, where group 2 was epothilone B and groups 3 to 6 were 5-fluorouracil, doxorubicin, methotrexate and topotecan, respectively. Groups 7 to 10 are combinations of epothilone B with 5 fluorouracil, doxorubicin, methotrexate and topotecan, respectively. All the drugs were placed intratumorally, except for epothilone B at 2.5mg/kg, the antimetabolite anticancer drugs were 17.5 mg/kg. Tumor volume was measured on day 30 after treatment and the treatment effect was compared (see table 7).
TABLE 7
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 56±12
2(6) Epothilone B 38±10 ＜0.05
3(6) 5-Fluorouracil 38±10 ＜0.01
4(6) Adriamycin 40±8 ＜0.01
5(6) Methotrexate (MTX) 38±8 ＜0.01
6(6) Topotecan 36±8 ＜0.01
7(6) Epothilone B + 5-fluorouracil 20±4.6 ＜0.001
8(6) Epothilone B + doxorubicin 16±2.2 ＜0.001
9(6) Epothilone B + methotrexate 18±4 ＜0.001
10(6) Epothilone B + topotecan 10±2 ＜0.001
Note: 5-fluorouracil, doxorubicin, methotrexate and topotecan are all anticancer drugs. The results show that compared with the control group, the epothilone B (group 2) and the anticancer drugs (groups 3 to 6) have certain tumor inhibition effects (P is less than 0.05) when being singly applied. However, the combination (groups 7 to 10) had a significant synergistic effect (P < 0.001).
Eleventh, the antitumor effect of antimetabolites and epothilone D was tested by topical application.
Using white rat as test object, 2X 105Individual esophageal cancer cells were injected subcutaneously into the quaternary costal region and divided into the following 10 groups 14 days after tumor growth (see table 8). The first group was control and groups 2 to 10 were treatment groups, where group 2 was epothilone D and groups 3 to 6 were 5-fluorouracil, cytarabine, methotrexate and topotecan, respectively. Groups 7 to 10 are combinations of epothilone D with 5-fluorouracil, cytarabine, methotrexate and topotecan, respectively. All the drugs were placed intratumorally, except for epothilone D at 5mg/kg, the antimetabolite anticancer drugs were 15 mg/kg. Tumor volume was measured on day 30 after treatment and the treatment effect was compared (see table 8).
TABLE 8
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 54±10
2(6) Epothilone D 36±8 ＜0.05
3(6) 5-Fluorouracil 38±10 ＜0.01
4(6) Cytarabine 44±8 ＜0.01
5(6) Methotrexate (MTX) 34±8 ＜0.01
6(6) Topotecan 34±8 ＜0.01
7(6) Epothilone D + 5-fluorouracil 24±4.6 ＜0.001
8(6) Epothilone D + cytarabine 18±2.2 ＜0.001
9(6) Epothilone D + methotrexate 22±6 ＜0.001
10(6) Epothilone D + topotecan 14±4 ＜0.001
Note: 5-fluorouracil, cytarabine, methotrexate and topotecan are all antimetabolites. The results show that compared with the control group, the epothilone D (group 2) and the antimetabolite anticancer drugs (groups 3 to 6) have certain tumor inhibition effect (P is less than 0.05) when being used alone. However, the combination (groups 7 to 10) had a significant synergistic effect (P < 0.001).
The same result is also found in the slow release agent prepared by using polylactic acid as an auxiliary material, and the slow release agent comprises the combination of antimetabolite anticancer drugs such as fluorouracil, mercaptopurine, 6-mercaptopurine, methotrexate, folic acid, calcium folinate, carmofur, tegafur, eufordine, uracil tegafur, 8-azaguanine, topotecan hydrochloride, cytarabine, hydroxyurea or hydroxyguanidine and the like and epothilone D, and the combination of antibiotic anticancer drugs such as adriamycin, epirubicin, mitomycin C, actinomycin D or dactinomycin and the epothilone B.
Particularly, the sustained-release preparation, particularly the sustained-release injection, has simple and convenient operation and good repeatability. Not only has good curative effect, but also has little toxic and side effect.
Different drug packages have different drug release characteristics from different biodegradable polymers. Further research finds that the slow-release auxiliary materials most suitable for the slow release of the medicament are one of or a combination of racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, terminal carboxyl polylactic acid/glycolic acid copolymer, polifeprosan, di-fatty acid and sebacic acid copolymer, poly (erucic aciddipolymer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer and albumin glue; the most suitable suspending agent is one or more of methylcellulose, hydroxymethyl cellulose, sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, or their combination.
In conclusion, the experimental results show the synergistic effect of the epothilone of the present invention on the listed antimetabolite anticancer drugs or antibiotic anticancer drugs. Therefore, the active ingredients of the anticancer compound of the present invention are combined or packaged separately of epothilone and any one (or more) antimetabolite anticancer drug or antibiotic anticancer drug. The above effective components can be made into any dosage form or shape, but preferably slow release dosage form, mainly sustained release injection or sustained release implant.
(IV) detailed description of the preferred embodiments
Example 1.
80mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak of 10000-25000 is put into a container, 100ml of dichloromethane is added, after the uniform dissolution and the mixing, 10mg of epothilone B and 10mg of adriamycin are added, the mixture is shaken again and then is dried in vacuum to remove the organic solvent. And (3) immediately forming the dried solid composition, subpackaging and sterilizing by rays to obtain the anti-cancer sustained-release preparation containing 10% of epothilone B and 10% of adriamycin. All are weight percent. The slow released anticancer preparation has the release time in physiological saline in vitro of 14-21 days and the release time under mouse skin of 25-45 days.
Example 2.
As described in example 1, except that the adjuvant is polylactic acid (PLGA, 75: 25) with molecular weight peak of 20000-: a combination of 10% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705, and 20% doxorubicin, epirubicin, mitomycin C, actinomycin D, dactinomycin, or actinomycin C.
Example 3.
70mg of a polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10mg of epothilone D and 20mg of fluorouracil are added, the mixture is shaken up again, and then the spray drying method is used for preparing the microspheres for injection containing 10% of epothilone D and 20% of fluorouracil. Then suspending the microspheres in physiological saline containing 15 percent mannitol to prepare the corresponding suspension type sustained-release injection with the viscosity of 20-300 cp (at 20-30 ℃). The slow release injection has the release time of 20-30 days in-vitro physiological saline and the release time of about 25-35 days under the skin of a mouse.
Example 4.
The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is that the used auxiliary materials are polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 50: 50), and the anticancer active ingredients and the weight percentage thereof are as follows: 1% -20% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furaetheromycin D or BMS-310705 with 2% -20% and 2% -40% fluorouracil, deoxyfluorouridine, 5-deoxyfluorouridine, propylthiouracil, fluorouracil, butylfluorouracil, tegafur, 5-fluoropyrimidine, sodium sulfadiazine, mercaptopurine, 6-aminopurine hydrochloride, glycinethiurine, thioguanine, methotrexate, fluoromethopterin, methotrexate, 10-ethyldeazaprinine, dioxamethotrexate, methotrexate, folic acid, 5, 10-dideoxyntrahydrofolic acid, calcium levofolinate, calcium folinate, carmofur, tegafur, eutrazine, uracil tegafur, a combination of 8-azaguanine, uracil, mercaptomethluropyrimidine, topotecan hydrochloride, cytarabine, cyclocytidine, hydroxyurea, or hydroxyguanidine. The viscosity of the slow release injection is 200-450 cp (at 20-30 ℃).
Example 5.
80mg of polylactic acid (PLA) with the molecular weight peak value of 10000-25000 is put into a container, 100ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 5mg of calcium levofolinate and 15mg of isoepothilone D are added, the mixture is shaken up again and then is dried in vacuum to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 5% calcium levofolinate and 15% isoepothilone D, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 220-340 cp (at 20-30 deg.C). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 6
The steps of the method for processing the sustained-release injection are the same as the example 5, but the difference is that the auxiliary material is polylactic acid (PLA) with the molecular weight peak value of 25000-50000, and the anti-cancer active ingredients and the weight percentage thereof are as follows: 20% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furaetheromycin D or BMS-310705 in combination with 10% carmofur, tegafur, idovudine, uracil tegafur, 8-azaguanine, uracil, thiouracil, topotecan hydrochloride, cytarabine, hydroxycytidine, hydroxyurea or hydroxyguanidine; the viscosity of the injection is 240-480 cp (at 20-30 deg.C).
Example 7.
70mg of polylactic acid (PLA) with the molecular weight peak value of 15000-30000 is put into a container, 100ml of dichloromethane is added, 20mg of BMS-247550 and 10mg of carmofur are added after being dissolved and mixed evenly, and injection microspheres containing 20% of BMS-247550 and 10% of carmofur are prepared by a spray drying method after being shaken again. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection with the viscosity of 180cp-260cp (at the temperature of 25 ℃ -30 ℃). The sustained release injection has a release time of 10-15 days in vitro physiological saline and a release time of about 20-30 days under mouse skin
Example 8.
The procedure of the process for preparing a sustained-release injection is the same as that of example 7, except that polylactic acid (PLA) having a molecular weight peak of 25000-50000 contains the following anticancer active ingredients: a combination of 5% azaepothilone B, furan epothilone D or BMS-310705 with 30% 5-FU, mercaptopurine, 6-mercaptopurine, methotrexate, folic acid, calcium levofolinate, calcium folinate, carmofur, tegafur, eufordine, uracil tegafur, topotecan, cytarabine or hydroxyurea; the viscosity is 400-560 cp (at 25-30 ℃).
Example 9
40mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) and 30mg of polylactic acid (PLA) with the molecular weight peak value of 15000-30000 are put into a container, 100ml of dichloromethane is added, after dissolving and mixing uniformly, 20mg of topotecan and 10mg of azaepothilone B are added, shaking uniformly again is carried out, and then a spray drying method is used for preparing the microspheres for injection containing 20% of topotecan and 10% of azaepothilone B. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection with the viscosity of 100cp-160cp (at 25 ℃ -30 ℃). The slow release injection has the release time in vitro physiological saline of 21-25 days and the release time under the skin of a mouse of about 20-30 days.
Example 10
The steps of the method for processing the sustained-release injection are the same as the example 9, but the difference is that the polifeprosan is 50: 50), the molecular weight peak value of PLA is 30000-50000, and the anticancer active ingredients are: a combination of 5% furan epothilone D or BMS-310705 with 25% 5-FU, methotrexate, uracil tegafur or cytarabine; the viscosity is 560cp-640cp (at 25 ℃ -30 ℃).
Example 11
40mg of a polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 50: 50) copolymer and 30mg of a PLGA (50: 50) copolymer with a molecular weight peak of 10000-25000 are placed in a container, 100ml of dichloromethane is added, after dissolving and mixing uniformly, 15mg of epirubicin and 15mg of epothilone D are added, after shaking uniformly again, the microspheres for injection containing 15% of epirubicin and 15% of epothilone D are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 20-25 days in-vitro physiological saline and the drug release time of about 20-30 days under the skin of a mouse.
Example 12
The procedure of the process for preparing a sustained release implant was the same as in example 11, except that the sustained release excipients used were: 40mg of polifeprosan (30: 70) and 30mg of PLGA (75: 25) having a molecular weight peak of 25000-45000; the anticancer active component is the combination of 20% of epothilone D or epothilone B and 10% of adriamycin, epirubicin, mitomycin C, actinomycin D, dactinomycin or actinomycin C.
Example 13
70mg of difatty acid and sebacic acid copolymer (PFAD-SA) with the molecular weight peak value of 10000-35000 is put into a container, 100ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10mg of mitomycin C and 20mg of epothilone B are added, after the mixture is shaken again evenly, the microspheres for injection containing 10% of mitomycin C and 20% of epothilone B are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 20-25 days in-vitro physiological saline and the drug release time of about 35-50 days under the skin of a mouse.
Example 14
The steps of the method for processing the sustained-release implant are the same as those of the examples 11 to 13, but the difference is that the used auxiliary material is poly (sebacic acid fumarate) [ P (FA-SA) ] with the molecular weight peak of 25000-45000, and the anticancer active ingredients and the weight percentage are as follows:
(a) a combination of 5-30% epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705, and 5-30% doxorubicin, epirubicin, mitomycin C, actinomycin D, dactinomycin or actinomycin C; or
(b) 5-30% of epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furaetheromycin D, or BMS-310705 in combination with 5-30% of 5-FU, mercaptopurine, 6-mercaptopurine, methotrexate, folic acid, calcium levofolinate, calcium folinate, carmofur, tegafur, eufordine, uracil tegafur, topotecan, cytarabine, cytidine, or hydroxyurea.
Example 15
70mg of poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ] with the molecular weight peak of 10000-35000 is put into a container, 100ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10mg of dactinomycin and 20mg of epothilone B are added, after the mixture is shaken up again, the microspheres for injection containing 10% of dactinomycin and 20% of epothilone B are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time in vitro physiological saline of 24-28 days and the release time under the skin of a mouse of about 30-35 days.
Example 16
The procedure of processing into sustained release preparation is the same as that of examples 1-15, except that the sustained release excipient is one or a combination of the following:
a) polylactic acid (PLA) with a molecular weight peak of 10000-;
b) a copolymer (PLGA) of polyglycolic acid and glycolic acid, wherein the ratio of the polyglycolic acid to the glycolic acid is 50-95: 50-50, and the peak value of the molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
c) polifeprosan, p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) in a ratio of 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
d) polifeprosan in combination with PLA or PLGA;
e) di-fatty acid and sebacic acid copolymer (PFAD-SA);
f) poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ];
g) poly (fumaric-sebacic acid) [ P (FA-SA) ];
h) xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin or albumin glue;
i) racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.
Example 17
The procedure for preparing a sustained-release injection is the same as in examples 1 to 10, except that the suspending agent used is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20.
The above examples further describe the technical process of the present invention. Are intended to be illustrative and not limiting of the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are, of course, intended to be within the scope of the appended claims. It should be understood, therefore, that the foregoing description focuses on certain specific embodiments of the invention and that equivalent alterations and substitutions made thereto are within the spirit and scope of the appended claims.
The invention is disclosed and claimed.

Claims (10)

1. An anticancer pharmaceutical composition, characterized in that the anticancer pharmaceutical composition comprises the combination of epothilone or derivatives thereof and an anticancer drug selected from antitumor antibiotics and/or antimetabolites.
2. The anticancer pharmaceutical composition according to claim 1, wherein said antitumor antibiotic is selected from the group consisting of doxorubicin, epirubicin, mitomycin C, actinomycin D, dactinomycin and actinomycin C.
3. The anticancer pharmaceutical composition according to claim 1, wherein said epothilone derivatives are selected from epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, 4-demethyl-9-one-epothilone C, 12, 13-dihydro-13-oxoepothilone C, 21-aminoepothilone B, 26-aminoepothilone B, 21, 26 , F Hobemycin ,9, 10-dehydroepothilone B, 10, 11-hydroepothilone B, 26, 27-halogenoepothilone B, epothilone B in which position 9, 10, 11, 14, 21, 26 are substituted with hydroxyl groups respectively, epothilone B in which position 21, 26-dihydroxy epothilone B, 21-hydroxy-10, 11-dehydroepothilone B, epothilone B in which position 10, 11, 14, 21, 26 are substituted with hydroxyl groups respectively, 4-demethyl-9-one-epothilone B, 4-demethyl-9, 10-didehydro-epothilone B, 4-demethyl-10, 11-didehydro-epothilone B, 6-demethyl-10, 11-didehydro-epothilone B, 21-aminoepothilone B, 21-hydroxyepothilone B, 26-fluoroepothilone B, 26-aminoepothilone B, 12, 13-cyclopropylepothilone B, 12, 13-cyclobutyl epothilone B, ixabepilone, azaepothilone B, 26-trifluoro- (E) -9, 10-dehydro-12, 13-deoxyepothilone B, epothilone D in which positions 21 and 26 are individually or simultaneously replaced by amino, 9-and 10-dehydroepothilone D, 10, 11-dehydroepothilone D, 26, 27-halogen-substituted epothilone D, 9-epothilone D, 10-hydroxy-10, 11-dehydroepothilone D, 4-demethyl-9-one-epothilone D, 4-demethyl-9, 10-didehydro epothilone D, 4-demethyl-10, 11-didehydro epothilone D, 6-demethyl-10, 11-didehydro epothilone D, 21-hydroxyepothilone D, 21-aminopeptidase D, 26-hydroxyepothilone D, 26-aminoepothilone D, 26-fluoroepothilone D, isoepothilone, isoepothilone D, 9, 10 dehydroepothilone D, 10, 11 dehydroepothilone D, furaetheromycin D, (E) -9, 10-dehydro-12, 13-desoxyepothilone D, BMS-310705, 6-ethyl, 16-fluoro, 17-pyridinepothilone D, one of 11, 12-dehydro-12, 13-dehydro-13-desoxyepothilone D, 9-oxy epothilone D, 8-epi-9-oxy epothilone D or a combination thereof.
4. The anticancer pharmaceutical composition according to claim 1, wherein the antimetabolites are selected from the group consisting of fluorouracil, deoxyfluorouridine, 5-deoxyfluorouridine, prothiocypyrimidine, fluorouracil, butylfluorouracil, bispyranopyridine, 5-fluoropyrimidine, sodium sulfhydrylthiopurine, mercaptopurine, 6-aminopurine hydrochloride, glycothiopurine, thioguanine, methotrexate, fluoromethopterin, methotrexate, 10-ethyldeazaprinine, methotrexate, folic acid, 5, 10-dideoxynitridotetrahydrofolic acid, calcium levofolinate, calcium folinate, carmofur, tegafur, idodine, uracil tegafur, 8-azaguanine, uracil, thiouracil, topotecan hydrochloride, cytarabine, cytosine arabinoside, and a pharmaceutically acceptable salt thereof, One or a combination of cyclocytidine, hydroxyurea or hydroxyguanidine.
5. The anticancer pharmaceutical composition of claim 1, wherein the anticancer pharmaceutical composition is an anticancer sustained release injection, and comprises the following components:
(A) a sustained release microsphere comprising:
the biological effective component is 0.5-60%
The sustained-release auxiliary material is 41 to 99.9 percent
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active component is the combination of epothilone derivative and anticancer drugs selected from antitumor antibiotics and/or antimetabolites, the weight ratio of the epothilone to the anticancer drugs is 1-19: 1 to 1: 1-19;
the slow release auxiliary material is selected from one or the combination of the following materials:
a) polylactic acid;
b) copolymers of polyglycolic acid and glycolic acid;
c) polifeprosan;
d) polifeprosan in combination with polylactic acid or polyglycolic acid and glycolic acid copolymer;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer-sebacic acid) copolymer;
g) poly (fumaric acid-sebacic acid) copolymer;
h) xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin or albumin glue;
i) racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.
The suspending agent is selected from sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40 and Tween-80 or their combination, and has viscosity of 100-3000 cp (at 20-30 deg.C).
6. The sustained-release anticancer injection according to claim 5, wherein:
a) the molecular weight peak value of the polylactic acid is 10000-;
b) in the copolymer of polyglycolic acid and glycolic acid, the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
c) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.
7. The sustained-release anticancer injection according to claim 1, wherein the suspending agent is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20;
f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;
g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;
h) 5-20% of mannitol and 0.1-0.5% of Tween 80;
i)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
8. The sustained-release anticancer injection according to claim 1, wherein the pharmaceutical preparation is a sustained-release implant made of sustained-release microspheres, and is administered by intratumoral or peritumoral injection or placement.
9. The sustained-release anticancer implant according to claim 8, characterized in that the sustained-release excipients used in the sustained-release implant are selected from one or a combination of the following:
a) polylactic acid;
b) copolymers of polyglycolic acid and glycolic acid;
c) polifeprosan;
d) polifeprosan in combination with polylactic acid or polyglycolic acid and glycolic acid copolymer;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer-sebacic acid) copolymer;
g) poly (fumaric acid-sebacic acid) copolymer;
h) xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin or albumin glue;
i) racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.
10. The sustained-release anticancer implant according to claim 7, characterized in that the anticancer active ingredients and the weight percentages thereof are:
(a) 1% -50% of an epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705 in combination with 2% -40% of doxorubicin, epirubicin, mitomycin C, actinomycin D, dactinomycin or actinomycin C; or
(b) 1% -50% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furaetheromacin D or BMS-310705 in combination with 2% -40% fluorouracil, deoxyfluorouridine, 5-deoxyfluorouridine, propylthiouracil, fluorouracil, butyl fluorouracil, bispyrazole, 5-fluoropyrimidine, sodium mercaptopurine, 6-aminopurine hydrochloride, glycinethiurine, thioguanine, methotrexate, fluoromethameterin, dioxymethotrexate, 10-ethyldeazaprinine, dioxymethotrexate, methotrexate, folic acid, 5, 10-dideoxyntrahydrofolic acid, calcium levofolinate, tretazapine, fluxathioprine, methotrexate, fluxathiopterine, doxiflurin, 10-ethyl deazaprinine, doxycycline, epothilone B, furaetherin, epothilone D, or BMS-310705, A combination of calcium folinate, carmofur, tegafur, eufordine, uracil tegafur, 8-azaguanine, uracil, mercaptomethluropyrimidine, topotecan hydrochloride, cytarabine, cyclocytidine, hydroxyurea, or hydroxyguanidine.
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CN111518037A (en) * 2020-05-31 2020-08-11 湖北工业大学 [2- (5' -fluorouracil) acetic acid-ethyl phenyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111592498A (en) * 2020-06-08 2020-08-28 湖北工业大学 [2- (5' -fluorouracil) acetic acid-diethyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111662237A (en) * 2020-06-22 2020-09-15 湖北工业大学 [2- (5' -fluorouracil) acetic acid-pyrrolidinyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111825623A (en) * 2020-06-30 2020-10-27 湖北工业大学 [2- (5' -fluorouracil) acetic acid- (N-ethyl) piperazinyl dithiocarbamate ] anhydride and application thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111518037A (en) * 2020-05-31 2020-08-11 湖北工业大学 [2- (5' -fluorouracil) acetic acid-ethyl phenyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111518037B (en) * 2020-05-31 2021-04-23 湖北工业大学 [2- (5' -fluorouracil) acetic acid-ethyl phenyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111592498A (en) * 2020-06-08 2020-08-28 湖北工业大学 [2- (5' -fluorouracil) acetic acid-diethyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111592498B (en) * 2020-06-08 2021-04-23 湖北工业大学 [2- (5' -fluorouracil) acetic acid-diethyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111662237A (en) * 2020-06-22 2020-09-15 湖北工业大学 [2- (5' -fluorouracil) acetic acid-pyrrolidinyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111662237B (en) * 2020-06-22 2021-04-23 湖北工业大学 [2- (5' -fluorouracil) acetic acid-pyrrolidinyl dithiocarbamic acid ] anhydride and application thereof in preparation of anti-cancer drugs
CN111825623A (en) * 2020-06-30 2020-10-27 湖北工业大学 [2- (5' -fluorouracil) acetic acid- (N-ethyl) piperazinyl dithiocarbamate ] anhydride and application thereof
CN111825623B (en) * 2020-06-30 2021-04-23 湖北工业大学 [2- (5' -fluorouracil) acetic acid- (N-ethyl) piperazinyl dithiocarbamate ] anhydride and application thereof

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