CN1969816A - Anticancer sustained release agent containing epothilone - Google Patents

Anticancer sustained release agent containing epothilone Download PDF

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CN1969816A
CN1969816A CNA2006102012704A CN200610201270A CN1969816A CN 1969816 A CN1969816 A CN 1969816A CN A2006102012704 A CNA2006102012704 A CN A2006102012704A CN 200610201270 A CN200610201270 A CN 200610201270A CN 1969816 A CN1969816 A CN 1969816A
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epothilone
acid
sustained
release
anticancer
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孙娟
张婕
邹会凤
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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

Disclosed is an anti-cancer drugs slow release agent containing Epothilone which comprises 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 constituents include Epothilone, Epothilone derivatives, Epothilone B, Epothilone D and combination of anti-cancer drugs selected from phosphoinositide-3-kinase inhibitor, of pyrimidine analogues and/or DNA restoring enzyme inhibitor, the slow release auxiliary materials include polylactic acid and its copolymer, polyethylene glycol, PLA-COOH copolymer, di-aliphatic acid and sebacylic acid copolymer, poly(erucic aciddipolymer-sebacylic acid), poly(fumaric acid-sebacylic acid), Polifeprosan, polylactic acid and other biocompatible high polymers, the viscosity of the suspension adjuvant is 100-3000cp (at 20-30 deg C), and is selected from sodium carboxymethylcellulose. The anticancer active constituents and the slow release microspheres can also be prepared into slow release implanting agent for intra-tumor or around-tumor injection or placement for the effective suppression of tumor growth and for the appreciable enhancement for curative effects of non-operative treatments such as chemotherapy.

Description

Anticancer sustained-release agent containing epothilone
(I) technical field
The invention relates to an anticancer sustained release agent containing epothilone, belonging to the technical field of medicaments. Specifically, the invention provides a sustained-release injection and a sustained-release implant containing epothilone and a synergist thereof.
(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 No. 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 which contains an epothilone derivative and can be used together with an anticancer drug to realize the synergy. More specifically, the pharmaceutical composition is a sustained-release agent for resisting solid tumors, and mainly comprises a sustained-release implant and a sustained-release injection. Can inhibit tumor growth and increase the sensitivity of tumor cells to anticancer drugs.
In addition, the epothilone and/or the anticancer drug are prepared into the sustained release preparation (mainly a sustained release injection and a sustained release implant), so that not only can the local drug concentration of the tumor be greatly improved, the drug concentration of the drug in a circulatory system be reduced, the toxicity of the drug to normal tissues be reduced, but also the drug injection can be greatly facilitated, the complications of the operation can be reduced, and the cost of a patient can be reduced. The anticancer medicine can inhibit tumor growth and raise the sensitivity of tumor cell to epothilone and its derivative.
The anti-solid tumor sustained release agent comprises an anti-cancer active ingredient and a pharmaceutic adjuvant, wherein the anti-cancer active ingredient is a combination of epothilone and phosphoinositide 3-kinase (P13K) inhibitor, pyrimidine analogue and/or DNA repair enzyme inhibitor.
The epothilone derivative is 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 D13-oxythiolone D, 12, 13-dehydro-13-desoxyepothilone D (12, 13-dihydro13-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, ixabepilone (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%.
Phosphoinositide 3-kinase (abbreviated as P13K) inhibitors are selected from one or a combination of the following: 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine, inositol polyphosphate, tetradecyl phosphocholine, hexadecanoylphosphonic acid (N-N-N-trimethyl) hexanolamine, inositol phosphate, and mixtures thereof, Octadecyl phosphorylcholine or octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate. Among them, 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, and hexadecylphosphocholine are preferable.
The pyrimidine analogue is mainly selected from one or more of O4-benzyl folic acid, 2, 4, 5-triamino-6-benzyloxy pyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine and 2-amino-O4-benzyl pteridine.
The DNA repair enzyme inhibitor can be any one of DNA-dependent protein kinase inhibitor and/or poly (ADP-ribose) polymerase inhibitor, but is selected from imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinol-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine, hexakis (N-N-trimethyl) hexanolamine, and mixtures thereof, Octadecylphosphocholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, Aminotriazole (AT) and butylthionine sulfoximine are preferred.
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) ], and, 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.
The medicinal auxiliary materials are more than hundreds of medicinal auxiliary materials with slow release function, particularly, the effective components selected in the invention can not be obviously slowly released in human bodies or animal bodies within a certain time, and the selection of the specific slow release auxiliary materials and the slow release medicines can be determined only by a great deal 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 compositions of the invention may be prepared in a manner known per se, for example, by means of conventional mixing, dissolving, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The carrier includes various excipients and adjuvants. Suitable formulations may be prepared according to the chosen route of administration. Such as injection, oral administration, inhalation, suppository, patch, implant, etc. For transmucosal and transdermal administration, the use of penetrants appropriate to the permeation barrier in the formulation is generally known in the art.
Can be made into oral preparation in the form of tablet, pill, disintegrating agent, dragee, capsule, push-fit capsule, soft capsule, liquid, gel, syrup, slurry, suspension, etc.
Among the various formulations, long acting formulations are preferred, with topical application of long acting formulations being most preferred. The latter can be applied locally to the tumor by implantation (rectal, transmucosal, transdermal, enteral, intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections), with significantly reduced systemic toxicity while effectively achieving and maintaining local drug concentrations.
Administration is by topical means, e.g., by direct injection into a particular tissue, usually in the form of a depot or sustained release formulation.
The main form of the invention is sustained release preparation, including sustained release implant and sustained release injection.
The main form of the invention is a sustained-release injection, which consists of sustained-release microspheres and a 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 the combination of a P13K inhibitor, a pyrimidine analogue and/or a DNA repair enzyme inhibitor and an epothilone derivative;
the slow release auxiliary material is selected from one or the combination of the following materials:
a) polylactic acid (PLA);
b) copolymers of polyglycolic acid and glycolic acid (PLGA);
c) polifeprosan;
d) polifeprosan in combination with PLA or PLGA;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer sebacic acid) copolymers;
g) poly (sebacic fumarate) copolymers.
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 viscosity of the suspending agent is 100cp-3000cp (at 20 ℃ -30 ℃).
The anticancer active ingredients in the sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
the anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows:
(1) 1-40% of an epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705 in combination with 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, or hexadecylphosphocholine;
(2) 1-40% of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705, and 1-40% of O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, epothilone B, epothilone C, epothilone D, S-D, E, a combination of 2, 4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine; or
(3) 1-40% of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furaetherin D, BMS-310705, in combination with 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-ylpyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazinomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, Combinations of phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphocholine, hexakisdecyl (N-N-trimethyl) hexanolamine phosphate, octadecyl phosphocholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine; or
(4) 1-40% of 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.
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 25-60% polifeprosan with 25-60% PLA or 25-60% PLGA;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer 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.
In the combination, the total amount of all auxiliary materials does not exceed 98 percent of the weight of the preparation.
In addition to the above-mentioned adjuvants, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming and high-tech). 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. 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.
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 anticancer component in injection, the used auxiliary materials are 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.
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 (b).
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 be selected from the type and composition of suspending agent, the composition, properties and required amount of the medicine suspended in the solvent, sustained release microsphere (or microcapsule), and the preparation method of injection, such as dissolving sodium carboxymethylcellulose (1.5%) + mannitol and/or sorbitol (15%) and/or Tween-80 (0.1%) in physiological saline to obtain corresponding solvent with viscosity of 10ep-650cp (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). Such a viscosity is suitable for 18-22 gauge needles and for 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 pharmaceutical excipients can be any one or more of the above pharmaceutical excipients, but water-soluble high molecular polymers are taken as the main choice, and in various high molecular polymers, polylactic acid, sebacic acid, a mixture or copolymer of high molecular polymers containing polylactic acid or sebacic acid are taken as the first choice, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, a mixture of PLA and PLGA, and a mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride. 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.
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. The size of the volume depends on the location and size of the lesion. 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 and the weight percentage in the sustained-release implant can refer to the sustained-release injection thereof, but the sustained-release implant is preferably as follows:
(1) 1-40% of an epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705 in combination with 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, or hexadecylphosphocholine;
(2) 1-40% of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705, and 1-40% of O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, epothilone B, epothilone C, epothilone D, S-D, E, a combination of 2, 4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine; or
(3) 1-40% of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furaetherin D, BMS-310705, in combination with 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinol-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazinomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, Combinations of phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphocholine, hexakisdecyl (N-N-trimethyl) hexanolamine phosphate, octadecyl phosphocholine, octadecyl [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine; or
(4) 1-40% of 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.
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) a combination of 25-60% polifeprosan with 25-60% PLA or 25-60% PLGA;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer 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.
In the combination, the total amount of all auxiliary materials does not exceed 98 percent of the weight of the preparation.
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 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 clinically used dose of the anticancer agent may be from 0.1 to 3000mg/kg body weight, preferably 0.5 to 2000mg/kg, most preferably 0.8 to 1000mg/kg, depending on the patient.
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 technical process of the invention is further described by the following tests and examples:
test 1 comparison of local drug concentrations after different modes of epothilone application
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 1 cm in diameter. Each group was 2.5mg/kg epothilone B. The results of the determination of the content (%) of the medicament in the tumor at different times show that the concentration difference of the local medicament of the epothilone B after different modes of application is obvious, the local administration can obviously improve and effectively maintain the effective medicament concentration of the part where the tumor is located, wherein the slow release implant is placed in the tumor and the tumor is placed in the tumorThe effect of injecting the sustained-release injection is best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. This finding constitutes an important feature of the present invention. This is further confirmed by the following relevant tumor inhibition test.
Experiment 2 comparison of in vivo tumor suppression Effect after different modes of epothilone D application
Using white rat as test object, 2X 105Individual breast tumor cells were injected subcutaneously into the quaternary costal region and grouped after tumors grew to 0.5 cm diameter. Each group was dosed at 5mg/kg epothilone D. The volume of the tumor was measured on the 20 th day after treatment, and the therapeutic effect was compared. The results show that the difference of the tumor inhibition effect of the epothilone D after different modes of application is obvious, the effective drug concentration of the tumor part can be obviously improved and effectively maintained by local administration, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. Not only has good curative effect, but also has little toxic and side effect.
Experiment 3 in vivo tumor inhibition effect of epothilone and anticancer drug (sustained release injection)
Using white rat as test object, 2X 105Individual pancreatic tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 1). The first group was the control, and groups 2 to 10 were the treatment groups, all of which were intratumorally injected. The epothilone B is 2.5mg/kg, and the anticancer drug is 10 mg/kg. Tumor volume was measured on day 21 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 64±10
2(6) Epothilone B 46±5.0 ＜0.05
3(6) UCN-01 44±2.2 ＜0.01
4(6) UCN-02 32±2.4 ＜0.01
5(6) MIL 44±5.0 ＜0.01
6(6) D-21266 42±3.0 ＜0.01
7(6) Epothilone B + UCN-01 20±2.2 ＜0.001
8(6) Epothilone B + UCN-02 30±3.4 ＜0.001
9(6) Epothilone B + MIL 22±3.2 ＜0.001
10(6) Epothilone B + D-21266 18±2.0 ＜0.001
The results show that the epothilone B and the anti-cancer drug-phosphoinositide 3-kinase (PI3K) inhibitor (UCN-01: 7-hydroxyl-astrosporin; UCN-02: 7-O-alkyl-astrosporin; MIL: Miltefosine; D-21266: octadecyl- (1, 1-dimethyl-4-piperidine) phosphate or perifosine) have obvious inhibition effect on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.
Test 4 antitumor Effect of epothilone B and anticancer drugs (sustained Release injection)
The tumor cells include CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), etc. The medicine is injected intratumorally. Therapeutic efficacy (see table 2). The epothilone B is 7.5mg/kg, and the anticancer drugs are 2.5 mg/kg. The size of tumor volume was measured on day 20 after the treatment, and the treatment effect was compared using the tumor growth inhibition (%) as an index (see table 2).
TABLE 2
Tumor cell Epothilone D O4-BA UCN-01 UCN-02 Epothilone D + O4-BA Epothilone D + UCN-01 Epothilone D + UCN-02
CNS 34％ 52％ 62％ 62％ 86％ 84％ 80％
C6 34％ 64％ 60％ 64％ 74％ 80％ 90％
SA 28％ 60％ 50％ 62％ 86％ 82％ 82％
BC 38％ 62％ 54％ 66％ 74％ 82％ 82％
BA 28％ 60％ 62％ 60％ 92％ 90％ 82％
LH 42％ 56％ 62％ 58％ 80％ 86％ 80％
PAT 40％ 52％ 66％ 52％ 90％ 84％ 82％
The results show that the epothilone D and the anti-cancer drugs (O4-BA: O4-benzyluric acid; UCN-01: 7-hydroxyl-group astrosporin; UCN-02: 7-O-alkyl-astrosporin) have obvious inhibition effects on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effects when being jointly applied.
Test 5 antitumor Effect of Isoepothilone D and anticancer drugs (sustained Release injection)
Using white rat as test object, 2X 105Individual liver tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 3). The first group was the control, and groups 2 to 10 were the treatment groups, with the sustained release implant placed intratumorally. The content of isoepothilone D is 2.5mg/kg, and the content of anticancer drug is 15 mg/kg. The size of tumor volume was measured on day 20 after the treatment, and the treatment effect was compared using the tumor growth inhibition (%) as an index (see table 3).
TABLE 3
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 60±12
2(6) ilmofosine 48±5.0 ＜0.05
3(6) Isoepothilone D 40±2.2 ＜0.01
4(6) ilmofosine + isoepothilone D 30±2.6 ＜0.001
5(6) AMG-PC 46±3.2 ＜0.01
6(6) AMG-PC + Isoepothilone D 20±3.0 ＜0.001
7(6) edelfosine 30±2.6 ＜0.01
8(6) Edelfosine + isoepothilone D 18±2.4 ＜0.001
9(6) IDOU 32±3.4 ＜0.01
10(6) IDOU + Isoepothilone D 18±2.2 ＜0.001
The above results indicate that the epothilone (hyaluronidase) and the anti-cancer drug-PI 3K inhibitor (AMG-PC: 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine; edelfosine: 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine; ilmofosine: 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphorylcholine; IDOU: 5-iodo-2' -deoxyguanosine) used have significant inhibitory effects on the growth of various tumor cells when used alone at these concentrations, and exhibit significant synergistic effects when used in combination.
Test 6 antitumor Effect of epothilone D and anticancer drugs (sustained Release injection)
Using white rat as test object2 × 10 of5Individual prostate tumor cells were injected subcutaneously into the quaternary pleural region and were classified into negative control (blank), monotherapy (epothilone D or anti-cancer drug) and combination therapy (epothilone D and anti-cancer drug) after 14 days of tumor growth. Epothilone D (2mg/kg) was injected intratumorally and the anti-cancer drug (18mg/kg) was injected intraperitoneally. Measuring the volume of tumor on day 20 after treatment, and comparing the therapeutic effects using the tumor growth inhibition rate as an index (see Table 4)
TABLE 4
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Epothilone D 58 ＜0.05
3(6) Imidazopiperazines 26 ＜0.01
4(6) Imidazopyridines as inhibitors of HIV 38 ＜0.01
5(6) Wortmannin 32 ＜0.01
6(6) Benzopyrans 30 ＜0.01
7(6) Epothilone D + imidazopiperazines 82 ＜0.001
8(6) Epothilone D + imidazopyridines 86 ＜0.001
9(6) Epothilone D + wortmannin 86 ＜0.001
10(6) Epothilone D + benzopyran 84 ＜0.001
The results show that the epothilone D and the anti-cancer drug-DNA-dependent protein kinase inhibitor (wherein, the imidazopiperazine, the imidazopyridine, the wortmannin and the benzopyran) have obvious inhibition effects on the growth of various tumor cells when being used independently at the concentration, and can show obvious synergistic effects when being used together.
Test 7 antitumor Effect of epothilone B and anticancer drugs (sustained Release injection)
Using white rat as test object, 2X 105Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. Epothilone B (18mg/kg) was injected intraperitoneally and the anti-cancer drug (2mg/kg) was injected peritumorally. Tumor volume was measured on day 21 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 5).
TABLE 5
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Epothilone B 40 ＜0.05
3(6) LY294002 50 ＜0.01
4(6) SU11752 42 ＜0.01
5(6) SN-38 52 ＜0.01
6(6) OK-1035 46 ＜0.01
7(6) Epothilone B + LY294002 76 ＜0.001
8(6) Epothilone B + SU11752 76 ＜0.001
9(6) Epothilone B + SN-38 70 ＜0.001
10(6) Epothilone B + OK-1035 80 ＜0.001
The results show that the epothilone B and the anti-cancer drug-DNA-dependent protein kinase inhibitor (LY 294002: 2- (4-morpholino) -8-phenylchromone; SU 11752: kinase inhibitor; SN-38: 7-ethyl-10-hydroxycamptothecin; OK-1035: 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1) have obvious inhibition effect on the growth of various tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used in combination.
Test 8 antitumor Effect of epothilone C and anticancer drugs (sustained Release implants)
Using white rat as test object, 2X 105Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The slow release implant is placed in the tumor. Epothilone C (5mg/kg) was injected intraperitoneally and the anti-cancer drug (10mg/kg) was injected peritumorally. Tumor volume was measured on day 21 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 6).
TABLE 6
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Epothilone C 46 ＜0.05
3(6) Methoxyamine 30 ＜0.05
4(6) Minocycline 32 ＜0.05
5(6) Hydroxy amines 34 ＜0.05
6(6) O-methylhydroxylamine 36 ＜0.01
7(6) Epothilone C + methoxamine 80 ＜0.01
8(6) Epothilone C + minocycline 88 ＜0.01
9(6) Epothilone C + hydroxylamine 84 ＜0.01
10(6) Epothilone C + O-methylhydroxylamine 78 ＜0.001
The results show that the epothilone C and the anti-cancer drug-DNA-dependent protein kinase inhibitor have obvious inhibition effect on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.
Test 9 antitumor Effect of epothilone and anticancer drug (sustained Release implant)
The tumor-inhibiting effects of epothilones and anticancer drugs (sustained release implants) were determined as described in test 8, and the tumor growth inhibition rates are shown in Table 7.
TABLE 7
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Epothilones 46 ＜0.05
3(6) 3-AB 40 ＜0.01
4(6) Benzamide derivatives 36 ＜0.01
5(6) PD128763 30 ＜0.01
6(6) AG14361 26 ＜0.01
7(6) Epothilone +3-AB 70 ＜0.001
8(6) Epothilone + benzamide 78 ＜0.001
9(6) Epothilone + PD128763 74 ＜0.001
10(6) Epothilone + AG14361 82 ＜0.001
The results show that the epothilone and the anti-cancer drug poly (ADP-ribose) polymerase inhibitor (wherein, 3-AB: 3-aminobenzamide; benzamide; PD 128763: 3, 4-dihydromethoxyisoquinoline-1 (2H) -benzamide; AG 14361: polymerase inhibitor) have obvious inhibition effect on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.
Experiment 10, antitumor Effect of epothilone E and anticancer drug (sustained Release injection)
The tumor-inhibiting effects of epothilones and anticancer drugs (sustained release implants) were determined as described in test 8, and the tumor growth inhibition rates are shown in Table 8.
TABLE 8
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Epothilone E 48 ＜0.05
3(6) BZ1-6 50 ＜0.01
4(6) TI1-5 30 ＜0.01
5(6) TBC 36 ＜0.01
6(6) Benzimidazole compounds 42 ＜0.01
7(6) Epothilone E + BZ1-6 86 ＜0.001
8(6) Epothilone E + TI1-5 82 ＜0.001
9(6) Epothilone E + TBC 78 ＜0.001
10(6) Epothilone E + benzimidazole 78 ＜0.001
The results show that the epothilone E and the anti-cancer drug poly (ADP-ribose) polymerase inhibitor (wherein BZ 1-6: benzimidazole-4-carboxamide; TI 1-5: tricyclic lactam hydrogen sulfide; TBC: tricyclic benzimidazole carboxamide, benzimidazole) have obvious inhibition effects on the growth of various tumor cells when being used alone at the concentration, and can show obvious synergistic effects when being used in combination.
Test 11 antitumor Effect of Azaegylomycin B and/or anticancer drug (sustained Release implant)
The tumor-inhibiting effect of epothilones and/or anticancer drugs (sustained release implants) was determined as described in test 8, and the tumor growth inhibition rate is shown in Table 9.
TABLE 9
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Azaetheriomycin B 36 ＜0.05
3(6) NU1025 36 ＜0.01
4(6) PBC 40 ＜0.01
5(6) MPBC 48 ＜0.01
6(6) NU1085 48 ＜0.01
7(6) Azaethylomycin B + NU1025 86 ＜0.001
8(6) Azaethylomycin B + PBC 76 ＜0.001
9(6) Azaetheromycin B + MPBC 88 ＜0.001
10(6) Azaetheromycin B + NU1085 78 ＜0.001
The above results indicate that the azaepothilone B and the anti-cancer drug poly (ADP-ribose) polymerase inhibitor (PBC: 2-phenyl-1H-benzimidazole-4-carboxamide; MPBC: 2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamide (2- (3-methoxyphenyl) -1H-benzamidine-4-carboxamide); NU 1025: 8-hydroxy-2-methylquinazolinone; NU 1085: 2- (4-hydroxyphenyl) benzimidazole-4-carboxamide) used have significant inhibitory effects on the growth of various tumor cells when used alone at these concentrations and show significant synergistic effects when used in combination.
Test 12 antitumor Effect of Ixabepilone and/or anticancer drugs (sustained Release implants)
Ixabepi lone and/or anti-cancer drugs (sustained release implants) were tested for their tumor-inhibiting effects as described in test 6, and the tumor growth inhibition rates are shown in Table 10.
Watch 10
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Ixabepilone 48 ＜0.05
3(6) BSO 46 ＜0.01
4(6) Amino triazoles 36 ＜0.01
5(6) Lasiosphaeric acid 42 ＜0.01
6(6) Podophyllotoxin 30 ＜0.01
7(6) Ixabepilone+BSO 78 ＜0.001
8(6) Ixabepilone + aminotriazole 88 ＜0.001
9(6) Ixabepilone + puffball acid 82 ＜0.001
10(6) Ixabepilone + neopodophyllotoxin 86 ＜0.001
The results show that the used Ixabepilone and the anti-cancer drug poly (ADP-ribose) polymerase inhibitor (wherein BSO is butylthionine sulfoximine) have obvious inhibition effect on the growth of various tumor cells when being used alone at the concentration, and can show obvious synergistic effect when being used in combination.
Experiment 13, comparison of in vivo Release of Furan epothilone D sustained Release implants made with polylactic acid of different molecular weights
Rats were used as test subjects, and divided into groups (3/group) and subcutaneously administered equivalent amounts of furan 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 (12%), 3 (26%), 7 (56%), 14 (80%), 21 (86%), 28 (92%) and 35 (94%). Comparing in vivo release of sustained-release implants made of polylactic acids of different molecular weights, it was found that the release was slowed down with increasing molecular weight, and as an example at day 7, the tumor suppression rate was increased with increasing molecular weight of polylactic acids, in the order of 68% (MW: 5000), 62% (MW: 15000), 54% (MW: 25000), 52% (MW: 40000) and 46 (MW: 60000), as compared with the systemic administration group.
The same result is also seen in the slow release preparation containing BMS-310705 and anticancer medicine, which is prepared with polylactic acid as supplementary material.
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 epothilone derivative and various anti-cancer drugs have obvious inhibition effect on the growth of various tumor cells when being applied independently, and can show obvious synergistic effect when being applied in combination. Therefore, the active ingredient of the invention is the combination of the epothilone derivative and any one (or more than one) anti-cancer drug. The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein suspension injection formed by combining with special solvent containing suspending agent is preferred.
The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.
(IV) detailed description of the preferred embodiments
Example 1.
80mg of a polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after uniform dissolution, 10mg of epothilone B and 10mg of 7-hydroxide radical-astrosporin are added, after re-shaking, spray drying is carried out to prepare microspheres for injection containing 10% of epothilone B and 10% of 7-hydroxide radical-astrosporin. Then suspending the microspheres in physiological saline containing 15 percent of mannitol to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 200-400 cp (at 20-30 ℃), the medicine release time of the sustained-release injection in vitro physiological saline is 18-25 days, and the medicine release time under the skin of a mouse is about 20-30 days.
Example 2.
The steps of the method for processing the sustained-release injection are the same as the example 1, but the difference is that the polifeprosan is 50: 50, and the anticancer active ingredients and the weight percentage thereof are as follows: a combination of 5% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D or BMS-310705 with 15% 7-hydroxide-oxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine,
the viscosity of the injection is 200-400 cp (at 20-30 deg C).
Example 3.
70mg of polylactic acid (PLA) with the molecular weight peak value of 10000-20000 is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 20mg of epothilone D and 10mg of 7-ethyl-10-hydroxycamptothecin are added, the mixture is shaken again evenly and then is dried in vacuum to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 20% epothilone D and 10% 7-ethyl-10-hydroxycamptothecin, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained release injection. The viscosity of the injection is 240cp-420ep (at 20-30 ℃), the medicine release time of the sustained-release injection in vitro physiological saline is 20-35 days, and the medicine release time under the skin of a mouse is about 35-50 days.
Example 4
The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is polylactic acid (PLA) with the molecular weight peak of 40000-60000, which contains the effective anticancer components in percentage by weight:
15% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, Isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furaetheromycin D or BMS-310705 with 20% imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazinomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, salt, Tetradecyl phosphocholine, hexakisdecyl (N-N-trimethyl) hexanolamine phosphate, octadecyl phosphocholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine.
Example 5.
70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 10000-20000 is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 20mg of isoepothilone D and 10mg of benzimidazole are added, the mixture is shaken up again and then spray drying is carried out to prepare the microsphere for injection containing 20% of isoepothilone D and 10% of benzimidazole. Then suspending the microspheres in injection containing 5-15% of sorbitol to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 260-480 cp (at 20-30 ℃), the medicine release time of the sustained-release injection in vitro physiological saline is 10-15 days, and the medicine release time under the skin of a mouse is about 20-30 days.
Example 6.
The procedure of the process for preparing the sustained-release injection is the same as that of example 5, except that the anticancer active ingredients are: a combination of 10% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone, azaepothilone B, furan epothilone D, or BMS-310705 with 10% O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or 2-amino-O4-benzylpteridine.
Example 7.
70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak of 20000-40000 is put into a container, 100 ml of dichloromethane is added, 20mg of BMS-247550 and 10mg of butylthionine sulfoximine are added after being dissolved and mixed evenly, and the microspheres for injection containing 20% of BMS-247550 and 10% of butylthionine sulfoximine are prepared by a spray drying method after being shaken again evenly. 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. The viscosity of the injection is 300-480 cp (at 20-30 ℃), the medicine release time of the sustained-release injection in vitro physiological saline is 18-25 days, and the medicine release time under the skin of a mouse is about 25-35 days.
Example 8.
The procedure of the method for preparing the sustained-release injection is the same as that of example 7, except that the polylactic acid (PLGA, 75: 25) with the molecular weight peak of 40000-60000 is different from the contained anticancer active ingredient: 10% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone, azaepothilone B, furan epothilone D, or BMS-310705 in combination with 15% O4-benzylfolate.
Example 9
40mg of a polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 50: 50) copolymer and 30mg of polylactic acid (PLA) with the molecular weight peak value of 10000-20000 are placed in a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 20mg of azaepothilone B and 10mg of O4-benzyl folic acid are added, after shaking uniformly again, the microspheres for injection containing 20% of azaepothilone B and 10% of O4-benzyl folic acid are prepared by a spray drying method. 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. The slow release injection has the release time in vitro physiological saline of 24-35 days and the release time under the skin of a mouse of about 28-40 days.
Example 10
The process steps for preparing the sustained release injection are the same as the example 9, but the difference is that the sustained release excipients are 40mg of polifeprosan (50: 50) copolymer and 30mg of PLGA (50: 50) with the molecular weight peak of 20000-40000, and the anticancer active ingredients are: 10-30% of epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone, azaepothilone B, furan epothilone D or BMS-310705 in combination with 10-40% O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or 2-amino-O4-benzylpteridine.
Example 11
70mg of a polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 30: 70) copolymer is put into a container, 100 ml of dichloromethane is added, after uniform dissolution, 10mg of 7-hydroxide radical-astrosporin and 20mg of furan epothilone D are added, after re-shaking, spray drying is carried out to prepare microspheres for injection containing 10% of 7-hydroxide radical-astrosporin and 20% of furan epothilone D. 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 21-25 days in-vitro physiological saline and the drug release time of about 30-40 days under the skin of a mouse.
Example 12
The procedure of processing into a sustained-release implant was the same as in example 11, except that the anticancer active ingredient contained therein was: 20% BMS-310705 in combination with 10% 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine.
Example 13
70mg of PLGA (50: 50) with a molecular weight peak of 60000-80000 was placed in a container, 100 ml of dichloromethane was added, after dissolving and mixing uniformly, 10mg of BMS-310705 and 20mg of neopodophyllotoxin were added, and after shaking uniformly again, microspheres for injection containing 10% BMS-310705 and 20% neopodophyllotoxin were prepared by spray drying. 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 25-30 days and the release time under the skin of a mouse of about 35-50 days.
Example 14
The procedure of processing into sustained release implant was the same as in examples 11 and 13, except that PLGA (70: 25) having a molecular weight peak of 40000 contained anticancer active ingredients:
10% BMS-310705 in combination with 20% aminotriazole, butylthioneoxime, lasiobic acid, S-hexyl glutathione, neopodophyllotoxin, hexacyclic camptothecin or tetraarylbenzamide.
Example 15
The procedure of processing into sustained release preparation is the same as that of examples 1-14, except that the sustained release excipient is one or a combination of the following:
a) polylactic acid (PLA) with the molecular weight peak value of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000;
b) a copolymer (PLGA) of polyglycolic acid and glycolic acid with a peak molecular weight of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of the polyglycolic acid to the glycolic acid is 50-95: 50-50;
c) ethylene vinyl acetate copolymer (EVAc);
d) p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) copolymer (polifeprosan) 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer sebacic acid) copolymers;
g) poly (sebacic fumarate) copolymers;
h) xylitol, oligosaccharide, chondroitin, chitin, chitosan, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin, poloxamer 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 16
The procedure for preparing a sustained release injection is the same as in examples 1 to 15, 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.
Example 17
The procedure of processing into sustained release injection is the same as in examples 11-15, except that the anticancer active ingredient is:
(1) a combination of 5-30% epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone, azaepothilone B, furaetheromycin D, or BMS-310705 with 5-30% 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, or hexadecylphosphocholine;
(2) a combination of 5-30% epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone, azaepothilone B, furaetheromycin D, or BMS-310705 with 5-30% O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or 2-amino-O4-benzylpteridine; or
(3) 5-30% of epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone, azaepothilone B, furaetheromycin D or BMS-310705, with 5-30% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, polyphosphate, tetradecyl phosphocholine, Combinations of hexakis (N-N-trimethyl) hexanolamine phosphate, octadecyl choline phosphate, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthioiolituroin.
The present invention is not to be limited in scope by the illustrated embodiments, which are intended as individual illustrations 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 above examples are intended to illustrate, but not limit, the application of the invention. The invention is disclosed and claimed.

Claims (10)

1. An anticancer sustained release agent containing epothilone, which is characterized in that the anticancer sustained release agent is a sustained release injection and comprises 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 derivatives or epothilone derivatives and anticancer drugs selected from phosphoinositide 3-kinase inhibitors, pyrimidine analogues and/or DNA repair enzyme inhibitors;
the suspending agent is selected from one or more of sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surface active substance, Tween 20, Tween 40 and Tween 80;
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 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, poloxamer or protein 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 has viscosity of 100-3000 cp (at 20-30 deg C), and is selected from one or more of sodium carboxymethylcellulose, hydroxymethyl cellulose, iodoglycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40, and Tween-80.
2. The sustained-release anticancer injection according to claim 1, wherein the phosphoinositide 3-kinase inhibitor is selected from the group consisting of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine, and, Inositol polyphosphate, cyclosporine A, tetradecyl phosphorylcholine, hexadecyl (N-N-N-trimethyl) hexanolamine phosphate, octadecyl phosphorylcholine, octadecyl- [2- (N methyl piperidine) ethyl ] -phosphate or a combination thereof.
3. The sustained-release injection for anticancer according to claim 1, wherein the pyrimidine analog is selected from one of O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, 2-amino-O4-benzylpteridine or a combination thereof.
4. The sustained-release anticancer injection according to claim 1, wherein the DNA repair enzyme inhibitor is selected from the group consisting of 2- (morphinan-4-yl) -chromen-4-yl, 2- (4-morpholino) -8-phenylchromone, 1- (2-hydroxy-4-morphinan-4-ylphenyl) -ethanone, kinase inhibitor, 2-aminopurine, 7-ethyl-10-hydroxycamptothecin, phenylbutyrate, methylamine, methoxyamine, hydroxylamine, minocycline, O-hydroxylamine, O-methylhydroxylamine, O-delta-aminooxybutylhydroxylamine, 3-aminobenzamide, benzamide, 3, 4-dihydromethoxyisoquinoline-1 (2H) -benzamide, 2H-aminobutyrylcamphane, and N-acetylsalicylic acid, Polymerase inhibitors, amino-substituted 2-arylbenzimidazole-4-carboxamides, benzimidazole-4-carboxamides, tricycloalkylamide hydrogen sulfide, tricyclo-benzimidazole carboxamides, benzimidazole, 1H-tricyclo-benzimidazole carboxamides, 2-aryl-1H-benzimidazole-4-carboxamides, 2-phenyl-1H-benzimidazole-4-carboxamides, 2- (4-hydroxymethylphenyl) -1H-benzimidazole-4-carboxamides, 2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamides, 8-hydroxy-2-methylquinazolinone, 2- (4-hydroxyphenyl) benzimidazole-4-carboxamides, substituted benzimidazole-amide derivatives, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof, Aminotriazoles, butylthioneoxime, puffball acid, S-hexyl glutathione, neopodophyllomycin, hexacyclic camptothecin or tetrarylcarboxamides.
5. The sustained-release anticancer injection according to claim 1, wherein the epothilone is selected from the group consisting of epothilone, 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-Tru ,9, 10-dehydroepothilone B, 10, 11-hydrogen epothilone B, 26, 27-halogenoepothilone B, 9, 10, 11, 14, 21, 26-hydroxy-substituted epothilone B, 21, 26, 21-dihydroxy epothilone B, 21-hydroxy-10, 11-dehydroepothilone B, 4-demethyl-9-one-epothilone B, and combinations thereof, 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-epothilone B, 21-and 26-deoxyamino-substituted epothilone D, 9-and 10-dehydroepothilone D, 10, 11-dehydroepothilone D, 26, respectively or simultaneously, epothilone D with halogen substituted at position 27, epothilone D with hydroxy substituted at positions 9, 10, 11, 14, 21, 26, 21-dihydroxy epothilone D, 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-hydroxyepothilone D, 21-aminoepothilone D, 26-hydroxyepothilone D, 26-aminoepothilone D, 26-fluoroepothilone D, isoepothilone D, 9, 10-dehydroepothilone D, 21-aminoepothilone D, and, 10, 11 dehydro epothilone D, furan epothilone D, (E) -9, 10-dehydro-12, 13-desoxy epothilone D, BMS-310705, 6-ethyl, 16-fluoro, 17-pyridine epothilone, 11, 12-dehydro-12, 13-dehydro-13-desoxy epothilone D, 9-oxy epothilone D or 8-epi-9-oxy epothilone D, or a combination thereof.
6. The sustained-release anticancer injection according to claim 1, wherein the sustained-release anticancer injection comprises the following active anticancer components in percentage by weight:
(1) 1-40% of an epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705 in combination with 1-40% of a 7-hydroxide radical star sporidin, 7-O-alkyl star sporidin, beta-methoxystar sporidin, alkyl phosphocholine or hexadecyl phosphocholine;
(2) 1-40% of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705, and 1-40% of O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, epothilone B, epothilone C, epothilone D, S-D, E, a combination of 2, 4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine; or
(3) 1-40% of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furaetheromycin D, BMS-310705, in combination with 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-ylpyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazinomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, A combination of methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphocholine, hexakisdecyl (N-N-N-trimethyl) hexanolamine phosphate, octadecyl phosphocholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine;
(4) 1-40% of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, BMS-247550, azaepothilone B, furaetheromycin D or BMS-310705
7. The sustained-release anticancer injection according to claim 1, wherein the sustained-release excipients are selected,
(1) the molecular weight peak value of the polylactic acid is selected from 5000-10000, 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
(2) 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 5000-10000, 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
(3) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.
8. 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) iodoglycerol, 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; or
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.
9. The sustained-release anticancer injection according to claim 1, wherein the anticancer active ingredient is used for preparing sustained-release implant for treating primary or secondary cancer, sarcoma or carcinosarcoma originating from brain, central nervous system, kidney, liver, gallbladder, head and neck, oral cavity, thyroid gland, skin, mucosa, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon or rectum of human and animal.
10. The sustained-release anticancer agent according to claim 9, wherein the weight ratio of the epothilone derivative to the anticancer drug in the anticancer active ingredient of the sustained-release anticancer implant is 1-9: 1 to 1: 1-9.
The slow release auxiliary material is one or the combination of the following materials:
a) polylactic acid with the molecular weight peak value of 10000-;
b) a copolymer of polyglycolic acid and glycolic acid, wherein 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) ethylene vinyl acetate copolymers;
d) polifeprosan, p-carboxyphenylpropane and sebacic acid at a ratio of 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer-sebacic acid);
g) poly (fumaric-sebacic acid);
h) xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer 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.
CNA2006102012704A 2006-12-12 2006-12-12 Anticancer sustained release agent containing epothilone Pending CN1969816A (en)

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