CN101385709A - Sustained-released injection containing carmustine of nitrosourea medicine - Google Patents

Sustained-released injection containing carmustine of nitrosourea medicine Download PDF

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CN101385709A
CN101385709A CNA2008103046181A CN200810304618A CN101385709A CN 101385709 A CN101385709 A CN 101385709A CN A2008103046181 A CNA2008103046181 A CN A2008103046181A CN 200810304618 A CN200810304618 A CN 200810304618A CN 101385709 A CN101385709 A CN 101385709A
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release
sustained
drug
injection
anticancer
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高化兰
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Jinan Shuaihua Pharmaceutical Technology Co Ltd
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Jinan Shuaihua Pharmaceutical Technology Co Ltd
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Abstract

An anticancer sustained release injection containing a nitrosourea drug carmustine consists of sustained release microspheres and a dissolvent, wherein, the sustained release microspheres comprise a nitrosourea drug selected from nimustine, carmustine and the like and/or an anticancer active component of topoisomerase inhibitor and a sustained release adjuvant, and the dissolvent is a common dissolvent or a special dissolvent containing a suspending agent. The suspending agent has the viscosity of 100cp-3000cp (at the temperature of 20-30 DEG C) and is selected from sodium carboxymethyl cellulose and the like; the sustained release adjuvant is selected from copolymer of polyphosphate esters such as p(LAEG-EOP) or p(DAPG-EOP) and the like, or copolymer or polyblend of the polyphosphate esters and PLA, polifeprosan, PLGA and poly(erucic acid dimmer-sebacic acid); the topoisomerase inhibitor is selected from camptothecin, hydroxyl camptothecin, topotecan, lurtotecanthe, irinotecan, etoposide or teniposide; the anticancer composite is also made into a sustained release implant, and injected into or placed inside or at the periphery of tumor to keep the effective drug concentration more than 60 days. The anticancer sustained release injection can also obviously reduce the general reaction of the drug, and selectively enhance the curative effects of non-operative therapies such as radiotherapy, chemotherapy and the like.

Description

Sustained-release injection containing carmustine as nitrosourea drug
(I) technical field
The invention relates to a sustained-release injection containing a nitrosourea drug and a topoisomerase inhibitor and a preparation method thereof, belonging to the technical field of medicines.
(II) background of the invention
As a common chemotherapeutic medicament, nitrosoureas medicaments are widely applied to the treatment of various malignant tumors and have 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 over-swollen and hyperplastic, and the interstitial pressure, tissue elastic pressure, fluid pressure and interstitial viscosity are higher than those of the surrounding normal tissues, the local formation of effective drug concentration in the tumor is difficult in conventional chemotherapy, see Kongqing et al, "J Surg Oncol.1998 Oct. (76-82) in J.69, 7682 pages (1998) of J.J.J.J.J.Surg Oncol. (69 (2)). 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 drug sustained-release agent containing a nitrosourea drug and a topoisomerase inhibitor, aiming at the defects of the prior art, and in particular relates to a sustained-release injection or sustained-release implant containing the nitrosourea drug and the topoisomerase inhibitor.
Nitrosoureas drugs are widely used for treating various solid tumors at home and abroad as a new class of anticancer drugs. 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 drugs in the circulatory system, a drug sustained-release system containing nitrosourea drugs 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 nitrosoureas, and are susceptible to development of resistance during treatment.
The invention discovers that the anticancer effect of the topoisomerase inhibitor and the nitrosoureas drug can be mutually strengthened by combining the topoisomerase inhibitor and the nitrosoureas drug; in addition, the anticancer drug sustained release preparation (mainly a sustained release injection and a sustained release implant) prepared by combining the nitrosourea drug and the topoisomerase inhibitor not only can greatly improve the drug concentration of local tumor, reduce the drug concentration of the drug in a circulatory system and reduce the toxicity of the drug to normal tissues, but also can greatly facilitate the drug injection, reduce the complications of surgical operation and reduce the cost of patients. The above unexpected findings constitute the subject of the present invention.
The invention also discovers that not all sustained-release excipients can achieve the sustained-release effect of effective release for the components with anticancer activity. 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 defects of burst release and over-quick release of the existing sustained-release preparation, and can release the medicine slowly for more than 40-100 days. The above findings constitute the main features of the present invention.
One form of the nitrosourea drug sustained release agent of the invention is sustained release injection, which consists of sustained release microspheres and dissolvent. 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%
0.030% 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 nitrosourea drugs and topoisomerase inhibitors.
The nitrosourea drug is selected from one or the combination of the following medicines: estramustine (Alestramustine), Amomum (Atrimustine), Amamustine (Ambamustine), Nimustine (ACNU, Nimustine), Bendamustine (Bendamustine), Ditiomustine (Ditiomustine), Perfumusine (Bofumustine), carmustine (carmustine, BCNU, carmustine), EMustine (Elmustine), Ecomustine (Ecomustine), Galamustine (GCNU), Fotemustine (Fotemustine), Moustine (Estraustine), Synamustine (Hemustine, Hemuscnu), Neumustine (Penramustine, Neramustine), Mannomustine (Nomamustine, Loustine, Hististine, Sarustine), Mostimustine (Neotamustine), Thimomustine (Glutamine, Glutamine (C-D), Thiomustine (Glutamine, Glutamine (C-D-S), Glutamine (Glutamine, one or a combination of Spiromustine (Spiromustine). The above nitrosoureas also include their salts, such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate, maleate, and the like.
The above nitrosourea drug is preferably selected from nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, and methyl lomustine.
The weight percentage of the nitrosourea drugs in the composition can be 0.1-50%, preferably 1-30%, and most preferably 5-20%.
The topoisomerase inhibitor is selected from one or a combination of the following: camptothecin (CPT), derivatives of camptothecin, Lurtotecan (Lurtocan), topotecan (10-hydroxy-9-methylenethomethyl- (S) -camptothecin, topotecan), irinotecan (IRINOTECT, IRT), 9-nitrocamptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxy-camptothecin (7-ethyl-10hydroxy-camptothecin, SN-38), 7-ethyl-10- [4- (1-piperidino) -1-piperidino ] carbonylcamptothecin (7-ethyl-10- [4- (1-piperidino) -1-piperidino ] carbonylcamptothecin, CPT-11), 10-hydroxy-camptothecin (10-camptothecin, CPT), homocamptothecin (HCdioxy), camptothecin (HCdioxy), 11-methylenedioxy, MD-CPT), (RS) -methylenedioxycamptothecin (10, 11-MD-20(RS) -CPT), (S) -methylenedioxycamptothecin glycinate (10, 11-MD20(S) -cpT-glycinate ester (Gly). HCl), 9-amino- (S) -methylenedioxycamptothecin glycinate (9-amino-10, 11-MD-20(S) -CPT-Gly), N- [2- (dimethylamino) ethyl ] piperidine-4-carboxamide (N- [2- (dimethylamino) ethyl ] acridine-4-carboxamide, DACA) and derivatives thereof substituted at position 5 or 7, podophyllotoxin, Etoposide, epipodophyllotoxins, Etoposide, VP-16, Teniposide (Teniposide, etoposide, VM-26), podophyllic acid, podophyllotoxin, trihydroxyisoflavone (Genistein), 14-hydroxydaunorubicin, Amrubicin (Amrubicin), doxorubicin (4 ' - (acridinylamino) methylsufon-m-aniside (amsacrine, m-AMSA)), 4-demethoxydaunorubicin (4-demethoxydaunorubicin), ditobicin, doxorubicin, epirubicin, 7-O-methylnocar-4 ' -epirubicin (7-O-methylnocalol-4 ' -epirubicin), Esorubicin (Esorubicin), carubicin, idarubicin (idarubicin, IDA), Robirubicin, epirubicin (Leuribin), doxorubicin, nemucin, Nemorubicin (Nemourin), doxorubicin, pivalocin (N-14-trifluralysin, 14-valrubicin, norubicin, valrubicin (14-valacilin, valrubicin (I-14-A), AD32, valrubicin), 2- [4- (7-chloro-2-quinoxalinyloxyphenoxy ] -propionic acid ((2- [4- (7-chloro-2-quinoxalinyloxyphenyloxy ] -propionicacic, XK469), Zorubicin (Zoluicin), N- (2-chloroethane) -N-nitrosoureidodaunorubicin (N- (2-Chloroethyl) -N-nitrosoureidodaunorubicin, AD312), pyrazolo [1, 5-a ] indole derivatives, such as, but not limited to, GS-2, -3, -4, GS-5, dioxopiperazine derivatives, such as, but not limited to, (+) -1, 2 bis (3, 5-dioxopiperazinyl) propane ((+) -1, 2-bis (3, 5-dioxopiperizinyl-1-yl) panane, ICRF-187), m-2, 3-bis (3, 5-dioxopiperazin-1-yl) butane (meso-2, 3-bis (3, 5-dioxopiperazine-1-yl) butane, ICRF-193), bis-dioxopiperazine (bisdioxopiperazine); suramin (Suramin), Deoxyguanosine (Deoxyguanosine), lithocholic acid (LCA) or sodium azide (sodium azide).
Among the above-mentioned topoisomerase inhibitors, camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, ditorexin, esorubicin, casrubicin, roxobicin, doxorubicin, medroxobin, nemorubicin, zorubicin or doxorubicin are preferable. The proportion of topoisomerase inhibitor in the composition is determined by the particular circumstances and, in general, may be from 1% to 50%, preferably from 2% to 40%, most preferably from 5% to 30%. All are weight percent.
The weight percentage of the anti-tumor drug in the drug sustained-release microspheres is 0.5-70%, preferably 2-40%, and most preferably 5-30%. When used in combination, the weight ratio of the nitrosourea drug to the topoisomerase inhibitor is from 1-9:1 to 1:1-9, preferably from 1-2:1 and 2-1:1, and most preferably 1: 1.
The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
1-40% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, samustine or lomustine in combination with 2-40% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, ditetracycline, esorubicin, carrubicin, roxobicin, epirubicin, nemolubicin, zorubicin or doxorubicin.
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), poly-dioxanone (PDO), polytrimethylene carbonate (PTMC), xylitol, oligosaccharides, chondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin or a protein gel.
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.
When polylactic acid (PLA), polyglycolic acid (PGA), a mixture of polylactic acid (PLA) and polyglycolic acid, and a copolymer of glycolic acid and hydroxycarboxylic acid (PLGA) are selected, the contents of PLA and PLGA are 0.1-99.9% and 99.9-0.1% by weight, respectively. The molecular weight peak of polylactic acid may be, but is not limited to, 5000-; 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 individually, 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-; the blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight), most preferably 75: 25. 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. 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. Among the various polymers, preferred are polylactic acid, sebacic acid, and mixtures or copolymers of polylactic acid or sebacic acid-containing polymers, which can be selected from, but not limited to, PLA, PLGA, mixtures of glycolic acid and hydroxycarboxylic acid, and mixtures or copolymers of sebacic acid with aromatic or aliphatic polyanhydrides. 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 contents of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization are respectively 10-60 percent and 20-90 percent by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
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, 520% 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. 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 1 to 300um, but preferably 20 to 200um, most preferably 30 to 150 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 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, 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. Such as the anti-cancer agent and the topoisomerase inhibitor, can be separately granulated and mixed together as desired to form a dosage form, which process includes at least granulation and forming.
The dosage of the anticancer active ingredients in the sustained-release implant can be referred to the sustained-release injection. But preferably as follows:
1-40% nimustine, carmustine, bendamustine, fotemustine, samustine or lomustine in combination with 240% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin or doxorubicin.
The above are all weight percentages.
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 carmustine application
Using white rat as test object, 2X 105Individual brain tumor cells were injected subcutaneously into the quaternary costal region 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 drug in the tumor at different times show that the difference of the local drug concentration of carmustine applied in different ways is obvious, the local administration can obviously improve and effectively maintain the effective drug concentration of the part where the tumor is located, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. This finding constitutes an important feature of the present invention. This is further confirmed by the following relevant tumor inhibition test.
Experiment 2 comparison of in vivo tumor inhibition effects after applying nimustine in different ways
Using white rat as test object, 2X 105Individual pancreatic tumor cells were injected subcutaneously into the quaternary costal region and grouped after tumors grew to 0.5 cm diameter. The dose of each group was 5 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 tumor inhibition effect difference of the nimustine applied by different modes is obvious, the local administration can obviously improve and effectively maintain the effective drug concentration of the tumor part, wherein 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. antitumor Effect of nitrosoureas drug and topoisomerase inhibitor (sustained Release injection)
Using white rat as test object, 2X 105The lung cancer tumor cells are injected into the quaternary costal area of the lung cancer tumor cells subcutaneously, and the lung cancer tumor cells are divided into a negative control (blank), a single medicine treatment group and a combined treatment group after the tumor grows for 14 days. The medicine is injected intratumorally. Topoisomerase inhibitors5mg/kg, and 30mg/kg of nitrosourea drugs. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 1).
TABLE 1
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Nitrosoureas drugs 56 <0.05
3(6) Camptothecin 56 <0.01
4(6) Hydroxycamptothecin 58 <0.01
5(6) Lurtotecan 48 <0.01
6(6) Topotecan 44 <0.01
7(6) Nitrosoureas drug + camptothecin 82 <0.001
8(6) Nitrosoureas drug + hydroxycamptothecin 84 <0.001
9(6) Nitrosoureas drug + lurtotecan 86 <0.001
10(6) Nitrosoureas drug + topotecan 88 <0.001
The results show that the nitrosourea drugs (carmustine) and the topoisomerase inhibitors (camptothecin, hydroxycamptothecin, lurtotecan and topotecan) have obvious inhibition effects on the growth of a plurality of tumor cells when being used alone at the concentration, and can show obvious synergistic effects when being used together.
Test 4. antitumor Effect of nitrosoureas drug and topoisomerase inhibitor (sustained Release injection)
Using white rat as test object, 2X 105Colon cancer cells were 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 topoisomerase inhibitor is 5mg/kg, and the nitrosourea drug is 20 mg/kg. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 2).
TABLE 2
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Nitrosoureas drugs 58 <0.05
3(6) Camptothecin 50 <0.05
4(6) Hydroxycamptothecin 48 <0.05
5(6) Topotecan 56 <0.05
6(6) Irinotecan 52 <0.01
7(6) Nitrosoureas drug + camptothecin 80 <0.01
8(6) Nitrosoureas drug + hydroxycamptothecin 84 <0.01
9(6) Nitrosoureas drug + topotecan 86 <0.01
10(6) Nitrosoureas drug + irinotecan 80 <0.001
The results show that the nitrosourea drugs (nimustine) and the topoisomerase inhibitors (camptothecin, hydroxycamptothecin, topotecan and irinotecan) have obvious inhibition effect on the growth of a plurality of tumor cells when being used alone at the concentration, and can show obvious synergistic effect when being used together.
Test 5 antitumor Effect of nitrosoureas drugs and topoisomerase inhibitors (sustained-Release injections)
Using white rat as test object, 2X 105The rectal cancer tumor cells are injected into the quaternary costal area of the tumor cells subcutaneously, and the tumor cells are divided into a negative control (blank), a single medicine treatment group and a combined treatment group after the tumor cells grow for 14 days. The medicine is injected intratumorally. The topoisomerase inhibitor is 5mg/kg, and the nitrosourea drug is 30 mg/kg. Tumor volume was measured on day 30 post-treatmentSize, comparison of therapeutic effect 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) Nitrosoureas drugs 48 <0.05
3(6) Camptothecin 50 <0.01
4(6) Hydroxycamptothecin 52 <0.01
5(6) Irinotecan 48 <0.01
6(6) Topotecan 52 <0.01
7(6) Nitrosoureas drug + camptothecin 78 <0.001
8(6) Nitrosoureas drug + hydroxycamptothecin 84 <0.001
9(6) Nitrosoureas drug + irinotecan 80 <0.001
10(6) Nitrosoureas drugs+ topotecan 86 <0.001
The results show that the nitrosourea drugs (fotemustine) and the topoisomerase inhibitors (camptothecin, hydroxycamptothecin, irinotecan and topotecan) have obvious inhibition effect on the growth of the liver cancer tumor cells when being applied independently at the concentration, and can show obvious synergistic effect when being applied together.
Test 6. tumor inhibition Effect of nitrosoureas drugs and topoisomerase inhibitors (sustained-Release injections)
Using white rat as test object, 2X 105The neck tumor cells were injected subcutaneously into the costal region of the patient, and the tumor was divided into negative control (blank), single drug treatment group and combination treatment group 14 days after the tumor had grown. The medicine is injected intratumorally. The topoisomerase inhibitor is 5mg/kg, and the nitrosourea drug is 30 mg/kg. The volume of the tumor was measured on day 30 after the treatment, and the treatment effect was compared using the tumor growth inhibition rate as an index. The results are shown in Table 4.
TABLE 4
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Nitrosoureas drugs 58 <0.05
3(6) Camptothecin 50 <0.05
4(6) Hydroxycamptothecin 48 <0.05
5(6) Topotecan 56 <0.05
6(6) Irinotecan 52 <0.01
7(6) Nitrosoureas drug + camptothecin 84 <0.01
8(6) Nitrosoureas drug + hydroxycamptothecin 82 <0.01
9(6) Nitrosoureas drug + topotecan 84 <0.01
10(6) Nitrosoureas drug + irinotecan 82 <0.001
The results show that the nitrosourea drugs (lomustine) and the topoisomerase inhibitors (camptothecin, hydroxycamptothecin, topotecan and irinotecan) have obvious inhibition effects on the growth of multiple tumor cells such as esophagus cancer, gastric cancer and the like when being used alone at the concentration, and can show obvious synergistic effects when being used in combination.
Test 7 antitumor Effect of nitrosoureas drugs and topoisomerase inhibitors (sustained Release implants)
Using white rat as test object, 2X 105The gastric cancer tumor cells were injected subcutaneously into the costal region of the patient, and were classified into negative control (blank), single drug treatment group, and combination treatment group after the tumor had grown for 14 days. The medicine is injected intratumorally. 10mg/kg of topoisomerase inhibitor and 10mg/kg of nitrosourea drug. Measuring tumor volume at 30 days after treatment, and comparing treatment effect with tumor growth inhibition rate as index. The results are shown in Table 5.
TABLE 5
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Nitrosoureas drugs 50 <0.05
3(6) Camptothecin 58 <0.01
4(6) Hydroxycamptothecin 56 <0.01
5(6) Irinotecan 46 <0.01
6(6) Topotecan 50 <0.01
7(6) Nitrosoureas drug + camptothecin 86 <0.001
8(6) Nitrosoureas drug + hydroxycamptothecin 84 <0.001
9(6) Nitrosoureas drug + irinotecan 78 <0.001
10(6) Nitrosoureas drug + topotecan 80 <0.001
The results show that the nitrosourea drugs (nimustine) and the topoisomerase inhibitors (camptothecin, hydroxycamptothecin, irinotecan and topotecan) have obvious inhibition effect on the growth of the liver cancer tumor cells when being applied independently at the concentration, and can show obvious synergistic effect when being applied together.
Test 8 antitumor Effect of nitrosoureas drug and topoisomerase inhibitor (sustained Release injection)
Using white rat as test object, 2X 105The brain tumor cells were injected subcutaneously into the costal region of the patient, and were divided into negative control (blank), single drug treatment group and combination treatment group 14 days after the tumor had grown. The medicine is injected intratumorally. The topoisomerase inhibitor is 15mg/kg, and the nitrosourea drug is 10 mg/kg. The volume of the tumor was measured on day 30 after the treatment, and the treatment effect was compared using the tumor growth inhibition rate as an index. The results are shown in Table 6.
TABLE 6
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Nitrosoureas drugs 58 <0.05
3(6) Camptothecin 50 <0.05
4(6) Hydroxycamptothecin 48 <0.05
5(6) Topotecan 56 <0.05
6(6) Irinotecan 52 <0.01
7(6) Nitrosoureas drug + camptothecin 78 <0.01
8(6) Nitrosoureas drug + hydroxycamptothecin 80 <0.01
9(6) Nitrosoureas drug + topotecan 88 <0.01
10(6) Nitrosoureas drug + irinotecan 82 <0.001
The results show that the nitrosourea drugs (carmustine) and the topoisomerase inhibitors (camptothecin, hydroxycamptothecin, topotecan and irinotecan) have obvious inhibition effect on the growth of brain tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used together
Experiment 9. tumor inhibition of nitrosoureas drugs and topoisomerase inhibitors (sustained-release injections)
Using white rat as test object, 2X 105The lung cancer tumor cells are injected into the quaternary costal area of the lung cancer tumor cells subcutaneously, and the lung cancer tumor cells are divided into a negative control (blank), a single medicine treatment group and a combined treatment group after the tumor grows for 14 days. The medicine is injected intratumorally. The topoisomerase inhibitor is 5mg/kg, and the nitrosourea drug is 30 mg/kg. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 7).
TABLE 7
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Nitrosoureas drugs 56 <0.05
3(6) Etoposide 48 <0.01
4(6) Teniposide 42 <0.01
5(6) Aminorubicin 58 <0.01
6(6) Doxorubicin 48 <0.01
7(6) Nitrosoureas drug and etoposide 78 <0.001
8(6) Nitrosoureas drug + teniposide 74 <0.001
9(6) Nitrosoureas drug + amrubicin 80 <0.001
10(6) Nitrosoureas drug + doxorubicin 86 <0.001
The results show that the used nitrosourea drugs (carmustine) and topoisomerase inhibitors (etoposide, teniposide, amrubicin and doxorubicin) have obvious inhibition effect on the growth of a plurality of tumor cells when being used alone at the concentration, and can show obvious synergistic effect when being used in combination.
Further research shows that the combination of the topoisomerase inhibitors such as camptothecin, hydroxycamptothecin, topotecan, lurtotecan, irinotecan and the like and the carmustine, the nimustine or the nedaplatin has obvious synergistic effect (P is less than 0.05) on pancreatic cancer, colorectal cancer, esophagus cancer, gastric cancer and the like.
In conclusion, the nitrosoureas drugs and/or various topoisomerase inhibitors have obvious inhibition effect on the growth of various tumor cells when being used alone, and can show obvious synergistic effect when being used together. Therefore, the active ingredients of the invention are the combination of any nitrosourea drug and/or any topoisomerase inhibitor. 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) (BHET-EOP: TC is 80: 20) copolymer are respectively put into a container A, a container B and a container C, then 100 ml of dichloromethane is added into each copolymer, after dissolving and mixing evenly, 20mg of carmustine, 20mg of camptothecin, 10mg of carmustine and 10mg of camptothecin are respectively added, after shaking up again, injection microspheres containing 20% of carmustine, 20% of camptothecin, 10% of carmustine and 10% of camptothecin 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 sustained-release injection has the drug release time of 60-70 days in-vitro physiological saline and the drug release time of more than 65 days under the skin of a mouse.
Example 2.
The procedure of the process for preparing a sustained-release injection is the same as in example 1, except that the excipients used are 50:50 of p (BHET-EOP/TC), comprises the following effective anticancer components in percentage by weight: a combination of carmustine or nimustine 5-40% and camptothecin or hydroxycamptothecin 1-20%.
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 the p (LAEG-EOP) is dissolved and uniformly mixed, 30mg of carmustine, 30mg of camptothecin, 25mg of carmustine and 5mg of camptothecin are respectively added into the three containers, the three containers are uniformly shaken again, and then the spray drying method is used for preparing the microsphere for injection containing 30% of carmustine, 30% of camptothecin, 25% of carmustine and 5% of camptothecin. 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 65-70 days in-vitro physiological saline and the release time of about 70 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: 5-50% carmustine, nimustine or lomustine in combination with 5-30% camptothecin, hydroxycamptothecin or irinotecan.
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 fotemustine and 10mg of hydroxycamptothecin are added to the mixture, the mixture is shaken again and evenly, and then the spray drying method is used for preparing the microsphere for injection containing 30% of fotemustine and 10% of hydroxycamptothecin. 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 in vitro physiological saline of 60-65 days and the release time under the skin of a mouse of about 65 days.
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-:
5-30% fotemustine or samustine in combination with 1-40% hydroxycamptothecin or topotecan.
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 the p is dissolved and mixed evenly, 25mg of gammadectin and 5mg of camptothecin are added, the mixture is shaken up again and then spray drying is carried out to prepare the microspheres for injection containing 25 percent of gammadectin and 5 percent of camptothecin. 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 in vitro physiological saline of 60-65 days and the release time under the skin of a mouse of about 65 days.
Example 8.
The procedure for preparing a sustained-release injection was the same as in example 7, except that the peak molecular weight of p (BHDPT-EOP/TC) was 40000-65000, BHDPT-EOP: TC is 50:50, the anticancer active ingredients are:
a combination of 10-20% camptothecin and 10-30% gammostat.
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 to dissolve and mix evenly, 30mg of carmustine, 30mg of hydroxycamptothecin, 5mg of carmustine and 25mg of hydroxycamptothecin are respectively added to the mixture, and the mixture is shaken up again and then is prepared into microspheres containing 30% of carmustine, 30% of hydroxycamptothecin, 5% of carmustine and 25% of hydroxycamptothecin for injection 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 60-75 days in vitro physiological saline and the release time of 65 days under the skin of a mouse.
Example 10.
The procedure for preparing the sustained-release injection is the same as in example 9, except that the ratio of p-carboxyphenylpropane in polifeprosan: sebacic acid 50:50, the molecular weight peak value of p (DAPG-EOP) is 40000-:
5-40% carmustine or nimustine and 5-30% camptothecine or hydroxycamptothecin.
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 irinotecan and 20mg of carmustine 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 irinotecan and 20% of carmustine. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 60-65 days in-vitro physiological saline and the drug release time of about 65 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:
10-20% irinotecan or topotecan in combination with 5-30% carmustine or nimustine.
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 camptothecin are added, after shaking uniformly again, the microspheres for injection containing 10% of carmustine and 20% of camptothecin are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 60-70 days in-vitro physiological saline and the drug 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) 1-40% of nimustine or carmustine and 2-40% of camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide or teniposide; or
(2) 1-40% bendamustine, galamustine or ranimustine with 2-40% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide or teniposide; or
(3) 1-40% fotemustine, samustine or lomustine in combination with 2-40% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, ditobicin, esorubicin, casrubicin, roxobicin, epirubicin, medroxobin, nemorubicin, zorubicin or doxorubicin.
(4) 20-40% of camptothecin or hydroxycamptothecin and 10-20% of nimustine or carmustine.
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) 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-: 5050;
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 1000030000, 30000-60000, 60000-100000 or 100000-150000;
d) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) in combination with polifeprosan, wherein the ratio of p-carboxyphenylpropane (p-CPP) in the polifeprosan: sebacic Acid (SA) 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) 5-40% camptothecin, hydroxycamptothecin, topotecan, lurtotecan, irinotecan, etoposide or teniposide, and 5-30% bendamustine, galamustine, ranimustine, fotemustine, estramustine, samamustine, semustine or lomustine; or
(2) 5-30% of nimustine and 5-30% of camptothecin, hydroxycamptothecin, topotecan, lurtotecan, irinotecan, etoposide or teniposide; or
(3) 5-20% carmustine in combination with 5-30% camptothecin, hydroxycamptothecin, topotecan, lurtotecan, irinotecan, etoposide or teniposide.
Example 18 comparison of drug Release characteristics of different Release excipients and their combinations (Table 8)
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 8
Sustained release excipients Molecular weight Medicine and content Time of release (Tian) Whether there is a burst release
(1) PLA (2) PLGA (50/50) (3) polifeprosan (20/80) (4) p (LAEG-EOP) (1): 4): 1(2): 4): 1(3): 4): 1(5) PLA (6) PLGA (75/25) (7) polifeprosan (50/50) (8) p (DAPG-EOP) (5): 8): 6:4(6): 8): 7:3(7): 8): 5 10000-2500020000-4000020000-4000015000-3500025000-4500010000-2000010000-2000035000-55000 Camptothecin (20%) carmustine (10%) 2228106664626026251076706660 Whether or not it is present or not is not present or not
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 (more than 60 days) and stably, and when the polyphosphate ester high polymer is combined with the sugar anhydride high polymer such as PLA, PLGA, polifeprosan and the like, the burst release caused by the sugar anhydride high polymer can be reduced, but the stable and slow drug release characteristics are not greatly influenced. Since polyphosphate ester high molecular weight polymers are expensive, this discovery may be beneficial in reducing the cost of sustained release formulations.
Example 19 comparison of drug Release characteristics of different Release excipients and their combinations (Table 9)
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 9
Sustained release excipients Molecular weight Medicine and content Time of release (Tian) Whether there is a burst release
(1) PLA (2) PLGA (50/50) (3) polifeprosan (20/80) (4) p (LAEG-EOP) (1): 4): 1(2): 4): 1(3): 4): 1(5) PLA (6) PLGA (75/25) (7) polifeprosan (50/50) (8) p (DAPG-EOP) (5): 8): 6:4(6): 8): 7:3(7): 8): 5 20000-3500030000-4500020000-4000025000-4500025000-4500020000-4000020000-4000035000-55000 Hydroxycamptothecin (20%) nimustine (20%) 2432127066646226261268646260 Whether or not it is present or not is not present or not
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 (more than 60 days) and stably, and when the polyphosphate ester high polymer is combined with the sugar anhydride high polymer such as PLA, PLGA, polifeprosan and the like, the burst release caused by the sugar anhydride high polymer 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.
Since polyphosphate ester high molecular weight polymers are expensive, this discovery may be beneficial in reducing the cost of sustained release formulations.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (3)

  1. [ claim 1 ] an anticancer sustained-release injection containing nitrosourea drugs, which is characterized in that the sustained-release injection consists of the following components:
    the anticancer active components are 5% carmustine and 25% hydroxycamptothecin, the slow release auxiliary materials are 30% para-carboxyphenyl propane: sebacic acid is 20: polifeprosan 80 and p (DAPG-EOP) copolymer with 40% of molecular weight peak value of 30000-45000, the solvent is normal saline containing 1.5% of sodium carboxymethylcellulose, 15% of sorbitol and 0.2% of Tween 80.
  2. 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 originating 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 or animal.
  3. The sustained-release anticancer injection according to claim 1, wherein the sustained-release anticancer injection is administered by intratumoral or peritumoral injection or placement, and is sustained-released in vivo for more than 60 days.
CNA2008103046181A 2007-04-28 2007-04-28 Sustained-released injection containing carmustine of nitrosourea medicine Pending CN101385709A (en)

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