CN1969818A - Anticancer sustained release injection containing epothilone derivatives - Google Patents

Anticancer sustained release injection containing epothilone derivatives Download PDF

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CN1969818A
CN1969818A CNA2006102012738A CN200610201273A CN1969818A CN 1969818 A CN1969818 A CN 1969818A CN A2006102012738 A CNA2006102012738 A CN A2006102012738A CN 200610201273 A CN200610201273 A CN 200610201273A CN 1969818 A CN1969818 A CN 1969818A
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epothilone
release
sustained
acid
copolymer
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孙娟
刘玉燕
孔庆新
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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 slow release injection containing Epothilone derivatives which comprises slow release microspheres and dissolvent, the slow release micro-balloons include anticancer drugs selected from Paclitaxel, alkyl agent and/or plant alkaloids, Epothilone derivatives and slow release auxiliary materials, the dissolvent being specific dissolvent containing suspension adjuvant. The Epothilone derivatives are selected from Epothilone B, Epothilone D, Isoepothilone D, BMS-247550, azaepothilone B, furaepothilone D or BMS-310705. The slow release auxiliary material is selected from poly-D, L-lactic acid and its glycolic copolymer, polyethylene glycol and polylactic acid copolymer, PLA-COOH copolymer, aliphatic acid and sebacylic acid copolymer, the viscosity of the suspension adjuvant is 100-3000cp (at 25-30 deg C), and is selected from sodium carboxymethylcellulose, The slow release microspheres can also be prepared into slow release implanting agent, for injection or placement in or around tumor with the period of local drug release can be about 40-50 days, as a result, the local medicinal concentration can be increased selectively, and the treatment effect of the non-operative treatment methods such as chemotherapy can be improved substancially.

Description

Anticancer sustained-release injection containing epothilone derivative
(I) technical field
The invention relates to a sustained-release injection containing epothilone derivatives, belonging to the technical field of medicaments. Specifically, the invention provides a sustained-release injection and a sustained-release implant containing epothilone derivatives.
(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 application Nos. 6,376,52581; 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 above unexpected findings constitute the subject of the present invention.
The anti-solid tumor sustained release agent comprises an anti-cancer active ingredient and a pharmaceutic adjuvant, wherein the anti-cancer active ingredient is selected from taxane, an alkylating agent and/or plant alkaloid and epothilone derivatives.
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 an epothilone derivative and an anticancer drug
The slow released epothilone derivative 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 derivatives and anticancer drugs, and the anticancer drugs are selected from taxane, alkylating agent and/or plant alkaloid; 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.
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 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, 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%.
The taxane (Taxanes) anticancer drugs in the anticancer active ingredient are mainly selected from paclitaxel (Taxol), Docetaxel (Docetaxel, taxotere, Docetaxel), 2 '-hydroxypaclitaxel-2' hydroxy, 10-deacetyl paclitaxel (10-deacetyltaxol) and 7-epi-paclitaxel (7-epi-Taxol). Paclitaxel and docetaxel are preferred.
The alkylating agent comprises one or the combination of estramustine, amostine, AMOMOTSINE, carmustine, nimustine, dithiomostine, brivustine, bendamustine, galamustine, ranimustine, fotemustine, emedastine, etomomustine, estramustine, lomustine, nemustine, mannomustine, lomustine, methyllomustine, splatemustine, uramustine, taulomustine, tamustine, spiromustine, streptozocin, samustine, semustine, methyllomustine, streptozocin, and mitozolamide. The above alkylating agents also include their salts such as, but not limited to, sulfates, phosphates, hydrochlorides, lactobionates, acetates, aspartates, nitrates, citrates, purines or pyrimidines, succinates and maleates and the like.
The weight percentage of the alkylating agent in the sustained-release agent is 0.01-99.99%, preferably 1-50%, and most preferably 5-30%
The plant alkaloid is selected from vincristine, vinblastine, vinorelbine, vindesine, vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
The proportion of the plant alkaloid in the composition is determined by specific conditions, and generally, the weight percentage can be from 0.01% to 99.99%, preferably from 1% to 50%, and most preferably from 5% to 30%.
When the anticancer drug in the drug sustained-release microspheres is only an epothilone derivative or an anticancer drug, the anticancer sustained-release injection is mainly used for increasing the effect of the epothilone derivative or the anticancer drug applied in other ways or for enhancing the effect of radiotherapy or other therapies. When the anticancer drug in the drug sustained-release microspheres is only an epothilone derivative 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 the epothilone derivative is locally injected, and the anti-cancer drug is applied by other ways;
(2) local injection of slow release injection containing anticancer medicine and other application of epothilone derivative;
(3) locally injecting a slow release injection containing epothilone derivatives and a slow release injection containing anticancer drugs; or
(4) Local injection is slow released injection containing epothilone derivative and anticancer medicine.
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 derivative and/or the anticancer drug in the drug sustained release microsphere is 0.5-60%, preferably 2-40%, and most preferably 5-30%. The weight ratio of epothilone derivative to anticancer agent is 1-20: 1 and 1: 1-20, preferably 1-9: 1 to 1: 1-9, preferably 1-2: 1 to 1: 1-2.
The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
(a) 2-40% 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, or BMS-310705 in combination with 2-40% of paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetylpaclitaxel, or 7-epi-paclitaxel;
(b) 2-40% of epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isoepothilone D, epothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D or BMS-310705, with 2-40% of estramustine, amoxastine, ammustine, carmustine, nimustine, dithiomustine, pofuramustine, bendamustine, galamustine, ranimustine, combinations of fotemustine, emedastine, etotemustine, estramustine, co-temustine, nemustine, mannomustine, lomustine, methyllomustine, splatemustine, uramustine, tautemustine, tamustine, spiromustine, streptozocin, samustine, semustine, methyllomustine, streptozocin, or midazolamine; or
(c) 2-40% 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 or BMS-310705 in combination with 2-40% of vincristine, vinblastine, vinorelbine, vindesine, vinmegallate, vincristine, vinorelbine, vinleucinol, vinglycinate, vinfosiltine, vincimid, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
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 35-60% polifeprosan with 35-60% PLA or 35-60% PLGA;
(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)), di-fatty 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, the viscosity is 10-650 cp (at 20-30 ℃).
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-. 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) ], 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.
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) a combination of 2-40% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705 with 2-40% paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetylpaclitaxel or 7-epi-paclitaxel;
(b) 2-40% 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% carmustine, nimustine, bendamustine, fotemustine, estramustine, lomustine, spiromustine, streptozocin, samustine, semustine or midazolamine; or
(c) 2-40% 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 or BMS-310705 in combination with 2-40% of vincristine, vinblastine, vinorelbine or vindesine.
The slow release auxiliary material can be various water-soluble or water-insoluble high molecular polymers. 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 35-60% polifeprosan with 35-60% PLA or 35-60% PLGA;
(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 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 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 application of epothilone derivatives
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 dosed at 2.5mg/kg of epothilone derivative. The results of the determination of the content (%) of the medicament in the tumor at different times show that the local medicament concentration difference of the epothilone derivative 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, 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. 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 antitumor Effect of epothilone derivatives applied in different ways
Using white rat as test object, 2X 105Individual pancreatic 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 of epothilone derivative. The volume of the tumor was measured on the 10 th day after the treatment, and the treatment effect was compared. The results show that the epothilone derivatives have obvious difference in tumor inhibition effect after being applied in different modes, the local administration can obviously improve and effectively maintain the effective drug concentration of the tumor part, 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.
Test 3 in vivo antitumor Effect of epothilone derivatives and anticancer drugs (sustained Release injection)
Using white rat as test object, 2X 105Individual breast 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, and the drug was injected intratumorally. Epothilone B was 1.5mg/kg, and the anti-cancer drug was 7.5 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 60±10
2(6) Epothilone B 38±5.2 ＜0.05
3(6) Paclitaxel 30±6.0 ＜0.01
4(6) Docetaxel 30±4.0 ＜0.01
5(6) Hydroxy paclitaxel 34±6.0 ＜0.01
6(6) 7 epi-taxol 36±8.0 ＜0.01
7(6) Paclitaxel + epothilone B 18±4.2 ＜0.001
8(6) Docetaxel + epothilone B 20±4.4 ＜0.001
9(6) Hydroxypaclitaxel + epothilone B 16±3.0 ＜0.001
10(6) 7 epitaxol + epothilone B 16±2.6 ＜0.001
The results show that the epothilone B and the synergist-taxane anticancer drugs (paclitaxel, docetaxel, 2' -hydroxypaclitaxel and 7-epi-paclitaxel) thereof have obvious inhibition effect on the growth of various tumor cells when being applied independently at the concentration, and can show obvious synergistic effect when being applied jointly. This finding constitutes a further important feature of the present invention.
Test 4 antitumor Effect of epothilone derivatives and anticancer drugs (sustained Release injections)
The tumor cells include brain tumor (CNS-1, C6), gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), thyroid Papillary Adenocarcinoma (PAT), etc. The content of epothilone D is 1.5mg/kg, and the content of anticancer drugs is 7.5 mg/kg. The tumor volume was measured on day 21 after the treatment, and the tumor cell growth inhibition (%) thereof was shown in Table 2.
TABLE 2
Tumor cell Carmustine Nimustine Fotemustine Epothilone D Carmustine + epothilone D Nimustine + epothilone D Fotemustine + epothilone D
CNS 42％ 48％ 42％ 46％ 72％ 76％ 88％
C6 60％ 52％ 40％ 24％ 64％ 76％ 78％
SA 48％ 60％ 26％ 22％ 68％ 82％ 60％
BC 52％ 48％ 34％ 64％ 64％ 86％ 80％
BA 54％ 52％ 52％ 22％ 68％ 72％ 78％
LH 52％ 50％ 22％ 18％ 60％ 82％ 82％
PAT 42％ 50％ 40％ 58％ 72％ 84％ 80％
The results show that the anticancer drugs (carmustine, nimustine, fotemustine) and epothilone D have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied. The same effect can be seen in other tumors, such as esophageal cancer, ovarian cancer, pancreatic cancer, liver cancer, intestinal cancer, etc.
Test 5 antitumor Effect of epothilone derivatives and anticancer drugs (sustained Release injections)
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into the quaternary rib area and 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 epothilone derivative is 7.5mg/kg, and the anticancer drugs are 2.5 mg/kg. Tumor volume was measured on day 20 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 60±10
2(6) Epothilone derivatives 53±4.0 ＜0.05
3(6) Nimustine 40±4.0 ＜0.01
4(6) Epothilone derivatives + nimustine 18±6.2 ＜0.001
5(6) Carmustine 38±3.2 ＜0.01
6(6) Epothilone derivatives + carmustine 18±1.8 ＜0.001
7(6) Fotemustine 38±2.8 ＜0.01
8(6) Epothilone derivatives + fotemustine 22±2.6 ＜0.001
9(6) Satemustine 36±4.0 ＜0.01
10(6) Epothilone derivatives + samustine 14±2.2 ＜0.001
The results show that the epothilone derivative (isoepothilone D) and the anti-cancer drug-alkylating agent (nimustine, carmustine, fotemustine, samustine) 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. This finding constitutes a further important feature of the present invention.
Test 6 antitumor Effect of epothilone derivatives and anticancer drugs (sustained Release injections)
Using white rat as test object, 2X 105Individual pancreatic tumor cells were injected subcutaneously into the costal region of the patient and were classified into a negative control (blank), a monotherapy group (epothilone derivative or anticancer drug) and a combination therapy group (epothilone derivative and anticancer drug) 14 days after the tumor had grown. The medicine is injected intratumorally. The epothilone derivative is 2.5mg/kg, and the anticancer drugs are 5 mg/kg. Tumor volume was measured on day 20 after treatment and the effect of treatment was compared (see table 4). Measuring tumor volume on day 20 after treatment, and comparing with tumor growth inhibition rate as indexTherapeutic efficacy (see table 4).
TABLE 4
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Epothilone derivatives 48 ＜0.05
3(6) Semustine 46 ＜0.01
4(6) Lomustine 42 ＜0.01
5(6) Estramustine 50 ＜0.01
6(6) Chain zotard 42 ＜0.01
7(6) Epothilone derivatives + semustine 76 ＜0.001
8(6) Epothilone derivatives + lomustine 74 ＜0.001
9(6) Epothilone derivatives + estramustine 82 ＜0.001
10(6) Epothilone derivatives + streptozocin 86 ＜0.001
The results show that the epothilone derivative (BMS-247550) and the anti-cancer drug-alkylating agent (semustine, lomustine, estramustine and streptozocin) have obvious inhibition effects on the growth of various tumor cells when being applied independently at the concentration, and can show obvious synergistic effects when being applied jointly.
Test 7 antitumor Effect of epothilone derivatives and anticancer drugs (sustained Release injections)
Using white rat as test object, 2X 105Injecting the breast tumor cells into the quaternary costal region of the patient under the skin to allow the tumor to growAfter 14 days, the treatment was divided into a negative control (blank), a single-drug treatment group and a combination treatment group. The medicine is injected intratumorally. The dosage is 5 mg/kg. Tumor volume was measured on day 20 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 derivatives 30 ＜0.05
3(6) Gatemustine 54 ＜0.01
4(6) Ramomustine 46 ＜0.01
5(6) Fotemustine 32 ＜0.01
6(6) Tamustine (Tamustine) 44 ＜0.01
7(6) Epothilone derivatives plus galamustine 74 ＜0.001
8(6) Epothilone derivatives + ramustine 82 ＜0.001
9(6) Epothilone derivatives + fotemustine 84 ＜0.001
10(6) Epothilone derivatives + tamoxifen 76 ＜0.001
The results show that the epothilone derivative (azaepothilone B) and the anti-cancer drug-alkylating agent (galemustine, ranimustine, fotemustine and tamustine) have obvious inhibition effect on the growth of various tumor cells when being applied independently at the concentration, and can show obvious synergistic effect when being applied jointly. This finding constitutes a further important feature of the present invention.
Test 8 antitumor Effect of epothilone derivatives and anticancer drugs (sustained Release injections)
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 sustained release implant is placed intratumorally. The epothilone derivative is 2.5mg/kg, and the anticancer drugs are 5 mg/kg. Tumor volume was measured on day 20 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 derivatives 36 ＜0.05
3(6) Vincristine 58 ＜0.01
4(6) Catharanthine 52 ＜0.01
5(6) Vinorelbine 68 ＜0.01
6(6) Vindesine 46 ＜0.01
7(6) Epothilone derivatives + vincristine 82 ＜0.001
8(6) Epothilone derivatives + vinblastine 84 ＜0.001
9(6) Epothilone derivatives + vinorelbine 82 ＜0.001
10(6) Epothilone derivatives + vindesine 86 ＜0.001
The results show that the epothilone derivative (furan epothilone D) and the anti-cancer drug-plant alkaloid (vincristine, vinblastine, vinorelbine and vindesine) have obvious inhibition effect on the growth of various tumor cells when being applied independently at the concentration, and can show obvious synergistic effect when being applied jointly. This finding constitutes a further important feature of the present invention.
Test 9 antitumor Effect of epothilone derivatives and anticancer drugs (sustained Release injections)
The antitumor effects of epothilone derivatives and anticancer drugs (sustained release injections) were determined as described in test 7, and the results showed that BMS 310705 significantly enhanced the antitumor effects of alkylating agents such as carmustine, nimustine, bendamustine, galamustine, ranimustine, fotemustine, lomustine, tamustine, spiromustine, streptozocin, samustine, semustine, methyllomustine, streptozocin, or midazolamine on breast and prostate cancers at 38-70% (P < 0.01).
Test 10 antitumor Effect of epothilone derivatives and anticancer drugs (sustained Release injections)
The tumor inhibiting effect of BMS-310705 and anticancer drugs (sustained release injection) was determined by the method described in test 7, and the results showed that the tumor inhibiting effect of taxane anticancer drugs such as paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetyl paclitaxel or 7-epi-paclitaxel on lung cancer and pancreatic cancer could be significantly enhanced, with a synergistic effect of 40-80% (P < 0.01).
Experiment 11. antitumor Effect of anticancer drug (sustained Release injection)
The antitumor effects of epothilone derivatives (BMS-310705) and anticancer drugs (sustained release injections) were determined as described in test 7, and the results showed that epothilone derivatives significantly enhanced the antitumor effects of vincristine, vinblastine, vinorelbine, vindesine on gastric and colon cancers with a synergistic effect of 60-80% (P < 0.01).
Experiment 12 comparison of in vivo Release of epothilone derivative sustained Release implants made with polylactic acid of different molecular weights
Rats were used as subjects, and divided into groups (3/group) and subcutaneously administered equivalent amounts of epothilone B 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 B 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 66% (MW: 5000), 62% (MW: 15000), 54% (MW: 25000), 50% (MW: 40000) and 46 (MW: 60000).
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 differ from different biodegradable polymers in their essential characteristics. Further research shows that the slow release auxiliary materials most suitable for the slow release of the drug of the invention 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 sustained release preparation prepared by the sustained release auxiliary materials has no obvious phenomenon of sudden drug release; 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 ingredients of the invention are epothilone derivatives and any one of the anticancer drugs. 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 polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing evenly, 10mg of paclitaxel and 10mg of epothilone B are added, after shaking up again, the microspheres for injection containing 10% of paclitaxel and 10% of epothilone B are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 15 percent of mannitol to prepare the corresponding suspension type sustained-release injection with the viscosity of 220-460 cp (at 20-30 ℃). 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 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 20: 80, and the anticancer active ingredients and the weight percentage thereof are as follows:
(a) a combination of 5% 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 25% paclitaxel or docetaxel;
(b) a combination of 20% 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, with 10% carmustine, nimustine, bendamustine, galamustine, ramustine, fotemustine, lomustine, methyl lomustine, uramustine, samustine, semustine, streptozocin, or midazolamine; or
(c) 20% 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 20% of vincristine, vinblastine, vinorelbine or vindesine. The viscosity of the slow release injection is 200-450 cp (at 20-30 ℃).
Example 3.
70mg of polylactic acid (PLGA, 75: 25) with the molecular weight peak of 40000-65000 is put into a container, 100 ml of dichloromethane is added, after the uniform dissolution, 15mg of epothilone D and 15mg of nimustine are added, the mixture is shaken again and dried in vacuum to remove the organic solvent. The dried drug-containing solid composition is frozen and crushed into micro powder containing 15 percent of epothilone D and 15 percent of nimustine, and then the micro powder is suspended in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection with the viscosity of 300-400 cp (at the temperature of 20-30 ℃). 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 4
The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is PLGA (50: 50) with the molecular weight peak of 20000-40000, and the anti-cancer active ingredients and the weight percentage thereof are as follows: 2-40% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furaetheromycin D or BMS-310705 in combination with 2-40% carmustine, nimustine, bendamustine, fotemustine, lomustine, tamustine, spiromustine, samustine or midazolam.
Example 5.
70mg of polylactic acid (PLA) with the molecular weight peak value of 40000-65000 is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 20mg of vincristine and 10mg of isoepothilone D are added, after shaking up again, the microsphere for injection containing 20% of vincristine and 10% of isoepothilone D is prepared by a spray drying method. Then suspending the microspheres in injection containing 5-15% sorbitol to obtain corresponding suspension type sustained release injection with viscosity of 100-200 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 procedure of the method for preparing the sustained-release injection is the same as that of example 5, except that the polylactic acid (PLA) with the molecular weight peak of 20000-45000 contains the following effective anticancer components: 10% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furazaepothilone D or BMS-310705 in combination with 20% vincristine, vinblastine, vinorelbine or vindesine.
Example 7.
40mg of polifeprosan (20: 80) and 30mg of polylactic acid (PLA) with the molecular weight peak value of 20000-45000 are put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 20mg of paclitaxel and 10mg of BMS-247550 are added, after shaking up again, injection microspheres containing 20% of paclitaxel and 10% of BMS-247550 are prepared by a spray drying method. 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 80-150 cp (at the temperature of 20-25 ℃). 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 8.
The procedure of the method for preparing the sustained release injection is the same as that of example 7, except that the sustained release excipients used are 30mg of polifeprosan (30: 70) and 40mg of polylactic acid (PLA) with the molecular weight peak of 10000-: a combination of 20% paclitaxel or docetaxel and 10% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furan epothilone D, or BMS-310705.
Example 9
40mg of polifeprosan (20: 80) and 30mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 20000-45000 are put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 20mg of docetaxel and 10mg of furan epothilone D are added, after shaking up again, the microspheres for injection containing 20% of docetaxel and 10% of furan epothilone D 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 with the viscosity of 560cp to 640cp (at the temperature of 20 ℃ to 30 ℃). 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 10
The procedure of the process for preparing the sustained-release injection is the same as that of example 9, except that the anticancer active ingredients are: a combination of 10% paclitaxel or docetaxel and 10% furan epothilone D.
Example 11
40mg of polifeprosan (30: 70) and 30mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 10000-25000 are placed into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of carmustine and 20mg of BMS-310705 are added, after shaking uniformly again, the microspheres for injection containing 10% of carmustine and 20% of BMS-310705 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 of 10-15 days in-vitro physiological saline and the release time of about 30-40 days under the skin of a mouse.
Example 12
The procedure of the process for preparing the sustained release implant is the same as that of example 11, except that the sustained release excipient is 30mg of polifeprosan (40: 60) and 40mg of polylactic acid (PLA) with the molecular weight peak value of 15000-30000 is polylactic acid (PLA) with the molecular weight peak value of 35000, and the anticancer active ingredient is 15% of epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furaegycol D or BMS-310705 in combination with 10% of nimustine, bendamustine, carmustine, galamustine, fotemustine, lomustine, ranimustine, samustine, spiromustine or midazolamine.
Example 13
70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 15000-35000 is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 10mg of epothilone D and 20mg of vinorelbine are added, after shaking up again, the microspheres for injection containing 10% of epothilone D and 20% of vinorelbine 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 of 10-15 days in vitro physiological saline and the release time of about 35-50 days under the skin of a mouse.
Example 14
The procedure of processing into sustained release implant is the same as in examples 11 and 13, except that the anticancer active ingredient is:
(a) a combination of 5-15% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705, and 10-35% paclitaxel or docetaxel;
(b) a combination of 5-15% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705, and 5-20% nimustine, carmustine, fotemustine, estramustine, lomustine, methyllomustine, bendamustine or, ranimustine or midazolamine; or
(c) A combination of 5-15% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furaetheromycin D or BMS-310705, and 15-25% vincristine, vinblastine, vinorelbine, vindesine or vinrosidine.
Example 15.
70mg of polylactic acid (PLA) with the molecular weight peak value of 10000-35000 is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 15mg of isoepothilone D and 15mg of vinblastine 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 15% of isoepothilone D and 15% of vinblastine, and suspending in physiological saline containing 1.5% of sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 220-260 cp (at 25-30 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 16
The steps of the method for processing the sustained-release injection are the same as the example 15, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows:
a combination of 10% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B or furan epothilone D with 10% vincristine, vinblastine, vinorelbine or vindesine.
Example 17.
80mg of a difatty acid and Sebacic Acid (SA) copolymer with the molecular weight peak of 20000-30000 (the difatty acid: sebacic acid is 20: 80) is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and uniformly mixed, 5mg of azaepothilone B and 15mg of vincristine are added, the mixture is shaken again and dried in vacuum to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 5% azaepothilone B and 15% vincristine, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 380-460 cp (at 25-30 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 18.
The steps of the method for processing the sustained-release injection are the same as the example 17, but the difference is that the sustained-release auxiliary material is the anti-cancer active ingredient contained in the copolymer of the double fatty acid and the Sebacic Acid (SA) with the molecular weight peak value of 30000-50000 (the double fatty acid and the sebacic acid are 50: 50) and the weight percentage is as follows:
a combination of 15% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B or furan epothilone D with 15% vincristine, vinblastine, vinorelbine, vindesine, or vincristine.
Example 19
The procedure of processing into sustained release preparation is the same as that of examples 1-18, 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 in combination with PLA or PLGA;
d) polifeprosan, p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) at a ratio of 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
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 20
The procedure for preparing a sustained release injection is the same as in examples 1 to 19, 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 21
The procedure of processing into sustained release injection is the same as in examples 1-20, except that the anticancer active ingredient is: a combination of 15% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B or furan epothilone D with 5-25% paclitaxel, docetaxel, nimustine, carmustine, fotemustine, lomustine, midazolamine, vincristine, vinblastine or vinorelbine.
Example 22
The procedure of processing into sustained release injection is the same as in examples 1-20, except that the anticancer active ingredient is:
(a) a combination of 5-15% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705, and 10-35% paclitaxel or docetaxel;
(b) a combination of 5-15% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705, and 5-20% nimustine, carmustine, fotemustine, bendamustine or ramustine or midazolamine; or
(c) A combination of 5-15% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furaetheromycin D or BMS-310705, and 15-25% vincristine, vinblastine, vinorelbine or vindesine.
The foregoing examples are intended to illustrate and not to limit 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.

Claims (10)

1. An anticancer sustained-release injection containing epothilone derivatives 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 ingredient is the combination of epothilone derivatives and anticancer drugs selected from taxane, alkylating agent and/or plant alkaloid;
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) 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 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 ℃).
2. The sustained-release anticancer injection according to claim 1, wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetyl paclitaxel and 7-epi-paclitaxel.
3. The sustained-release anticancer injection according to claim 1, wherein the alkylating agent is selected from one of amomustine, amoxicillin, ammustine, nimustine, bendamustine, dithiomustine, brivustine, carmustine, emestine, etomustine, dithiomustine, gamustine, fotemustine, estramustine, lomustine, nemustine, mannomustine, lomustine, methyllomustine, semustine, ranimustine, punnimustine, uramustine, samustine, taulomustine, streptozocin, Tamomustine, spiromustine, and midazolamine or their combination.
4. The sustained-release anticancer injection according to claim 1, wherein the plant alkaloid is selected from vincristine, vinblastine, vinorelbine, vindesine, vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
5. The sustained-release anticancer injection according to claim 1, wherein the epothilone derivative is selected from the group consisting of epothilone B, 21, 26-dihydroxy epothilone B, 21, 26-amino epothilone B, 21, 26-diamino epothilone B, 9, 10-dehydroepothilone B, 10, 11-hydrogen epothilone B, 26, 27-halogenoepothilone B, 9, 10, 11, 14, 21, 26 substituted with hydroxy group at each of positions 9, 26-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-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 substituted by amino groups, respectively or simultaneously, 9-and 10-dehydroepothilone D, 10, 11-dehydroepothilone D, 26, 27-halogen-substituted epothilone D, 9-dehydroepothilone D, 10, 11, 14, 21, 26-hydroxy 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-hydroxy epothilone D, 21-amino epothilone D, 26-hydroxy epothilone D, 26-amino epothilone D, 26-fluoro epothilone D, isoepothilone, isoepothilone D, 9, 10-dehydroepothilone D, 10, 11-dehydroepothilone D, furan epothilone D, (E) -9, 10-dehydro-12, 13-desoxyepothilone D, BMS-310705, 6-ethyl, 16-fluoro, 17-pyridine epothilone, 11, 12-dehydro-12, 13-dehydro-13-desoxyepothilone D, 9-oxy epothilone D or 8-epi-9-oxy epothilone D.
6. The sustained-release anticancer injection according to claim 1, wherein the weight percentages of the epothilone derivative and the anticancer drug in the sustained-release anticancer injection are 1-20: 1 and 1: 1-20.
7. The sustained-release anticancer injection according to claims 1 and 5, characterized in that in the sustained-release excipients,
a) the peak value of the molecular weight of the polylactic acid is 10000-, 30000-, 300000-60000-, 60000-100000-or 100000-150000;
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.
The suspending agent is one or the 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; 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.
8. The sustained-release anticancer injection according to claims 1 and 5, characterized in that the sustained-release microspheres in the sustained-release anticancer injection are further used for preparing sustained-release implant for treating primary or secondary cancer, sarcoma or carcinosarcoma originated 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, and are injected or placed intratumorally or peritumorally.
9. The sustained-release anticancer implant according to claim 8, wherein the active anticancer constituents of the sustained-release implant are mainly one of the following:
(a) a combination of 2-40% epothilone B, epothilone D, isoepothilone D, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705 with 2-40% paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetylpaclitaxel or 7-epi-paclitaxel;
(b) 2-40% 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% carmustine, nimustine, bendamustine, fotemustine, estramustine, lomustine, spiromustine, streptozocin, samustine, semustine or midazolamine; or
(c) 2-40% 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 or BMS-310705 in combination with 2-40% of vincristine, vinblastine, vinorelbine or vindesine.
10. The sustained-release anticancer implant according to claim 9, characterized in that the sustained-release excipients used for preparing 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) 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.
CNA2006102012738A 2006-12-12 2006-12-12 Anticancer sustained release injection containing epothilone derivatives Pending CN1969818A (en)

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