CN101006978A - Anticancer medicinal composition containing taxane and alkylating agents - Google Patents

Abstract

Disclosed is a slow release injection agent of anticancer composition containing taxone and alkylating agent, which comprises slow release microspheres and dissolvent, wherein the slow release microballoons comprise anti-cancer active constituents selected from taxone and/or alkylating agent and slow release auxiliary materials, the dissolvent being conventional dissolvent or specific dissolvent containing suspension adjuvant. the viscosity of the suspension adjuvant is 100-3000cp (at 20-30 deg C), and is selected from sodium carboxymethylcellulose, the slow release auxiliary materials are selected from polyphosphate ester copolymers such as p(LAEG-EOP), p(DAPG-EOP), p(BHET-EOP/TC), p(BHET-EOP/TC), p(BHDPT-EOP/TC), p(BHDPT-EOP/TC), p(CHDM-HOP) or p(CHDM-EOP), copolymer of polyphosphate ester with polylactic acid, Polifeprosan, di-aliphatic acid and sebacylic acid, copolymer or blend of poly(erucic aciddipolymer-sebacylic acid) or poly(fumaric acid-sebacylic acid). The anticancer composition can also be prepared into slow release implanting agent, for injection or placement in or around tumor with a period of effective concentration maintenance over 40 days, as well as the treatment effect of appreciably lowering general reaction of the drugs, and improving the treatment effect of the non-operative treatment methods such as chemotherapy.

Description

Anticancer composition containing taxane and alkylating agent

(I) technical field

The invention relates to an anticancer composition containing taxane and/or alkylating agent, which is an anticancer sustained-release injection and sustained-release implant, and belongs to the technical field of medicines.

(II) background of the invention

As a common chemotherapeutic drug, the taxane is widely applied to the treatment of various malignant tumors and has obvious effect. However, its significant toxic effects greatly limit the wide use of this class of drugs.

Due to the fact that solid tumors are hyperproliferating and have higher interstitial pressure, tissue elastic pressure, fluid pressure and interstitial viscosity than the surrounding normal tissues, it is difficult for conventional chemotherapy to achieve effective drug concentration locally in the tumor, see Kongqing et al, "Intra-tumor Carmustine plus systemic Carmustine for treating brain tumor in rats", J.J.Oncol.1998 Oct (Kong Q et al, J.Surg Oncol.1998 Oct; 69 (2): 76-82). In addition, blood vessels, connective tissues, matrix proteins, fibrin and collagen in tumor stroma not only provide a scaffold and essential nutrients for the growth of tumor cells, but also influence the penetration and diffusion of chemotherapeutic drugs around tumors and in tumor tissues (see Niti et al, "influence of extracellular stroma conditions on drug transport in solid tumors" [ Cancer research ] No. 60, 2497 and 503 (2000)) (Netti PA, Cancer Res.2000, 60 (9): 2497 and 503)). Therefore, simply increasing the dosage is limited by systemic reactions. The problem of drug concentration may be solved to some extent by the local application of drugs, however, the surgical operations such as drug implantation and the like are complicated, the wound is large, and besides various complications such as bleeding, infection, immunity reduction and the like are easily caused, the diffusion and metastasis of tumors can be caused or accelerated. In addition, the preparation itself before and after the operation and the high cost often affect the effective implementation.

In addition, DNA repair function in many tumor cells is significantly increased following chemotherapy. The latter often leads to an increased tolerance of the tumor cells to anticancer drugs, with consequent therapeutic failure. In addition, low dose anti-cancer drug therapy not only increases drug resistance but also promotes invasive growth of cancer cells (see beam et al, "increasing drug resistance and in vitro infiltration capacity of human lung cancer cells with alteration of gene expression after anti-cancer drug pulse screening" [ J.Immunol.Cancer, 111, et al, Int J cancer.2004; 111 (4): 484-93) ].

Therefore, it is an important issue to research a preparation and a method which can maintain a high drug concentration in a tumor part and increase the sensitivity of tumor cells to drugs, while being convenient for operation.

Disclosure of the invention

The invention provides an anticancer medicine composition containing taxane and/or an alkylating agent aiming at the defects of the prior art, in particular to an anticancer sustained-release injection or sustained-release implant containing taxane and/or an alkylating agent.

Taxane is a new anticancer drug and is widely used for treating various solid tumors at home and abroad. However, during the application process, the obvious systemic toxicity greatly limits the application of the medicine.

In order to effectively increase the local drug concentration of tumor and reduce the drug concentration of the drug in the circulatory system, a drug sustained-release system containing taxane is researched, which comprises magnetic microspheres (see Chinese patent No. CN 200410044113.8; CN200410009233.4), sustained-release microspheres (capsules) (see Chinese patent No. CN200410023746.0) and nanoparticles (see Chinese patent No. CN 200410099292.5; CN200510002387.5) and the like. However, solid sustained-release implants (Chinese patent No. ZL 96115937.5; ZL 97107076.8; CN200410084621.9), mini implants with radioactive sources (Chinese patent No. CN200510011250.6) and sustained-release microspheres (Chinese patent No. ZL 00809160.9; U.S. Pat. No. 5,651,986) have the problems of difficult operation, poor curative effect, more complications and the like. In addition, many solid tumors are poorly sensitive to anticancer drugs, including taxanes, and are susceptible to development of resistance during treatment.

The invention discovers that the anticancer effect of the alkylating agent and the taxane can be mutually strengthened by combining the alkylating agent and the taxane; in addition, the anticancer drug sustained release preparation (mainly a sustained release injection and a sustained release implant) prepared by combining the taxane and the alkylating agent not only can greatly improve the local drug concentration of the tumor, reduce the drug concentration of the drug in the circulatory system and reduce the toxicity of the drug to normal tissues, but also can greatly facilitate the drug injection, reduce the complications of the operation and reduce the cost of patients. The above unexpected findings constitute the subject of the present invention.

The present invention also found that not all sustained-release excipients can achieve the sustained-release effect of effective release in terms of the components having anticancer activity such as taxane and alkylating agent. The medicinal auxiliary materials are more than hundreds of medicinal auxiliary materials with slow release function, in particular the medicinal auxiliary materials which can slowly release different medicines in human bodies or animal bodies within a certain time can be obtained through a large number of creative experiments, and the selection of the combination of the specific slow release auxiliary materials and the medicines which can be slowly released can be determined through a large number of creative labor. Too slow release to achieve effective drug concentration and thus ineffective killing of tumor cells; if too rapid a Release causes a burst, it is prone to induce general provincial toxicity reactions, such as polifeprosan (A.J. Domb et al, Biomaterials (1995), 16 (14): 1069-. 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 invention discovers that phosphate ester high molecular polymers such as polyphosphoester (polyphosphates), polyphosphoester (polyphosphate), polyphosphite (polyphosphate), polyphosphonate (polyphosphonate), poly (cyclophosphate), ethyl phosphate (EOP) and the like can stably and slowly release the active ingredients of the invention, and the release period is more than 40 to 100 days. And has no burst release, especially mixing or copolymerizing with anhydrosugar polymers such as polylactic acid. The discovery solves the problem of burst release and over-quick release of the existing sustained release preparation which takes the anhydrosugar polymers (such as PLA, PLGA, polifeprosan, and the like) such as polylactic acid and the like as the auxiliary materials, and can slowly release the drug for more than 40-100 days. The above findings constitute the main features of the present invention.

One form of the taxane slow release preparation is slow release injection, which consists of slow 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 components are taxane and/or alkylating agent.

The taxane (Taxanes) anticancer drug is mainly selected from paclitaxel, Docetaxel, 2 '-hydroxy paclitaxel (paclitaxel-2' -hydroxy), 10-deacetyl paclitaxel (10-deacetyltaxol), and 7-epi-paclitaxel (7-epi-taxol).

Preferably paclitaxel and docetaxel. The proportion of the component in the composition is determined by the particular circumstances, and in general, it is from 0.01% to 55%, preferably from 1% to 50%, and most preferably from 2% to 40%. All are weight percent.

Alkylating agents include Estramustine (Alestramustine), amostine (Atrimustine), AMOMOTINE (Ambamustine), Nimustine (ACNU, Nimustine), Bendamustine (Bendamustine), dithiomostine (Ditiomustine), brivustine (Bofumustine), carmustine (carmustine, BCNU, carmustine), Elmustine (Elmustine), Ecomustine (Ecmustine), Galamustine (GCNU), Fotemustine (Fotemustine), Estramustine (Estramustine), medustine (Samustine, Hecnu), nemustine (MCpentamustine, Neptamustine), Mannomustine (Mannomustine, NU), lomustine (1, lomustine), Semustine (CCumustine, Nutromustine, Numustine (CCumustine), Semustine (CCumustine, Nutromustine, Numustine, Nutmustine (CCumustine), and Triestramustine (CCumustine, Triestramustine, Taustine, Triestramustine, Taestramustine, Triestramustin, Triestris, Triestramustine, Taestramustine, Taestramustin, Taestramustine, Taestris, Taestramustine, One or a combination of Spiromustine (Spiromustine), Streptozocin (STZ), Mitozolomide (MTZ), cyclophosphamide and melphalan (melphalan).

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 alkylating agent is preferably nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyl lomustine, streptozocine, midazolam, cyclophosphamide, melphalan.

The weight percentage of the alkylating agent in the sustained-release agent is 0.1-60%, preferably 1-50%, and most preferably 5-30%.

The weight percentage of the anti-tumor drug in the drug sustained-release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. When used in combination, the weight ratio of taxane to alkylating agent is from 1-9: 1 to 1: 1-9, preferably 1-4: 1 and 4-1: 1, and most preferably 1-2: 1 and 2-1: 1.

The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:

(a) 1-40% of paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetylpaclitaxel or 7-epi-paclitaxel;

(b) 1-40% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyl lomustine, streptozocin, midazolamine, cyclophosphamide or melphalan; or

(c) 1-40% paclitaxel or docetaxel in combination with 1-40% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyl lomustine, midazolamine, cyclophosphamide, melphalan.

The viscosity range IV (dl/g) of the slow release auxiliary material is 0.05-1.8, preferably 0.1-1.4, and most preferably 0.1-1.4. The sustained-release excipients used in the present invention are selected from the group consisting of polyphosphates, polyphosphonates, polycycloalkylphosphates, ethyl phosphate (EOP), poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester, 80/20) (p (BHET-EOP/TC, 80/20)), p (BHET-EOP/TC, 50/50), poly (L-lactide-co-ethyl phosphate (p (LAEG-EOP)), poly (L-lactide-co-propyl phosphate) (p (DAPG-EOP)), trans (formula) -1, 4-dimethylcyclohexane (trans-1, 4-cyclohexanedimethanil, CHDM), hexyldichlorophosphate (hexyldichlorophosphate), HOP), 4-dimethylaminopyridine (4-dimethylaminopyridine, DMAP), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate hydrochloride, 80/20) (p (BHDPT-EOP/TC, 80/20)), p (BHDPT-EOP/TC, 50/50), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) (p (CHDM-HOP)), poly (trans) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)), or a combination thereof.

Among the above phosphates, p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) and p (CHDM-EOP) are preferable.

The sustained-release auxiliary material used by the invention is also selected from the phosphate ester, the racemic polylactic acid (D, L-PLA), the racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), the monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), the monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), the polyethylene glycol/polylactic acid (PLA-PEG-PLA), the polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), the carboxyl-terminated polylactic acid (PLA-COOH), the carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), the polifeprosan, the copolymer of difatty acid and sebacic acid (PFAD-SA), the poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], the poly (fumaric acid-sebacic acid) [ P (FA-SA) ], the polymer, 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, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin or a blend or copolymer of protein glue. Wherein the phosphate accounts for 1-99% by weight, preferably 40-80% by weight, and most preferably 50-60% by weight.

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.

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 addition to the above-mentioned adjuvants, other substances may be used as described in detail in U.S. Pat. No. 4757128 (4857311) (4888176 (4789724)) and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luomingsheng 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.

The content of the suspending agent depends on the composition, nature and required amount of the medicine suspended in the solvent, the sustained-release microsphere (or microcapsule), the preparation method of the injection, the kind and composition of the suspending agent, for example, the content of the sodium carboxymethylcellulose can be 0.5-5%, but is preferably 1-3%, the content of mannitol and/or sorbitol is 5-30%, but is preferably 10-20%, and the content of tween 20, tween 40 or tween 80 is 0.05-2%, but is preferably 0.10-0.5%. In most cases, the sustained-release particles are composed of active ingredients and sustained-release excipients, and the solvent is a special solvent. When the solvent is common solvent, the suspended drug or sustained release microsphere (or microcapsule) is composed of effective components, sustained release adjuvant and/or suspending agent. In other words, when the suspending agent in sustained release particle (A) is "0", solvent (B) is a special solvent, and when the suspending agent in sustained release particle (A) is not "0", solvent (B) can be a common solvent or a special solvent. 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 common solvent can be, but is not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared from various salts, and the pharmacopoeia has corresponding regulations; the special solvent in the invention is a common solvent containing a suspending agent, and the suspending agent can be, but is not limited to, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, a surfactant, tween 20, tween 40 and tween 80 or a combination thereof. The content of the suspending agent in the special solvent is 0.1-30% by volume weight, preferably as follows:

(a) 0.5-5% sodium carboxymethylcellulose; or

(b) 0.5-5% sodium carboxymethylcellulose and 0.1-0.5% tween 80; or

(c) 5-20% mannitol; or

(d) 5-20% mannitol and 0.1-0.5% tween 80; or (b).

(e) 0.5-5% of sodium carboxymethylcellulose, 5-20% of sorbitol and 0.1-0.5% of tween 80.

The above-mentioned all are volume weight percentages, and the weight of suspending agent contained in the common solvent of unit volume is the same as that in g/ml and kg/L.

The preparation of the injection comprises the preparation of sustained release microspheres or drug particles, the preparation of a solvent, the suspension of the sustained release microspheres or drug particles in the solvent and the final preparation of the injection.

Wherein, the sustained release microspheres or drug microparticles can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray-drying to prepare microspheres, dissolving in combination with freeze (dry) milling, liposome encapsulation, and emulsification. Among them, the dissolution method (i.e., solvent evaporation method), the freeze (dry) pulverization method, the drying method, the spray drying method and the emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections. The particle size of the suspension drug or sustained release microspheres (or microcapsules) is determined by specific needs and can be, but is not limited to, 1-300um, but is preferably 20-200um, and most preferably 30-150 um. The drug or the sustained-release microspheres can be prepared into microspheres, submicron spheres, micro-emulsion, nanospheres, granules or spherical pellets. The slow release auxiliary material is the above-mentioned biocompatible, biodegradable or non-biodegradable polymer.

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 and properties of the drug suspended in the solvent, the sustained release microsphere (or microcapsule), and the required amount thereof, and the preparation method of the injection, for example, sodium carboxymethylcellulose (1.5%) + mannitol and/or sorbitol (15%) and/or tween 80 (0.1%) are dissolved in physiological saline to obtain the corresponding solvent with viscosity of 10-650 cp (at 20-30 deg.C).

The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).

The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.

The application of the injection comprises the application of sustained-release microspheres or drug particles, the application of a solvent and the application of the injection prepared by suspending the sustained-release microspheres or the drug particles in the solvent.

The microsphere is used for preparing sustained release injection, such as suspension sustained release injection, gel injection, and block copolymer micelle injection. Among various injections, a suspension type sustained-release injection is preferable. The suspension type sustained-release injection is a preparation obtained by suspending medicament sustained-release microspheres or medicament particles containing active ingredients in a solvent, the used 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 solvent is, but not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared by various salts; 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. The polyethylene glycol (PEG) with the molecular weight of 1000-15000 is preferably used as a hydrophilic block of a micelle copolymer, a biodegradable polymer (such as PLA, polylactide, polycaprolactone and a copolymer thereof (with the molecular weight of 1500-25000) is preferably used as a hydrophobic block of the micelle copolymer, the particle size of the block copolymer micelle can be 1-300um, but 20-200um is preferred, and 30-150um is most preferred, and the gel injection is prepared by dissolving the biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the drug to be miscible (or suspended) to form gel with better fluidity, and injecting the gel around or in tumor.

The application of the solvent mainly refers to the application of the special solvent in effectively suspending, stabilizing and/or protecting various medicines or sustained-release microspheres (or microcapsules) so as to prepare corresponding injections. The application of the special solvent can lead the prepared injection to have better injection property, stability and higher viscosity.

The injection is prepared by using special solvent with high viscosity to make drug-containing microparticles, especially slow-release microparticles, into corresponding slow-release injection, so that the corresponding drug can be injected into the body of patient or mammal. The injected drug may be, but is not limited to, the above drug fine powder or drug sustained-release fine particles.

The route of administration of the injection depends on various factors. For non-proliferative lesions, intravenous, lymphatic, subcutaneous, intramuscular, intraluminal (e.g., intraperitoneal, thoracic, intraarticular, and intraspinal), intrahistological, intratumoral, peritumoral, elective arterial, intralymph node, and intramedullary injections may be used. For proliferative lesions, such as solid tumors, selective arterial, intraluminal, intratumoral, or peritumoral injection is preferred, although administration can be by the routes described above.

In order to obtain effective concentration at the site of primary or metastatic tumor, it can also be administered by combination of multiple routes, such as intravenous, lymphatic, subcutaneous, intramuscular, intracavity (such as intraperitoneal, thoracic, intraarticular and intraspinal) or selective arterial injection in combination with local injection. Such combination administration is particularly useful for solid tumors. For example, the injection is combined with the systemic injection at the same time of intratumoral injection and peritumoral injection.

The invention can be used for preparing medicaments for treating various tumors of human and animals, and is mainly a sustained-release injection.

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, granules, spheres, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred.

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 route of administration of the sustained release agent depends on various factors, and in order to obtain an effective concentration at the site of primary or metastatic tumor, the drug may be administered by various routes, such as subcutaneous, intraluminal (e.g., intraperitoneal, thoracic, and intraspinal), intratumoral, peritumoral injection or placement, selective arterial injection, intralymphatic, and intramedullary injections. 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 tumors of the viscera can be of different pathological types, the tumors of the lymph nodes are Hodgkin lymphoma and non-Hodgkin lymphoma, the lung cancer comprises small cell lung cancer, non-small cell lung cancer and the like, and the brain tumor comprises glioma and the like. However, common tumors include solid tumors such as brain tumor, brain glioma, kidney cancer, liver cancer, gallbladder cancer, head and neck tumor, oral cancer, thyroid cancer, skin cancer, hemangioma, osteosarcoma, lymphoma, lung cancer, thymus cancer, esophageal cancer, stomach cancer, breast cancer, pancreatic cancer, retinoblastoma of eyes, nasopharyngeal cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, and testicular cancer.

The application and the synergy mode of the sustained-release implant are the same as those of an anticancer sustained-release injection, namely the combination of a locally-placed chemotherapy synergist and an anticancer medicament administrated by other routes, the combination of a locally-placed anticancer medicament and a chemotherapy synergist administrated by other routes, and the combination of a locally-placed anticancer medicament and a locally-placed chemotherapy synergist. Wherein the locally applied anticancer drug and the chemotherapeutic synergist can be produced, packaged, sold and used separately or jointly. The package refers to the loading process of the drug for the auxiliary materials and the internal and external package of the drug-containing sustained release agent for transportation and/or storage. Drug loading processes include, but are not limited to, weighing, dissolving, mixing, drying, shaping, coating, spraying, granulating, and the like.

The dosage of the anticancer active ingredients in the sustained-release implant can be referred to the sustained-release injection. But preferably as follows:

(a) 1-40% paclitaxel or docetaxel;

(b) 1-40% nimustine, carmustine, bendamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, cyclophosphamide or melphalan; or

(c) A combination of 1-40% paclitaxel or docetaxel with 1-40% nimustine, carmustine, bendamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, cyclophosphamide or melphalan.

The sustained-release injection prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic, anticoagulant, hemostatic, etc.

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 paclitaxel 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. The dose of each group was 5 mg/kg. 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 paclitaxel applied in different modes is obvious, the effective medicament concentration of the part where the tumor is positioned 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. 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 inhibition effects of paclitaxel applied in different ways

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. The dose of each group was 15 mg/kg. 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 paclitaxel after being applied in different modes 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.

Test 3 tumor inhibition of paclitaxel and alkylating agent (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 1). The first group was the control, and groups 2 to 10 were the treatment groups, with the sustained release implant placed intratumorally. The doses of paclitaxel and alkylating agent were 40mg/kg and 5mg/kg, respectively. Tumor volume was measured on day 20 after treatment and the effect was compared (see table 1).

TABLE 1

Test set (n)	Is treated by	Tumor volume (cm)3)	P value
				1(6)	Control	50±10
2(6)	Paclitaxel	34±5.0	＜0.05
				3(6)	Nimustine	38±5.0	＜0.01
4(6)	Paclitaxel + nimustine	20±3.2	＜0.001
				5(6)	Carmustine	38±5.2	＜0.01
6(6)	Carmustine + paclitaxel	16±3.0	＜0.001
				7(6)	Fotemustine	30±2.6	＜0.01
8(6)	Fotemustine + paclitaxel	20±2.2	＜0.001
				9(6)	Satemustine	42±4.4	＜0.01
10(6)	Samustine + paclitaxel	22±2.2	＜0.001

The results show that the paclitaxel and the alkylating agent (nimustine, carmustine, fotemustine, estramustine and samustine) have obvious inhibition effect on the growth of a plurality of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used jointly. This finding constitutes a further important feature of the present invention.

Test 4 antitumor Effect of paclitaxel and alkylating agent (sustained Release injection)

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 single-drug treatment group (paclitaxel or alkylating agent) and a combination treatment group (paclitaxel and alkylating agent) after 14 days of tumor growth. The medicine is injected intratumorally. The doses of paclitaxel and alkylating agent were 20mg/kg and 5mg/kg, respectively. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 2).

TABLE 2

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
				1(6)	Control	-
2(6)	Paclitaxel	46	＜0.05
				3(6)	Semustine	48	＜0.01
4(6)	Lomustine	42	＜0.01
				5(6)	Methyl lomustine	52	＜0.01
6(6)	Chain zotard	40	＜0.01
				7(6)	Paclitaxel + semustine	80	＜0.001
8(6)	Paclitaxel + lomustine	87	＜0.001
				9(6)	Paclitaxel + Methylomustine	90	＜0.001
10(6)	Paclitaxel + streptozocin	94	＜0.001

The results show that the paclitaxel and the alkylating agents (semustine, lomustine, methyl lomustine and streptozocin) 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 5 antitumor Effect of paclitaxel and alkylating agent (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. The medicine is injected intratumorally. The doses of paclitaxel and alkylating agent were 10mg/kg and 10mg/kg, respectively. Tumor volume was measured on day 20 after treatment and the treatment effect was compared using tumor growth inhibition as an index (see table 3).

TABLE 3

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
				1(6)	Control	-
2(6)	Paclitaxel	58	＜0.05
				3(6)	Gatemustine	54	＜0.01
4(6)	Ramomustine	46	＜0.01
				5(6)	Cyclophosphamide	48	＜0.01
6(6)	Melphalan	46	＜0.01
				7(6)	Paclitaxel + gamoxystin	76	＜0.001
8(6)	Paclitaxel + ramustine	86	＜0.001
				9(6)	Paclitaxel + cyclophosphamide	90	＜0.001
10(6)	Paclitaxel + melphalan	92	＜0.001

The results show that the paclitaxel and the alkylating agent (the gammopiptin, the ranimustine, the cyclophosphamide and the melphalan) have obvious inhibition effect on the growth of various tumor cells when being applied at the concentration alone, and can show obvious synergistic effect when being applied in combination. This finding constitutes a further important feature of the present invention.

Test 6 tumor inhibition of paclitaxel and alkylating agent (sustained release injection)

Using white rat as test object, 2X 10⁵Individual brain tumor cells were injected subcutaneously into the quaternary costal region and divided into the following 10 groups 14 days after tumor growth (see table 4). The first group was the control, and groups 2 to 10 were the treatment groups, with the sustained release implant placed intratumorally. The doses of paclitaxel and alkylating agent were 20mg/kg and 20mg/kg, respectively. Tumor volume was measured on day 30 after treatment and the effect was compared (see table 4).

TABLE 4

Test set (n)	Is treated by	Tumor volume (cm)3)	P value
				1(6)	Control	50±10
2(6)	Docetaxel	34±5.0	＜0.05
				3(6)	Nimustine	38±5.0	＜0.01
4(6)	Docetaxel + nimustine	20±3.2	＜0.001
				5(6)	Carmustine	38±5.2	＜0.01
6(6)	Carmustine + docetaxel	16±3.0	＜0.001
				7(6)	Fotemustine	30±2.6	＜0.01
8(6)	Fotemustine + docetaxel	20±2.2	＜0.001
				9(6)	Satemustine	42±4.4	＜0.01
10(6)	Samustine + docetaxel	22±2.2	＜0.001

The results show that the paclitaxel and the alkylating agent (nimustine, carmustine, fotemustine and 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 7 antitumor Effect of paclitaxel and alkylating agent (sustained Release injection)

Using white rat as test object, 2X 10⁵One breast tumor cell was injected subcutaneously into the costal region of the patient and 14 days after tumor growth was assigned to negative control (blank), single drug treatment (paclitaxel or alkylating agent) and combination treatment (paclitaxel and alkylating agent). The medicine is injected intratumorally. The doses of paclitaxel and alkylating agent were 5mg/kg and 40mg/kg, respectively. Treatment ofThe tumor volume was measured on the following day 20, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see Table 5).

TABLE 5

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
				1(6)	Control	-
2(6)	Paclitaxel	46	＜0.05
				3(6)	Semustine	48	＜0.01
4(6)	Lomustine	42	＜0.01
				5(6)	Methyl lomustine	52	＜0.01
6(6)	Melphalan	40	＜0.01
				7(6)	Paclitaxel + semustine	80	＜0.001
8(6)	Paclitaxel + lomustine	87	＜0.001
				9(6)	Paclitaxel + Methylomustine	90	＜0.001
10(6)	Paclitaxel + melphalan	94	＜0.001

The results show that the paclitaxel and the alkylating agents (semustine, lomustine, methyl lomustine and melphalan) 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.

The above results show that when used in combination, the weight ratio of taxane to alkylating agent is 1-9: 1 to 1: 1-9, preferably 1-4: 1 and 4-1: 1, most preferably 1-2: 1 and 2-1: 1.

Further research shows that the combination of alkylating agents such as nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyl lomustine, streptozocin, midazolam, cyclophosphamide, melphalan and other tumors such as paclitaxel or docetaxel has obvious synergistic effect (P is less than 0.05).

In conclusion, the taxane and/or various alkylating agents have obvious inhibition effect on the growth of various tumor cells when being used independently, and can show obvious synergistic effect when being used in combination. Therefore, the active ingredients of the invention are the combination of any one taxane and/or any one alkylating agent. 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.

80, 80 and 80mg of p (BHET-EOP/TC) (the BHET-EOP: TC is 80: 20) copolymer are respectively put into three containers of A, B and C, then 100 ml of dichloromethane is added into each of the three containers, after dissolving and mixing uniformly, 20mg of paclitaxel, 20mg of carmustine, 10mg of paclitaxel and 10mg of carmustine are respectively added, after shaking uniformly again, the microspheres for injection containing 20% of paclitaxel, 20% of carmustine, 10% of paclitaxel and 10% of carmustine 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. The slow release injection has the release time of 40-50 days in vitro physiological saline and the release time of more than 50 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 used auxiliary material is p (BHET-EOP/TC) with the ratio of 50: 50, the anticancer active ingredients and the weight percentage thereof are as follows:

(1) 5-40% paclitaxel or docetaxel;

(2) 1-30% carmustine, nimustine or lomustine; or

(3) A combination of 5-40% paclitaxel and 1-30% carmustine, nimustine or lomustine.

Example 3.

70mg of p (LAEG-EOP) with the molecular weight peak value of 10000-25000 is respectively placed into a container A, a container B and a container C, then 100 ml of dichloromethane is added into each container, after dissolving and mixing evenly, 30mg of docetaxel, 30mg of carmustine, 20mg of docetaxel and 10mg of carmustine are respectively added into the three containers, after shaking up again, the microspheres for injection containing 30% of docetaxel, 30% of carmustine, 20% of docetaxel and 10% of carmustine are prepared by a spray drying method. Suspending the dried microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 55-65 days in vitro physiological saline and the release time of about 60 days under the skin of a mouse.

Example 4

The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is that the molecular weight peak value of p (LAEG-EOP) is 25000-45000, and the anticancer active ingredients and the weight percentage thereof are as follows:

(1) 5-30% carmustine, nimustine, cyclophosphamide or melphalan; or

(2) 5-40% docetaxel or paclitaxel; or

(3) 5-30% docetaxel or paclitaxel in combination with 5-30% carmustine nimustine, cyclophosphamide or melphalan.

Example 5.

60mg of p (DAPG-EOP) with the molecular weight peak value of 10000-25000 is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 30mg of paclitaxel and 10mg of melphalan are added to the mixture, the mixture is shaken up again and then spray drying is carried out to prepare microspheres for injection containing 30% of paclitaxel and 10% of melphalan. Then suspending the microspheres in injection containing 15 percent of sorbitol to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 50-55 days in-vitro physiological saline and the release time of about 55 days under the skin of a mouse.

Example 6.

The steps of the method for processing the sustained-release injection are the same as the example 5, but the difference is that the molecular weight peak value of the used auxiliary materials is 25000-:

(1) 5-40% paclitaxel; or

(2) 1-20% melphalan; or

(3) A combination of 5-30% paclitaxel and 1-20% melphalan.

Example 7.

70mg of p (BHDPT-EOP/TC, 80/20) with the molecular weight peak value of 10000-25000 is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 25mg of paclitaxel and 5mg of lomustine are added, and after being shaken again, the microspheres for injection containing 25 percent of paclitaxel and 5 percent of lomustine 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. The slow release injection has the release time of 40-45 days in vitro physiological saline and the release time of about 50 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 peak value of the molecular weight of p (BHDPT-EOP/TC) is 40000-65000, the peak value of the molecular weight of BHDPT-EOP: TC is 50: 50, and the anti-cancer active ingredients are as follows:

(1) 10-20% of lomustine;

(2) 10-25% of a combination of paclitaxel; or

(3) 10-20% of lomustine and 10-25% of paclitaxel.

Example 9.

30mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) and 40mg of p (DAPG-EOP) copolymer with the molecular weight peak value of 30000-45000 are put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed uniformly, 30mg of docetaxel, 30mg of bendamustine, 5mg of docetaxel and 25mg of bendamustine are respectively added, and after the mixture is shaken uniformly again, injection microspheres containing 30% of docetaxel, 30% of bendamustine, 5% of docetaxel and 25% of bendamustine 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 of 40-45 days in vitro physiological saline and the release time of about 45 days under the skin of a mouse.

Example 10.

The steps of the method for processing the sustained-release injection are the same as the example 9, but the difference is that the ratio of the p-carboxyphenylpropane to the sebacic acid in the polifeprosan is 50: 50, the molecular weight peak value of p (DAPG-EOP) is 40000-65000, and the anticancer active ingredients are:

(1) 5-30% docetaxel;

(2) 20-40% bendamustine;

(3) a combination of 5-20% docetaxel and 10-40% bendamustine.

Example 11

40mg of (LAEG-EOP) copolymer with the molecular weight peak value of 20000-45000p and 30mg of PLA copolymer with the molecular weight peak value of 10000-25000 p are placed into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and uniformly mixed, 10mg of nimustine and 20mg of docetaxel are added, the mixture is uniformly shaken again, and then the spray drying method is used for preparing the microspheres for injection containing 10% of nimustine and 20% of docetaxel. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 40-45 days in vitro physiological saline and the release time of about 45 days under the skin of a mouse.

Example 12

The steps of the method for processing the sustained-release implant are the same as the example 11, but the difference is that the used auxiliary materials are (LAEG-EOP) with the molecular weight peak value of 40000-65000p and PLA with the molecular weight peak value of 25000-45000, and the anti-cancer active ingredients are as follows:

(1) 10-20% nimustine; or

(2) 10-20% docetaxel; or

(3) 10-20% of nimustine and 10-20% of docetaxel.

Example 13

40mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 15000-35000 and 30 (LAEG-EOP) with the molecular weight peak value of 20000-45000p are placed in a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of carmustine and 20mg of paclitaxel are added, after shaking uniformly again, the microspheres for injection containing 10% carmustine and 20% paclitaxel 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 50-60 days in vitro physiological saline and the release time of about 60 days under the skin of a mouse.

Example 14

The procedure for manufacturing the sustained-release implant was the same as in examples 11 and 13, except that the anticancer active ingredient contained:

(1) 10-20% paclitaxel or docetaxel; or

(2) 10-20% carmustine or nimustine; or

(3) A combination of 10-20% paclitaxel or docetaxel with 10-20% carmustine, bendamustine or nimustine.

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) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP);

b) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer (PLGA) of polyglycolic acid and glycolic acid having a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;

c) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) with polylactic acid (PLA) having a molecular weight peak of 10000-;

d) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or a combination of p (CHDM-EOP) and polifeprosan, wherein the ratio of p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) in the polifeprosan is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) p (BHET-EOP/TC), P (LAEG-EOP), P (DAPG-EOP), P (BHDPT-EOP/TC), P (CHDM-HOP) or P (CHDM-EOP) in combination with a di-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) ], xylitol, oligosaccharides, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or gelatin.

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 for manufacturing the sustained-release implant was the same as in examples 11 and 13, except that the anticancer active ingredient contained:

(1) 5-35% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, lomustine, cyclophosphamide or melphalan; or

(2) 1-40% paclitaxel or docetaxel; or

(3) 1-40% paclitaxel in combination with 5-30% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, lomustine, cyclophosphamide, or melphalan; or

(4) 1-40% docetaxel in combination with 5-30% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, lomustine, cyclophosphamide or melphalan.

Example 18 comparison of drug Release characteristics of different Release excipients and their combinations (Table 6)

The procedure of the method for manufacturing the sustained-release implant is the same as that of example 11, and the release characteristics of different sustained-release excipients and the combined sustained-release excipients are compared. The first day of drug release (in vitro) exceeds 20% of the total is burst release.

TABLE 6

Sustained release excipients	Molecular weight	Medicine and content	Time of release (Tian)	Whether there is a burst release
					(1)PLA	10000-25000	Paclitaxel (20%)	22	Is free of
(2)PLGA(50/50)	20000-40000	Paclitaxel (20%)	28	Is free of
					(3) Polifeprosan (20/80)	20000-40000	Paclitaxel (20%)	10	Is provided with
(4)p(LAEG-EOP)	15000-35000	Paclitaxel (20%)	48	Is free of
					(1)∶(4)＝1∶1		Paclitaxel (20%)	42	Is free of
(2)∶(4)＝1∶1		Paclitaxel (20%)	44	Is free of
					(3)∶(4)＝1∶1		Paclitaxel (20%)	40	Is free of
(5)PLA	25000-45000	Nimustine (20%)	26	Is free of
					(6)PLGA(75/25)	10000-20000	Nimustine (20%)	25	Is free of
(7) Polifeprosan (50/50)	10000-20000	Nimustine (20%)	10	Is provided with
					(8)p(DAPG-EOP)	35000-55000	Nimustine (20%)	56	Is free of
(5)∶(8)＝6∶4		Nimustine (20%)	52	Is free of
					(6)∶(8)＝7∶3		Nimustine (20%)	50	Is free of
(7)∶(8)＝5∶5		Nimustine (20%)	48	Is free of

The data in the table show that when the anhydroglucose high-molecular polymers such as PLA, PLGA (50/50), polifeprosan (20/80) and the like are independently applied, the drug release is fast, wherein the drug release time of the polifeprosan is 8-10 days and the polifeprosan has obvious burst release. The polyphosphate ester high molecular polymers such as p (LAEG-EOP) and p (DAPG-EOP) are slow and stable in drug release, and when the polyphosphate ester high molecular polymers are combined with the sugar anhydride high molecular polymers such as PLA, PLGA and polifeprosan, the burst release caused by the sugar anhydride high molecular polymers can be reduced, but the stable and slow drug release characteristics are not greatly influenced. This unexpected finding constitutes a further main technical feature of the present invention. Because the polyphosphate ester high molecular polymer is expensive, the cost of the sustained-release preparation can be reduced, and the drug release characteristic of the sustained-release preparation can be improved.

Example 19 comparison of drug Release characteristics of different Release excipients and their combinations (Table 7)

The procedure of the method for manufacturing the sustained-release implant is the same as that of example 11, and the release characteristics of different sustained-release excipients and the combined sustained-release excipients are compared. The first day of drug release (in vitro) exceeds 20% of the total is burst release.

TABLE 7

Sustained release excipients	Molecular weight	Medicine and content	Time of release (Tian)	Whether there is a burst release
					(1)PLA	20000-35000	Docetaxel (20%)	24	Is free of
(2)PLGA(50/50)	30000-45000	Docetaxel (20%)	32	Is free of
					(3) Polifeprosan (20/80)	20000-40000	Docetaxel (20%)	12	Is provided with
(4)p(LAEG-EOP)	25000-45000	Docetaxel (20%)	50	Is free of
					(1)∶(4)＝1∶1		Docetaxel (20%)	44	Is free of
(2)∶(4)＝1∶1		Docetaxel (20%)	46	Is free of
					(3)∶(4)＝1∶1		Docetaxel (20%)	42	Is free of
(5)PLA	25000-45000	Carmustine (10%)	26	Is free of
					(6)PLGA(75/25)	20000-40000	Carmustine (10%)	26	Is free of
(7) Polifeprosan (50/50)	20000-40000	Carmustine (10%)	12	Is provided with
					(8)p(DAPG-EOP)	35000-55000	Carmustine (10%)	58	Is free of
(5)∶(8)＝6∶4		Carmustine (10%)	54	Is free of
					(6)∶(8)＝7∶3		Carmustine (10%)	52	Is free of
(7)∶(8)＝5∶5		Carmustine (10%)	48	Is free of

The data in the table show that when the anhydroglucose high-molecular polymers such as PLA, PLGA (50/50), polifeprosan (20/80) and the like are independently applied, the drug release is fast, wherein the drug release time of the polifeprosan is 8-10 days and the polifeprosan has obvious burst release. The polyphosphate ester high polymer such as p (LAEG-EOP) and p (DAPG-EOP) releases drug slowly and stably (more than 50 days), and when the polyphosphate ester high polymer is combined with the sugar anhydride high polymer such as PLA, PLGA and polifeprosan, the burst release caused by the latter can be reduced, but the smooth and slow drug release characteristic of the former is not greatly influenced. This unexpected finding constitutes a further main technical feature of the present invention. Because the polyphosphate ester high molecular polymer is expensive, the cost of the sustained-release preparation can be reduced, and the drug release characteristic of the sustained-release preparation can be improved.

This release profile is also seen for other drug combinations, such as carmustine with paclitaxel and nimustine with docetaxel.

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 composition containing taxane and alkylating agent, which is characterized in that the anticancer composition is a slow 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 taxane and/or alkylating agent;

the slow release auxiliary material is selected from phosphate ester high molecular polymer or the mixture or copolymer of the phosphate ester high molecular polymer and the polysaccharide anhydride high molecular polymer:

the taxane is mainly selected from paclitaxel, docetaxel, 2' -hydroxy paclitaxel, 10-deacetyl paclitaxel, and 7-epi-paclitaxel;

the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), and is selected from one or more of sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40 and Tween-80.

2. The anti-cancer composition according to claim 1, wherein the alkylating agent is selected from the group consisting of nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyl lomustine, midazolam, cyclophosphamide and melphalan.

3. The anticancer composition according to claim 1, wherein the anticancer sustained release injection comprises the following anticancer active ingredients:

(1) 5-35% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, lomustine, cyclophosphamide or melphalan; or

(2) 1-40% paclitaxel or docetaxel; or

(3) 1-40% paclitaxel in combination with 5-30% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, lomustine, cyclophosphamide, or melphalan.

The above are all weight percentages.

The slow release auxiliary material is one or the combination of the following materials:

a) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP);

b) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer of polyglycolic acid and glycolic acid with a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;

c) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) with polylactic acid having a molecular weight peak of 10000-;

d) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or a combination of p (CHDM-EOP) and polifeprosan, wherein the ratio of p-carboxyphenylpropane to sebacic acid in the polifeprosan is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer of di-fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or egg gelatin.

4. 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; or

f) Glycerin, dimethicone, propylene glycol, or carbomer.

5. The sustained-release anticancer injection according to claim 1, wherein the suspending agent is one of the following:

A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;

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.

6. The anticancer composition according to claim 1, which is a sustained-release implant.

7. The sustained-release anticancer implant according to claim 6, characterized in that the anticancer active ingredients are:

(1) 5-35% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, lomustine, cyclophosphamide or melphalan; or

(2) 1-40% paclitaxel or docetaxel; or

(3) 1-40% paclitaxel in combination with 5-30% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, lomustine, cyclophosphamide, or melphalan.

The slow release auxiliary material is selected from phosphate ester high molecular polymer or the mixture or copolymer of phosphate ester high molecular polymer and polysaccharide anhydride high molecular polymer.

8. The sustained-release anticancer implant according to claim 6, characterized in that the sustained-release excipients are selected from one of the following:

a) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP);

b) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer of polyglycolic acid and glycolic acid with a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;

c) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) with polylactic acid having a molecular weight peak of 10000-;

d) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or a combination of p (CHDM-EOP) and polifeprosan, wherein the ratio of p-carboxyphenylpropane to sebacic acid in the polifeprosan is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer of di-fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or egg gelatin.

9. The sustained-release anticancer injection according to claim 1, wherein the active ingredients of the sustained-release anticancer injection are used for preparing a pharmaceutical preparation for treating primary or secondary cancer, sarcoma or carcinosarcoma originated from brain, central nervous system, kidney, liver, gallbladder, head and neck, oral cavity, thyroid, 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 injection and sustained-release injection as claimed in claims 1 and 6, wherein the sustained-release injection is administered by intratumoral or peritumoral injection or placement and is sustained-released in vivo for more than 40 days.