CN101637445A - Compound anti-cancer slow release agent - Google Patents
Compound anti-cancer slow release agent Download PDFInfo
- Publication number
- CN101637445A CN101637445A CN200810301486A CN200810301486A CN101637445A CN 101637445 A CN101637445 A CN 101637445A CN 200810301486 A CN200810301486 A CN 200810301486A CN 200810301486 A CN200810301486 A CN 200810301486A CN 101637445 A CN101637445 A CN 101637445A
- Authority
- CN
- China
- Prior art keywords
- release
- sustained
- slow release
- acid
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
The invention relates to a compound slow release agent which comprises slow release microspheres and a menstruum, wherein the microsphere comprises anti-cancer active ingredients and slow release auxiliary materials, and the menstruum is a special menstruum containing a suspending agent; the anti-cancer active ingredients are bendamustine and cytotoxicdrugs, and the cytotoxicdrugs are selected from antitaxane, an alkylating agent, a topoisomerase inhibitor and/or plant alkaloids, etc.; the slow release auxiliary materials are polylactic acid and glycollic acid copolymers thereof, polyethyleneglycol and polylactic acid copolymers thereof, terminal carboxyl group polylactic acid copolymers, EVAc, aliphatic acid, sebacic acid copolymers and the like; the suspending agent has a viscosity of 100cp-3000cp (25-30 DEG C), and is selected from sodium carboxymethylcellulose and the like. The slow release microspheres can be prepared into slow release implants. When injected or placed into tumors or at peripheries of tumors, the injections or the slow release implants can reduce the general reaction of the medicine and selectively raise and maintain local concentration for about 30-50 days;therefore, besides the application in tumor treatment, the slow release microspheres can enhance the tumoricidal effect of non-operative methods, such as chemotherapy and/or radiotherapy, etc.
Description
(I) technical field
The invention relates to a compound anticancer sustained release agent and a preparation method thereof, belonging to the technical field of medicines. Specifically, the invention provides an anticancer drug sustained-release preparation containing bendamustine and cytotoxic drugs, which is mainly a sustained-release injection and a sustained-release implant.
(II) background of the invention
As one of the conventional cancer treatment methods, chemotherapeutic drugs are widely applied to the treatment of various malignant tumors, and the effect is obvious. However, its apparent systemic toxicity greatly limits the utility of the drug.
Due to the fact that solid tumors are over-swollen and hyperplastic, and the interstitial pressure, the tissue elastic pressure, the fluid pressure and the interstitial viscosity are higher than those of the surrounding normal tissues, the effective drug concentration is difficult to form locally in the tumor in conventional chemotherapy, see Kongqing et al, "cisplatin and systemic carmustine can be placed in the tumor to treat the brain tumor of rats" [ J. Onck. (1998) 76-82 pages 69 (Kong Q et al, J Surg Onck. (1998 Oct.; 69 (2)): 76-82), and the simple increase of the administration dose is limited by the systemic reaction. 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, 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) ].
Furthermore, blood vessels, connective tissues, matrix proteins, fibrin, collagen, etc. in the 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 and in tumor tissues (see Niti et al, "influence of extracellular stromal status on drug transport in solid tumors" ("Cancer research 60: 2497-. Therefore, preparations and methods that facilitate the maintenance of high drug concentrations locally in tumors and increase the sensitivity of tumor cells to drugs have become an important subject of research.
Disclosure of the invention
Bendamustine or cytotoxic drugs are used as new or common anticancer drugs, and have been widely used for treating various solid tumors such as brain tumors, pancreatic cancers, breast cancers, lung cancers, colon cancers and the like 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 sustained-release system containing anticancer drug has been studied, which includes sustained-release microspheres (capsule) (see: Chinese patent No. ZL 00809160.9; application No. 91109723.6), Ciftci K, etc. "research on treating solid tumor and drug release using fluorouracil-containing polylactic acid microspheres" [ drug development technology (Pharm Dev Technol.) ] 2 (2): 151-60, 1997), sustained-release implant (see: Chinese patent No. ZL 96115937.5; ZL97107076.8), etc. However, the solid sustained-release implant (Chinese patent No. ZL 96115937.5; ZL97107076.8) and the existing sustained-release microspheres for treating brain tumor (ZL00809160.9) or the 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 bendamustine, and are susceptible to developing resistance during treatment. It has been found that the combination of the cytotoxic agents mentioned in the present invention with bendamustine potentiates the anticancer effect thereof (hereinafter, the cytotoxic agent that potentiates the anticancer effect of bendamustine is referred to as a bendamustine potentiator). Besides, the combination of bendamustine and the synergist thereof is packaged in a specific sustained-release auxiliary material and is matched with a special solvent to prepare the anticancer drug sustained-release injection, so that the local drug concentration of tumors can be greatly improved, the drug concentration of the drugs in a circulatory system can be reduced, the toxicity of the drugs to normal tissues can be reduced, the drug injection can be greatly facilitated, the complications of surgical operation can be reduced, and the cost of patients can be reduced. The cytotoxic drug can inhibit tumor growth and increase the sensitivity of tumor cells to bendamustine. The above unexpected findings constitute the subject of the present invention.
Aiming at the defects of the prior art, the invention provides a novel sustained-release preparation containing bendamustine and/or cytotoxic drugs, which comprises a sustained-release injection and a sustained-release implant.
The invention relates to a bendamustine sustained release injection, which consists of sustained release microspheres and a solvent. Specifically, the anticancer sustained-release injection consists of the following components:
(A) a sustained release microsphere comprising:
0.5-60% of anticancer active ingredient
Sustained release auxiliary materials 40-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the effective anticancer components are bendamustine and cytotoxic drug;
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, hyaluronic acid, collagen, gelatin, protein glue or a combination thereof; 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 anticancer drug is mainly administrated by conventional ways such as oral administration or intravenous injection, and the administration mode of the invention is local sustained release administration, which obviously enhances the treatment effect of the drug and simultaneously obviously reduces the systemic toxicity. Many anticancer active ingredients are reported to be applied by a slow release way, and not all the anticancer active ingredients can achieve the slow release effect of effective release in slow release auxiliary materials. The medicinal auxiliary materials are more than hundreds of medicinal auxiliary materials with slow release effect, particularly the slow release ratio of the bendamustine selected in the invention in human bodies or animal bodies within a certain time is not obvious, and the selection of the specific slow release auxiliary materials and the slow release medicine combination can be determined by a large amount of creative labor. The related data, particularly the data of the release characteristics in animals, can be obtained through a large number of creative experiments in vivo and in vitro, can not be determined through limited experiments, and is non-obvious.
Bendamustine in the present invention may also be replaced by fotemustine, tamustine, amoxustine, semustine, carmustine, nimustine, lomustine or ranimustine, as the mechanism of action found in the present invention is similar to that of bendamustine.
The proportion of bendamustine in the composition of the present invention is determined by the specific circumstances, and may be 0.1% to 50%, preferably 1% to 40%, and most preferably 5% to 30%.
The cytotoxic drug is selected from camptothecin, procarbazine, paclitaxel, meclizine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine [ DL-Buthionine- (S, R) -sulfoximine, BSO for short ], O6-benzylguanine, O4-benzylfolic acid (O4-benzylfolilic acid).
The weight percentage of the cytotoxic drug in the sustained release agent is 0.01-99.99%, preferably 1-50%, and most preferably 5-30%.
When the effective anticancer component in the drug sustained-release microspheres is only bendamustine or a cytotoxic drug, the anticancer sustained-release injection is mainly used for increasing the effect of the bendamustine or the cytotoxic drug applied by other ways or for the synergy of radiotherapy or other therapies. When the anticancer active ingredient in the drug sustained-release microspheres is only bendamustine or the synergist thereof (cytotoxic drug), the application and the synergy mode of the anticancer sustained-release injection are as follows:
(1) the slow release injection containing bendamustine is locally injected, and the cytotoxic drug is applied by other ways;
(2) local injection of slow-release injection containing cytotoxic drug, and other ways of using bendamustine;
(3) local injection of slow release injection containing bendamustine and slow release injection containing cytotoxic drug; or
(4) The slow release injection containing bendamustine and cytotoxic drug is injected locally.
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, intravenous, intraperitoneal, subcutaneous, intraluminal administration.
The weight percentage of the anticancer active ingredient bendamustine and/or the cytotoxic drug in the drug sustained-release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. The weight ratio of bendamustine to cytotoxic drug is 1-9: 1 to 1: 1-9, preferably 1-2: 1.
The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
(1) a combination of 2-40% bendamustine or fotemustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolate;
(2) 2-40% of tamoxifen or estramustine in combination with 2-40% of camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine, O6-benzylguanine, O4-benzylfolate;
(3) a combination of 2-40% carmustine or nimustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolate; or
(4) A combination of 2-40% amoxastine, lomustine or ranimustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolic acid.
The slow release auxiliary materials can be various water-soluble or non-water-soluble high molecular polymers, and preferably one or a combination of racemic polylactic acid, a racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid, a monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid, a polyethylene glycol/polylactic acid copolymer, terminal carboxyl polylactic acid, a terminal carboxyl polylactic acid/glycolic acid copolymer, polifeprosan, a copolymer of di-fatty acid and sebacic acid, poly (erucic aciddipolymer-sebacic acid), poly (fumaric acid-sebacic acid), an ethylene vinyl acetate copolymer, polylactic acid, a copolymer of polyglycolic acid and glycolic acid, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue is selected from the slow release auxiliary materials.
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) 55-90% EVAc;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, 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 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 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 method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to form fine powders, liposome-encapsulating, and emulsifying. Among them, a dissolving method (i.e., solvent evaporation method), a drying method, a spray drying method and an emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections, and the method is arbitrary. The microspheres used may have a particle size in the range of 5-400um, preferably 10-300um, most preferably 20-200 um.
The microspheres can also be used for preparing other sustained-release injections, such as gel injections and block copolymer micelle injections. The block copolymer micelle is formed by a hydrophobic-hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be injected around tumor or in tumor. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly.
The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutic adjuvant can be any one or more of the above pharmaceutic adjuvants, but the water-soluble high polymer is selected as the main choice, and the mixture or copolymer of polylactic acid, sebacic acid, and high polymer containing polylactic acid or sebacic acid is selected as the first choice among various high polymers, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, mixture of PLA and PLGA, mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride, fatty acid dimer-sebacic acid [ P (EAD-SA) ], 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 slow release auxiliary materials can be various water-soluble or non-water-soluble polymer, and the anticancer active ingredients and the weight percentage of the anticancer slow release implant are preferably as follows:
(1) a combination of 2-40% bendamustine or fotemustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolate;
(2) 2-40% of tamoxifen or estramustine in combination with 2-40% of camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine, O6-benzylguanine, O4-benzylfolate;
(3) a combination of 2-40% carmustine or nimustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolate; or
(4) A combination of 2-40% amoxastine, lomustine or ranimustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolic acid.
The slow release microspheres can also be used for preparing slow release implanting agent, the slow release adjuvant can be any one or more of the above medicinal adjuvants, and water soluble high molecular polymer is selected from various 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) 55-90% EVAc;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, 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 technique of the present invention is further described by the following tests and examples:
test 1 comparison of local drug concentrations after different modes of bendamustine application
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 1 cm in diameter. Each group dose was 5mg/kg bendamustine. 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 bendamustine after different modes of application is obvious, the effective medicament concentration of the part where the tumor is located 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 anti-tumor effects after different modes of bendamustine administration
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 0.5 cm diameter. Each group dose was 5mg/kg bendamustine. 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 benzydaThe tumor inhibition effect difference of the momentine applied by 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.
Experiment 3. in vivo tumor inhibition effect of nimustine and cytotoxic drug (sustained release injection)
Using white rat as test object, 2X 105Individual pancreatic tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 1). The first group was the control, and groups 2 to 10 were the treatment groups, and the drug was injected intratumorally. The dosage is 5 mg/kg. Tumor volume was measured on day 10 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 | 68±10 | |
| 2(6) | Nimustine | 46±5.2 | ＜0.05 |
| 3(6) | Paclitaxel | 40±2.2 | ＜0.01 |
| 4(6) | Medicine for curing tumor | 44±2.6 | ＜0.01 |
| 5(6) | Cyclophosphamide | 48±3.4 | ＜0.01 |
| 6(6) | O6-benzylguanine | 42±3.6 | ＜0.01 |
| 7(6) | Paclitaxel + nimustine | 18±2.0 | ＜0.001 |
| 8(6) | Oncoclonine + nimustine | 16±2.2 | ＜0.001 |
| 9(6) | Cyclophosphamide + nimustine | 24±2.0 | ＜0.001 |
| 10(6) | O6-benzylguanine + nimustine | 22±2.0 | ＜0.001 |
The results show that nimustine and its synergist (paclitaxel, oncoclonine, cyclophosphamide, O6-benzyl guanine) have obvious inhibition effect on the growth of various tumor cells when being used alone at the concentration, and can show obvious synergistic effect when being used in combination. This finding constitutes a further important feature of the present invention.
Experiment 4. antitumor Effect of carmustine and cytotoxic drug (sustained Release injection)
The tumor cells include CNS-1, C6, 9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), and liver cancer. Carmustine and cytotoxic drug were added to each tumor cell cultured in vitro for 24 hours at a concentration of 10ug/ml, and the total number of cells was counted after further culturing for 48 hours. The tumor cell growth inhibitory effect is shown in Table 2.
TABLE 2
| Tumor cell | Carmustine | Butyl guanine | Irinotecan | Vincristine | Butyl guanine + carmustine | Irinotecan + carmustine | Vincristine + carmustine |
| CNS | 50％ | 42％ | 36％ | 36％ | 84％ | 78％ | 84％ |
| C6 | 60％ | 50％ | 38％ | 24％ | 84％ | 86％ | 92％ |
| SA | 62％ | 40％ | 22％ | 26％ | 88％ | 88％ | 90％ |
| BC | 56％ | 44％ | 24％ | 24％ | 84％ | 86％ | 82％ |
| BA | 54％ | 40％ | 22％ | 28％ | 88％ | 78％ | 78％ |
| LH | 68％ | 50％ | 22％ | 28％ | 80％ | 86％ | 82％ |
| PAT | 62％ | 46％ | 28％ | 24％ | 90％ | 86％ | 86％ |
The results show that the cytotoxic drugs (butyl guanine, irinotecan and vincristine) and carmustine 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.
Test 5 antitumor Effect of bendamustine and cytotoxic drug (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 5). The first group was the control, and groups 2 to 10 were the treatment groups, with the sustained release implant placed intratumorally. The dosage is 5 mg/kg. Tumor volume was measured on day 10 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 | 62±12 | |
| 2(6) | Bendamustine | 44±4.2 | ＜0.05 |
| 3(6) | Leuprorelin | 40±2.0 | ＜0.01 |
| 4(6) | Bendamustine + leuprorelin | 16±1.2 | ＜0.001 |
| 5(6) | Colchicine | 36±3.2 | ＜0.01 |
| 6(6) | Bendamustine + colchicine | 18±1.6 | ＜0.001 |
| 7(6) | Amino triazoles | 32±2.6 | ＜0.01 |
| 8(6) | Bendamustine + aminotriazole | 16±2.4 | ＜0.001 |
| 9(6) | Butyl thionine sulfoximine | 38±4.0 | ＜0.01 |
| 10(6) | Bendamustine + butylthionine sulfoximine | 22±2.0 | ＜0.001 |
The results show that the bendamustine and the cytotoxic drugs (leuprorelin, colchicine, aminotriazole and butylthionine) 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. This finding constitutes a further important feature of the present invention.
Experiment 6. Fumustine and cytotoxic drug (slow release injection) for inhibiting tumor
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into the quaternary pleural space and were classified as negative controls (blank), monotherapy (fotemustine or cytotoxic drug) and combination therapy (fotemustine and cytotoxic drug) after 14 days of tumor growth. The medicine is injected intratumorally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see Table 4).
TABLE 4
| Test set (n) | Is treated by | Tumor inhibition ratio (%) | P value |
| 1(6) | Control | - | |
| 2(6) | Fotemustine | 46 | ＜0.05 |
| 3(6) | Amino triazoles | 36 | ＜0.01 |
| 4(6) | Butyl thionine sulfoximine | 42 | ＜0.01 |
| 5(6) | O6-benzylguanine | 52 | ＜0.01 |
| 6(6) | O4-Benzylphonic acid | 42 | ＜0.01 |
| 7(6) | Fotemustine and amino triazole | 76 | ＜0.001 |
| 8(6) | Fotemustine + butylthionine sulfoximine | 82 | ＜0.001 |
| 9(6) | Fotemustine + O6-benzylguanine | 80 | ＜0.001 |
| 10(6) | Fotemustine + O4-benzylfolic acid | 86 | ＜0.001 |
The results show that the fotemustine and the cytotoxic drugs (aminotriazole, butylthionine, O6-benzylguanine and O4-benzylfolic acid) 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.
Experiment 7. the antitumor Effect of estramustine and cytotoxic drug (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 dosage is 5 mg/kg. Measuring tumor volume on 10 days after treatment, and comparing the treatment with tumor growth inhibition rate as indexEffect (see table 5).
TABLE 5
| Test set (n) | Is treated by | Tumor inhibition ratio (%) | P value |
| 1(6) | Control | - | |
| 2(6) | Estramustine | 46 | ＜0.05 |
| 3(6) | Medicine for curing tumor | 44 | ＜0.01 |
| 4(6) | Methylguanine | 66 | ＜0.01 |
| 5(6) | Cyclophosphamide | 38 | ＜0.01 |
| 6(6) | Alkylguanine | 64 | ＜0.01 |
| 7(6) | Estramustine + oncoclonine | 76 | ＜0.001 |
| 8(6) | Estramustine + methylguanine | 84 | ＜0.001 |
| 9(6) | Estramustine + cyclophosphamide | 82 | ＜0.001 |
| 10(6) | Estramustine + alkylguanine | 80 | ＜0.001 |
The results show that the estramustine and the cytotoxic drug-alkylating agent (oncoclonine, methylguanine, cyclophosphamide and alkylguanine) 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.
Experiment 8. antitumor Effect of Ramomustine and cytotoxic drug (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 sustained release implant is placed intratumorally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see Table 6).
TABLE 6
| Test set (n) | Is treated by | Tumor inhibition ratio (%) | P value |
| 1(6) | Control | - | |
| 2(6) | Ramomustine | 42 | ＜0.05 |
| 3(6) | Vincristine | 40 | ＜0.01 |
| 4(6) | Irinotecan | 46 | ＜0.01 |
| 5(6) | Leuprorelin | 44 | ＜0.01 |
| 6(6) | Colchicine | 38 | ＜0.01 |
| 7(6) | Ramustine + vincristine | 72 | ＜0.001 |
| 8(6) | Ramostemine and irinotecan | 82 | ＜0.001 |
| 9(6) | Ramustine + leuprorelin | 86 | ＜0.001 |
| 10(6) | Ramustine + colchicine | 88 | ＜0.001 |
The results show that the ramustine and the cytotoxic drugs (irinotecan, vincristine, leuprorelin and colchicine) have obvious inhibition effect on the growth of a plurality of 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.
Experiment 9 antitumor Effect of bendamustine and cytotoxic drug (sustained Release injection)
The tumor-inhibiting effect of cytotoxic drugs (sustained release injections) was determined as described in test 7, and the results showed that cytotoxic drugs selected from camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolic acid and the like significantly enhanced the tumor-inhibiting effect of bendamustine, fotemustine, tamustine, amoxastine, semustine, carmustine, nimustine, lomustine or ranimustine, with a synergistic effect of 38-60% (P < 0.01).
Experiment 10 comparison of in vivo Release of bendamustine sustained Release implants made with polylactic acid of different molecular weights
Rats were used as subjects, and equal amounts of bendamustine-containing sustained release implants loaded with polylactic acid (PLA) of different Molecular Weights (MW) were grouped (3/group) and administered subcutaneously. 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 the in vivo release of bendamustine sustained release implants made of different molecular weight polylactic acids, it was found that the release was slowed down with the increase of molecular weight, and the bacterial inhibition rate was increased with the increase of molecular weight of polylactic acid, as compared to the systemic administration group, in the order of 68% (MW: 5000), 66% (MW: 15000), 54% (MW: 25000), 50% (MW: 40000) and 48 (MW: 60000), as exemplified by day 7.
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 finds that the slow-release auxiliary materials most suitable for the slow release of the medicament are one 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, hyaluronic acid, collagen, gelatin and albumin glue; the most suitable suspending agent is one or more of methylcellulose, hydroxymethyl cellulose, sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, or their combination.
In a word, the bendamustine, fotemustine, tamustine, amoxicillin, semustine, carmustine, nimustine, lomustine or ranimustine and various cytotoxic drugs 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 bendamustine, fotemustine, tamustine, amoxicillin, semustine, carmustine, nimustine, lomustine or ranimustine and any cytotoxic drug. The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein suspension injection formed by combining with special solvent containing suspending agent is preferred.
The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.
(IV) detailed description of the preferred embodiments
Example 1.
80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of paclitaxel and 10mg of bendamustine are added, and after shaking uniformly again, the microspheres for injection containing 10% of paclitaxel and 10% of bendamustine 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 anticancer active ingredients and the weight percentage thereof are as follows:
(1) a combination of 2-40% bendamustine or fotemustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolate;
(2) 2-40% of tamoxifen or estramustine in combination with 2-40% of camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine, O6-benzylguanine, O4-benzylfolate;
(3) a combination of 2-40% carmustine or nimustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolate; or
(4) A combination of 2-40% amoxastine, lomustine or ranimustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolic acid.
The used auxiliary materials are: 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 viscosity of the slow release injection is 10cp-650cp (at 20 ℃ -30 ℃).
Example 3.
70mg of polylactic acid (PLGA, 75: 25) with a molecular weight peak of 65000 was placed in a container, 100 ml of dichloromethane was added, after dissolving and mixing well, 15mg of carmustine and 15mg of cinchonine were added, shaking again and vacuum drying was carried out to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 15% carmustine and 15% cinchonine, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 300-400 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 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 anticancer active ingredients and the weight percentage thereof are as follows: 5-30% camptothecin, procarbazine, paclitaxel, meclizine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, or O4-benzylfolic acid in combination with 2-40% carmustine.
Example 5.
Putting 70mg of ethylene-vinyl acetate copolymer (EVAc) into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 20mg of vincristine and 10mg of nimustine, shaking up again, and preparing the microspheres for injection containing 20% of vincristine and 10% of nimustine 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 process for preparing the sustained-release injection is the same as that of example 5, except that the anticancer active ingredients are: 10-20% camptothecin, procarbazine, paclitaxel, meclizine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, or O4-benzylfolic acid, in combination with 10-20% nimustine.
Example 7.
70mg 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 the mixture is dissolved and mixed evenly, 20mg of lomustine and 10mg of camptothecin are added, the mixture is shaken up again, and then the microsphere for injection containing 20% of lomustine and 10% of camptothecin is 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 process for preparing the sustained-release injection is the same as that of example 7, except that the anticancer active ingredients are: 15-25% camptothecin, procarbazine, paclitaxel, meclizine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, or O4-benzylfolic acid in combination with 15-25% lomustine.
Example 9
70mg 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 the mixture is dissolved and mixed evenly, 20mg of fotemustine and 10mg of cyclophosphamide are added, the mixture is shaken up again, and the microspheres for injection containing 20% of fotemustine and 10% of cyclophosphamide 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: 20% camptothecin, procarbazine, paclitaxel, meclizine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, or O4-benzylfolic acid in combination with 20% fotemustine.
Example 11
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of O6-methylguanine and 20mg of estramustine are added, after shaking uniformly again, the microspheres for injection containing 10% of O6-methylguanine and 20% of estramustine 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 processing into a sustained-release implant was the same as in example 11, except that the anticancer active ingredient contained therein was: 10% camptothecin, procarbazine, paclitaxel, meclizine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, or O4-benzylfolic acid in combination with 10% estramustine.
Example 13
70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 35000 is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 10mg of O6-alkylguanine and 20mg of ramustine are added, after being shaken again evenly, microspheres for injection containing 10% of O6-alkylguanine and 20% of ramustine 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: 5-25% camptothecin, procarbazine, paclitaxel, meclizine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, or O4-benzylfolic acid in combination with 5-25% ranimustine.
Example 15.
Putting 70mg of polylactic acid (PLA) with the molecular weight peak value of 35000 into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 15mg of paclitaxel and 15mg of amoxicillin, shaking uniformly again, and drying in vacuum to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 15% paclitaxel and 15% amoxicillin, and suspending in physiological saline containing 1.5% 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: 15% camptothecin, procarbazine, paclitaxel, meclizine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, or O4-benzylfolic acid in combination with 15% amoxicillin.
Example 17.
70mg of a copolymer of difatty acid and Sebacic Acid (SA) with a molecular weight peak of 30000 (difatty acid: sebacic acid: 20: 80) was placed in a container, 100 ml of dichloromethane was added, after dissolution and mixing, 15mg of tamoxifen and 15mg of vincristine were added, shaking again and vacuum drying was carried out to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 15% of Tamustine and 15% of vincristine, and suspending in physiological saline containing 1.5% of 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 anticancer active ingredients and the weight percentage thereof are as follows:
10-25% O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, O6-benzylguanine or O4-benzylfolic acid in combination with 15% bendamustine, carmustine, nimustine, ranimustine, lomustine or estramustine.
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) ethylene vinyl acetate copolymer (EVAc);
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, 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: 2-20% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, or O4-benzylfolic acid in combination with 2-20% bendamustine.
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:
(1) a combination of 2-40% bendamustine or fotemustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolate;
(2) 2-40% of tamoxifen or estramustine in combination with 2-40% of camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine, O6-benzylguanine, O4-benzylfolate;
(3) a combination of 2-40% carmustine or nimustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolate; or
(4) A combination of 2-40% amoxastine, lomustine or ranimustine with 2-40% camptothecin, procarbazine, paclitaxel, meconine, cyclophosphamide, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzylxanthine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole, butylthionine oxime, O6-benzylguanine, O4-benzylfolic acid.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.
Claims (1)
1. A sustained-release injection containing compound anticancer comprises the following components:
(A) a sustained release microsphere comprising:
anticancer active ingredient
Sustained release excipients
And
(B) a solvent;
wherein,
the anticancer sustained-release injection comprises one of the following components:
(1) the anticancer active ingredients are 10% of paclitaxel and 10% of bendamustine, the slow release auxiliary material is polifeprosan with the ratio of p-carboxyphenylpropane to sebacic acid being 20: 80, and the solvent is physiological saline containing 15% of mannitol;
(2) the anticancer active ingredients are 15% of paclitaxel and 15% of amoxicillin, the slow release auxiliary material is polylactic acid with molecular weight peak value of 35000, the solvent is normal saline containing 1.5% sodium carboxymethylcellulose;
the above are all weight percentages.
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