CN101011343A - Slow release injection containing anti-metabolism medicament and alkylating agent - Google Patents

Slow release injection containing anti-metabolism medicament and alkylating agent Download PDF

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CN101011343A
CN101011343A CNA2007102001884A CN200710200188A CN101011343A CN 101011343 A CN101011343 A CN 101011343A CN A2007102001884 A CNA2007102001884 A CN A2007102001884A CN 200710200188 A CN200710200188 A CN 200710200188A CN 101011343 A CN101011343 A CN 101011343A
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poly
release
terephthalate
sustained
ethyl phosphate
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张红军
邹会凤
俞建江
张婕
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Jinan Kangquan Medicine Science and Technology Co Ltd
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Jinan Kangquan Medicine Science and Technology Co Ltd
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Abstract

Disclosed is a slow release injection containing antimetabolites and/or alkylating agents, which comprises slow release microspheres and dissolvent, the slow release microspheres include antimetabolites selected from Tegafur, Capecittabine, Pemetrexed, Carmofur or Gemcitabine, and/or alkylating agent anticancer active constituents and slow release auxiliary materials, the dissolvent being conventional dissolvent or specific dissolvent containing suspension adjuvant. The viscosity of the suspension adjuvant is 100-3000cp (at 20-30 deg C), and is selected from sodium carboxymethylcellulose, the slow release auxiliary materials are selected from polyphosphate ester copolymers such as p(LAEG-EOP), p(DAPG-EOP), copolymer or blend of polyphosphate ester with PLA, Polifeprosan, poly(dodecanedioic acid-tetradecanedioic acid) or poly(fumaric acid-sebacylic acid). The alkylating agent is selected from Carmustine, Nimustine, Fotemustine, Lomustine or bendamustine. The anticancer composition can also be prepared into slow release implanting agent, for injection or placement in or around tumor with a period of effective concentration maintenance over 50 days, as well as the treatment effect of appreciably lowering general reaction of the drugs, and improving the treatment effect of the non-operative treatment methods such as chemotherapy.

Description

Slow-release injection containing antimetabolite and alkylating agent
(I) technical field
The invention relates to a sustained-release injection containing an antimetabolite and/or an alkylating agent and a preparation method thereof, belonging to the technical field of medicaments.
(II) background of the invention
As a common chemotherapeutic drug, antimetabolite drugs 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 hyperproliferating and have higher interstitial pressure, tissue elastic pressure, fluid pressure and interstitial viscosity than the surrounding normal tissues, it is difficult for conventional chemotherapy to achieve effective drug concentration locally in the tumor, see Kongqing et al, "Intra-tumor Carmustine plus systemic Carmustine for treating brain tumor in rats", J.J.Oncol.1998 Oct (Kong Q et al, J.Surg Oncol.1998 Oct; 69 (2): 76-82). In addition, blood vessels, connective tissues, matrix proteins, fibrin and collagen in tumor stroma not only provide a scaffold and essential nutrients for the growth of tumor cells, but also influence the penetration and diffusion of chemotherapeutic drugs around tumors and in tumor tissues (see Niti et al, "influence of extracellular stroma conditions on drug transport in solid tumors" [ Cancer research ] No. 60, 2497 and 503 (2000)) (Netti PA, Cancer Res.2000, 60 (9): 2497 and 503)). Therefore, simply increasing the dosage is limited by systemic reactions. The problem of drug concentration may be solved to some extent by the local application of drugs, however, the surgical operations such as drug implantation and the like are complicated, the wound is large, and besides various complications such as bleeding, infection, immunity reduction and the like are easily caused, the diffusion and metastasis of tumors can be caused or accelerated. In addition, the preparation itself before and after the operation and the high cost often affect the effective implementation.
In addition, DNA repair function in many tumor cells is significantly increased following chemotherapy. The latter often leads to an increased tolerance of the tumor cells to anticancer drugs, with consequent therapeutic failure. In addition, low dose anti-cancer drug therapy not only increases drug resistance but also promotes invasive growth of cancer cells (see beam et al, "increasing drug resistance and in vitro infiltration capacity of human lung cancer cells with alteration of gene expression after anti-cancer drug pulse screening" [ J.Immunol.Cancer, 111, et al, Int J cancer.2004; 111 (4): 484-93) ].
Therefore, it is an important issue to research a preparation and a method which can maintain a high drug concentration in a tumor part and increase the sensitivity of tumor cells to drugs, while being convenient for operation.
Disclosure of the invention
Aiming at the defects of the prior art, the invention provides an anti-cancer drug sustained-release preparation containing an anti-metabolism drug and/or an alkylating agent, in particular to a sustained-release injection or a sustained-release implant containing the anti-metabolism drug and/or the alkylating agent.
Antimetabolites are widely used at home and abroad as a new anticancer drug for treating various solid tumors. However, during the application process, the obvious systemic toxicity greatly limits the application of the medicine.
In order to effectively increase the local drug concentration of tumor and reduce the drug concentration of the drug in the circulatory system, a drug sustained-release system containing an antimetabolite drug 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 antimetabolites, and are susceptible to development of resistance during treatment.
The invention discovers that the anticancer effect of the alkylating agent and the antimetabolite can be mutually strengthened by combining the alkylating agent and the antimetabolite; in addition, the anti-metabolism medicament and the alkylating agent are combined to prepare the anti-cancer medicament sustained release preparation (mainly a sustained release injection and a sustained release implant), which not only can greatly improve the medicament concentration of local tumor, reduce the medicament concentration of the medicament in a circulatory system and reduce the toxicity of the medicament to normal tissues, but also can greatly facilitate medicament injection, reduce the complication 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 would cause a burst, it would be susceptible to global 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 antimetabolite sustained release preparation of the invention is sustained release injection, which consists of sustained release microspheres and a solvent. Specifically, the anticancer sustained-release injection consists of the following components:
(A) a sustained release microsphere comprising:
0.5-60% of anticancer active ingredient
Sustained release auxiliary materials 40-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active components are antimetabolites and/or alkylating agents.
The antimetabolite may be, but is not limited to, 6-mercaptopurine, pemetrexed, disodium pemetrexed, methotrexate, 5-fluorouracil, folic acid, lumitrexed, doxifluridine, fluorouracil, mercaptopurine, thioguanine, carmofur, tegafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoletabine, mitoquinone, mitotane, cytarabine, hydroxyurea, capecitabine, gemcitabine, fludarabine, raltitrexed, dexrazoxane, cladribine, nolatrexed, and pentoside.
The antimetabolites are preferably pemetrexed, methotrexate, 5-fluorouracil, carmofur, tegafur, decitabine, flurocitabine, enocitabine, cytarabine, capecitabine, gemcitabine, fludarabine, raltitrexed, cladribine, and nolatrexed, and most preferably pemetrexed, methotrexate, 5-fluorouracil, carmofur, tegafur, decitabine, cytarabine, capecitabine, and gemcitabine.
The weight percentage of the antimetabolite in the composition is 0.1-70%, preferably 1-50%, and most preferably 5-30%.
Alkylating agents include Estramustine (Alestramustine), amostine (Atrimustine), AMOMOTINE (Ambamustine), Nimustine (ACNU, Nimustine), Bendamustine (Bendamustine), dithiomostine (Ditiomustine), brivustine (Bofumustine), carmustine (carmustine, BCNU, carmustine), Elmustine (Elmustine), Ecomustine (Ecmustine), Galamustine (GCNU), Fotemustine (Fotemustine), Estramustine (Estramustine), medustine (Samustine, Hecnu), nemustine (MCpentamustine, Neptamustine), Mannomustine (Mannomustine, NU), lomustine (CCmustine, Numustine), Semustine (CCmustine, Nutrostine), Semustine (CCmustine, Nutromustine, Numustine, Nutmustine (CCmustine, Numustine, Nutrostine, Numustine, Nutmustine, Numustine, Numasusine (CCmustine, Numasusine, Tausine, Nutrossine, Numasusine, Tausine, One or a combination of Spiromustine (Spiromustine), Streptozocin (STZ), Mitozolomide (MTZ), ifosfamide and melphalam (melphalan).
The above alkylating agents also include their salts such as, but not limited to, sulfates, phosphates, hydrochlorides, lactobionates, acetates, aspartates, nitrates, citrates, purines or pyrimidines, succinates and maleates and the like.
The alkylating agent is preferably nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyl lomustine, midazolam, ifosfamide, melphalan.
The weight percentage of the alkylating agent in the sustained-release agent is 0.1-60%, preferably 1-50%, and most preferably 5-30%.
The weight percentage of the anti-tumor drug in the drug sustained-release microspheres is 0.5-70%, preferably 2-40%, and most preferably 5-30%. When used in combination, the weight ratio of the antimetabolite to the antimetabolite alkylating agent is from 1-9: 1 to 1: 1-9, preferably 1-2: 1 and 2-1: 1, 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:
(a) 1-40% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyl lomustine, midazolam, ifosfamide or melphalan; or
(b) 1-40% pemetrexed, methotrexate, 5-fluorouracil, carmofur, tegafur, decitabine, flurocitabine, enocitabine, cytarabine, capecitabine, gemcitabine, fludarabine, raltitrexed, cladribine, or nolatrexed; or
(c) 1-40% pemetrexed, methotrexate, 5-fluorouracil, carmofur, tegafur, decitabine, flurocitabine, enocitabine, cytarabine, capecitabine, gemcitabine, fludarabine, ranitidine, cladribine or nolatrexed in combination with 1-40% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyllomustine, midazolamine, ifosfamide or melphalan.
The viscosity range IV (dl/g) of the slow release auxiliary material is 0.05-1.8, preferably 0.1-1.4, and most preferably 0.1-1.4. The sustained-release excipients used in the present invention are selected from the group consisting of polyphosphates, polyphosphonates, polycycloalkylphosphates, ethyl phosphate (EOP), poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester, 80/20) (p (BHET-EOP/TC, 80/20)), p (BHET-EOP/TC, 50/50), poly (L-lactide-co-ethyl phosphate (p (LAEG-EOP)), poly (L-lactide-co-propyl phosphate) (p (DAPG-EOP)), trans (formula) -1, 4-dimethylcyclohexane (trans-1, 4-cyclohexanedimethanil, CHDM), hexyldichlorophosphate (hexyldichlorophosphate), HOP), 4-dimethylaminopyridine (4-dimethylaminopyridine, DMAP), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate hydrochloride, 80/20) (p (BHDPT-EOP/TC, 80/20)), p (BHDPT-EOP/TC, 50/50), poly (trans- (formula) -ethyl 1, 4-dimethylcyclohexane phosphate) (p (CHDM-HOP)), poly (trans- (formula) -1, 4-dimethylcyclohexylphosphorodichloridate (p (CHDM-EOP)), or a combination thereof.
Among the above phosphates, p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) and p (CHDM-EOP) are preferable.
The sustained-release auxiliary material used by the invention is also selected from the phosphate ester, the racemic polylactic acid (D, L-PLA), the racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), the monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), the monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), the polyethylene glycol/polylactic acid (PLA-PEG-PLA), the polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), the carboxyl-terminated polylactic acid (PLA-COOH), the carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), the polifeprosan, the copolymer of difatty acid and sebacic acid (PFAD-SA), the poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], the poly (fumaric acid-sebacic acid) [ P (FA-SA) ], the polymer, Ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), Polydioxanone (PDO), polytrimethylene carbonate (PTMC), xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin or a blend or copolymer of protein glue.
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 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-; the blending ratio of glycolic acid to hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight), and 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 the aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane sebacic acid) (P (CPP-SA)), difatty acid sebacic-diacid 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.
In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. The sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.
In addition to the above-mentioned adjuvants, other substances may be used as described in detail in U.S. Pat. No. 4757128 (4857311) (4888176 (4789724)) and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luomingsheng and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.
The content of the suspending agent depends on the composition, nature and required amount of the medicine suspended in the solvent, the sustained-release microsphere (or microcapsule), the preparation method of the injection, the kind and composition of the suspending agent, for example, the content of the sodium carboxymethylcellulose can be 0.5-5%, but is preferably 1-3%, the content of mannitol and/or sorbitol is 5-30%, but is preferably 10-20%, and the content of tween 20, tween 40 or tween 80 is 0.05-2%, but is preferably 0.10-0.5%. In most cases, the sustained-release particles are composed of active ingredients and sustained-release excipients, and the solvent is a special solvent. When the solvent is common solvent, the suspended drug or sustained release microsphere (or microcapsule) is composed of effective components, sustained release adjuvant and/or suspending agent. In other words, when the suspending agent in sustained release particle (A) is "0", solvent (B) is a special solvent, and when the suspending agent in sustained release particle (A) is not "0", solvent (B) can be a common solvent or a special solvent. The viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃).
The common solvent can be, but is not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared from various salts, and the pharmacopoeia has corresponding regulations; the special solvent in the invention is a common solvent containing a suspending agent, and the suspending agent can be, but is not limited to, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, a surfactant, tween 20, tween 40 and tween 80 or a combination thereof. The content of the suspending agent in the special solvent is 0.1-30% by volume weight, preferably as follows:
(a) 0.5-5% sodium carboxymethylcellulose; or
(b) 0.5-5% sodium carboxymethylcellulose and 0.1-0.5% tween 80; or
(c) 5-20% mannitol; or
(d) 5-20% mannitol and 0.1-0.5% tween 80; or (b).
(e) 0.5-5% of sodium carboxymethylcellulose, 5-20% of sorbitol and 0.1-0.5% of tween 80.
The above-mentioned all are volume weight percentages, and the weight of suspending agent contained in unit volume of common solvent is the same as that in the following formula of g/ml, 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 anticancer drug and the alkylating agent, can be granulated separately and then mixed together as required to form a dosage form, which process at least comprises 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:
(a) 5-30% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyl lomustine, midazolam, ifosfamide or melphalan; or
(b) 5-50% pemetrexed, methotrexate, 5-fluorouracil, carmofur, tegafur, decitabine, flurocitabine, enocitabine, cytarabine, capecitabine, gemcitabine, fludarabine, raltitrexed, cladribine, or nolatrexed; or
(c) 1-40% pemetrexed, methotrexate, 5-fluorouracil, carmofur, tegafur, decitabine, flurocitabine, enocitabine, cytarabine, capecitabine, gemcitabine, fludarabine, ranitidine, cladribine or nolatrexed in combination with 1-30% nimustine, carmustine, bendamustine, galamustine, ranimustine, fotemustine, estramustine, samustine, semustine, lomustine, methyllomustine, midazolamine, ifosfamide or melphalan.
The sustained-release injection prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic, anticoagulant, hemostatic, etc.
The technical process of the invention is further described by the following tests and examples:
test 1 comparison of local drug concentrations after different modes of Fluorouracil application
Using white rat as test object, 2X 105Injecting brain tumor cells into the affected partThe ribs, which were grouped after the tumor had grown to a diameter of 1 cm. The dose of each group was 5 mg/kg. The results of the determination of the content (%) of the medicament in the tumor at different times show that the local medicament concentration difference of the fluorouracil applied in different modes is obvious, the local administration can obviously improve and effectively maintain the effective medicament concentration of the part where the tumor is located, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. This finding constitutes an important feature of the present invention. This is further confirmed by the following relevant tumor inhibition test.
Experiment 2 comparison of in vivo tumor inhibition effects of fluorouracil applied in different ways
Using white rat as test object, 2X 105Individual pancreatic tumor cells were injected subcutaneously into the quaternary costal region and grouped after tumors grew to 0.5 cm diameter. 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 fluorouracil applied in different modes is obvious, the effective drug concentration of the tumor part can be obviously improved and effectively maintained by local administration, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. Not only has good curative effect, but also has little toxic and side effect.
Test 3 anti-tumor Effect of anti-metabolites and alkylating agents (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. 5mg/kg of alkylating agent and 30mg/kg of antimetabolite. 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) Antimetabolites 58 ＜0.05
3(6) Carmustine 50 ＜0.01
4(6) Nimustine 52 ＜0.01
5(6) Lomustine 48 ＜0.01
6(6) Fotemustine 52 ＜0.01
7(6) Antimetabolites + carmustine 72 ＜0.001
8(6) Antimetabolites + nimustine 78 ＜0.001
9(6) Antimetabolites + lomustine 82 ＜0.001
10(6) Antimetabolites + fotemustine 80 ＜0.001
The results show that the antimetabolite (fluorouracil) and the alkylating agent (carmustine, nimustine, lomustine, fotemustine) have obvious inhibition effect on the growth of a plurality of tumor cells when being used at the concentration independently, and can show obvious synergistic effect when being used in combination.
Test 4 antitumor Effect of antimetabolite and alkylating agent (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. 5mg/kg of alkylating agent and 20mg/kg of antimetabolite. Tumor volume size was measured on day 20 post treatmentThe therapeutic effect was compared using the tumor growth inhibition rate as an index (see table 2).
TABLE 2
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Antimetabolites 58 ＜0.05
3(6) Carmustine 50 ＜0.05
4(6) Nimustine 48 ＜0.05
5(6) Fotemustine 56 ＜0.05
6(6) Bendamustine 52 ＜0.01
7(6) Antimetabolites + carmustine 86 ＜0.01
8(6) Antimetabolites + nimustine 84 ＜0.01
9(6) Antimetabolites + fotemustine 80 ＜0.01
10(6) Antimetabolites + bendamustine 82 ＜0.001
The results show that the antimetabolite (methotrexate) and the alkylating agent (carmustine, nimustine, fotemustine and bendamustine) 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 together.
Test 5 antitumor Effect of antimetabolite and alkylating agent (sustained Release injection)
Using white rat as test object, 2X 105Injecting tumor cells of individual rectal cancer into the seasonOn the flank, the tumor was classified into negative control (blank), single-drug treatment group, and combination treatment group 14 days after growth. The medicine is injected intratumorally. 5mg/kg of alkylating agent and 30mg/kg of antimetabolite. The volume of the tumor was measured on day 30 after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see table 3).
TABLE 3
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Antimetabolites 48 ＜0.05
3(6) Carmustine 50 ＜0.01
4(6) Nimustine 52 ＜0.01
5(6) Bendamustine 48 ＜0.01
6(6) Fotemustine 52 ＜0.01
7(6) Antimetabolites + carmustine 72 ＜0.001
8(6) Antimetabolites + nimustine 78 ＜0.001
9(6) Antimetabolites + bendamustine 82 ＜0.001
10(6) Antimetabolites + fotemustine 84 ＜0.001
The results show that the antimetabolite (carmofur) and the alkylating agent (carmustine, nimustine, bendamustine and fotemustine) 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 jointly.
Test 6 antitumor Effect of antimetabolite and alkylating agent (sustained Release injection)
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. 5mg/kg of alkylating agent and 30mg/kg of antimetabolite. 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) Antimetabolites 58 ＜0.05
3(6) Carmustine 50 ＜0.05
4(6) Nimustine 48 ＜0.05
5(6) Fotemustine 56 ＜0.05
6(6) Bendamustine 52 ＜0.01
7(6) Antimetabolites + carmustine 88 ＜0.01
8(6) Antimetabolites + nimustine 82 ＜0.01
9(6) Antimetabolites + fotemustine 90 ＜0.01
10(6) Antimetabolites + bendamustine 92 ＜0.001
The results show that the antimetabolite (tegafur) and the alkylating agent (carmustine, nimustine, fotemustine, bendamustine) have obvious inhibition effect on the growth of a plurality of tumor cells such as esophagus cancer, gastric cancer and the like when being used independently at the concentration, and can show obvious synergistic effect when being used together.
Test 7 antitumor Effect of antimetabolite and alkylating agent (sustained Release implant)
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. The alkylating agent is 10mg/kg, and the antimetabolite 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 5.
TABLE 5
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Antimetabolites 50 ＜0.05
3(6) Carmustine 58 ＜0.01
4(6) Nimustine 56 ＜0.01
5(6) Bendamustine 46 ＜0.01
6(6) Fotemustine 50 ＜0.01
7(6) Antimetabolites + carmustine 86 ＜0.001
8(6) Antimetabolites + nimustine 84 ＜0.001
9(6) Antimetabolites + bendamustine 78 ＜0.001
10(6) Antimetabolites + fotemustine 80 ＜0.001
The results show that the antimetabolite (gemcitabine) and the alkylating agent (carmustine, nimustine, bendamustine and fotemustine) have obvious inhibition effect on the growth of the hepatoma tumor cells when being applied independently at the concentration, and can show obvious synergistic effect when being applied in combination.
Test 8 antitumor Effect of antimetabolite and alkylating agent (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. 15mg/kg of alkylating agent and 10mg/kg of antimetabolite. 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) Antimetabolites 58 ＜0.05
3(6) Carmustine 50 ＜0.05
4(6) Nimustine 48 ＜0.05
5(6) Fotemustine 56 ＜0.05
6(6) Bendamustine 52 ＜0.01
7(6) Antimetabolites + carmustine 78 ＜0.01
8(6) Antimetabolites + nimustine 80 ＜0.01
9(6) Antimetabolites + fotemustine 88 ＜0.01
10(6) Antimetabolites + bendamustine 82 ＜0.001
The results show that the antimetabolite (capecitabine) and the alkylating agent (carmustine, nimustine, fotemustine and bendamustine) have obvious inhibition effect on the growth of the brain tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used together
Further research shows that the combination of alkylating agents such as carmustine, fotemustine, nimustine, lomustine, bendamustine or zeniplatin and fluorouracil, capecitabine or gemcitabine has obvious synergistic effect (P is less than 0.05) on pancreatic cancer, colorectal cancer, esophageal cancer, gastric cancer and the like.
In conclusion, the antimetabolite and/or various alkylating agents 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 described in the present invention are a combination of any one of the antimetabolites and/or any one of the alkylating agents. The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein suspension injection formed by combining with special solvent containing suspending agent is preferred.
The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.
(IV) detailed description of the preferred embodiments
Example 1.
80, 80 and 80mg of p (BHET-EOP/TC) (the BHET-EOP: TC is 80: 20) copolymer is 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 fluorouracil, 20mg of carmustine, 10mg of fluorouracil and 10mg of carmustine are respectively added, after shaking up again, the microspheres for injection containing 20% of fluorouracil, 20% of carmustine, 10% of fluorouracil and 10% of carmustine are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 15 percent of mannitol to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 50-60 days in-vitro physiological saline and the release time of more than 50 days under the skin of a mouse.
Example 2.
The steps of the method for processing the sustained-release injection are the same as the example 1, but the difference is that the used auxiliary material is p (BHET-EOP/TC) with the ratio of 50: 50, the anticancer active ingredients and the weight percentage thereof are as follows:
(1) 2-30% carmustine or nimustine;
(2) 5-40% fluorouracil, tegafur or capecitabine; or
(3) A combination of fluorouracil, tegafur or capecitabine 5-40% and carmustine 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 dissolving and mixing evenly, 30mg of fluorouracil, 30mg of nimustine, 25mg of fluorouracil and 5mg of nimustine are respectively added into the three containers, after shaking evenly again, the microspheres for injection containing 30% of fluorouracil, 30% of nimustine, 25% of fluorouracil and 5% of nimustine are prepared by a spray drying method. Suspending the dried microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 55-60 days in vitro physiological saline and the release time of about 60 days under the skin of a mouse.
Example 4
The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is that the molecular weight peak value of p (LAEG-EOP) is 25000-45000, and the anticancer active ingredients and the weight percentage thereof are as follows:
(1) 5-30% carmustine, nimustine or bendamustine; or
(2) 5-60% fluorouracil, methotrexate, carmofur or gemcitabine; or;
(3) a combination of 5-50% fluorouracil, methotrexate, carmofur or gemcitabine and 5-30% carmustine, nimustine or bendamustine.
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 carmofur and 10mg of nimustine are added to the mixture, and the mixture is shaken up again to prepare microspheres for injection containing 30 carmofur and 10% of nimustine by a spray drying method. Then suspending the microspheres in injection containing 15 percent of sorbitol to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 50-55 days in-vitro physiological saline and the release time of about 55 days under the skin of a mouse.
Example 6.
The steps of the method for processing the sustained-release injection are the same as the example 5, but the difference is that the molecular weight peak value of the used auxiliary materials is 25000-:
(1) 5-30% of carmofur or tegafur; or
(2) 1-40% of nimustine or fotemustine; or
(3) A combination of carmofur or tegafur in an amount of 5-30% and nimustine or fotemustine in an amount of 1-40%.
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 capecitabine and 5mg of carmustine are added, the mixture is shaken up again, and then the spray drying method is used for preparing the microsphere for injection containing 25 percent of capecitabine and 5 percent of carmustine. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 50-55 days in-vitro physiological saline and the release time of about 55 days under the skin of a mouse.
Example 8.
The procedure of the method for preparing the sustained-release injection is the same as that of example 7, except that the peak value of the molecular weight of p (BHDPT-EOP/TC) is 40000-65000, the peak value of the molecular weight of BHDPT-EOP: TC is 50: 50, and the anti-cancer active ingredients are as follows:
(1) 10-20% carmustine;
(2) 10-30% capecitabine; or
(3) A combination of 10-20% carmustine and 10-30% capecitabine.
Example 9.
30mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) and 40mg of p (DAPG-EOP) copolymer with the molecular weight peak value of 30000-45000 are put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed uniformly, 30mg of gemcitabine, 30mg of nimustine, 5mg of gemcitabine and 25mg of nimustine are respectively added, and after the mixture is shaken again, microspheres containing 30% of gemcitabine, 30% of nimustine, 5% of gemcitabine and 25% of nimustine for injection are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 50-55 days in-vitro physiological saline and the release time of about 55 days under the skin of a mouse.
Example 10.
The steps of the method for processing the sustained-release injection are the same as the example 9, but the difference is that the ratio of the p-carboxyphenylpropane to the sebacic acid in the polifeprosan is 50: 50, the molecular weight peak value of p (DAPG-EOP) is 40000-65000, and the anticancer active ingredients are:
(1) 5-50% gemcitabine;
(2) 10-30% nimustine;
(3) a combination of 5-40% gemcitabine and 5-30% nimustine.
Example 11
40mg of (LAEG-EOP) copolymer with a molecular weight peak value of 20000-45000p and 30mg of PLA copolymer with a molecular weight peak value of 10000-25000 p are placed in a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of bendamustine and 20mg of gemcitabine are added, after re-shaking uniformly, injection microspheres containing 10% of bendamustine and 20% of gemcitabine 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 50-55 days in-vitro physiological saline and the drug release time of about 60 days under the skin of a mouse.
Example 12
The steps of the method for processing the sustained-release implant are the same as the example 11, but the difference is that the used auxiliary materials are (LAEG-EOP) with the molecular weight peak value of 40000-65000p and PLA with the molecular weight peak value of 25000-45000, and the anti-cancer active ingredients are as follows:
(1) 10-20% bendamustine; or
(2) 10-40% gemcitabine; or
(3) 10-20% bendamustine in combination with 10-30% gemcitabine.
Example 13
40mg of polylactic acid (PLGA, 50: 50) with a molecular weight peak of 15000-35000 and 30mg of (LAEG-EOP) with a molecular weight peak of 20000-45000p are put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of pemetrexed and 20mg of carmustine are added, after shaking uniformly again, the microspheres for injection containing 10% of pemetrexed and 20% of carmustine are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 50-60 days in vitro physiological saline and the release time of about 60 days under the skin of a mouse.
Example 14
The procedure for manufacturing the sustained-release implant was the same as in examples 11 and 13, except that the anticancer active ingredient contained:
(1) 10-20% carmustine or nimustine; or
(2) 10-20% pemetrexed or fluorouracil; or
(3) 10-20% carmustine or nimustine in combination with 10-20% pemetrexed or fluorouracil.
Example 15
The procedure of processing into sustained release preparation is the same as that of examples 1-14, except that the sustained release excipient is one or a combination of the following:
a) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP);
b) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer (PLGA) of polyglycolic acid and glycolic acid having a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) with polylactic acid (PLA) having a molecular weight peak of 10000-;
d) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or a combination of p (CHDM-EOP) and polifeprosan, wherein the ratio of p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) in the polifeprosan is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) p (BHET-EOP/TC), P (LAEG-EOP), P (DAPG-EOP), P (BHDPT-EOP/TC), P (CHDM-HOP) or P (CHDM-EOP) in combination with a di-fatty acid and sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], xylitol, oligosaccharides, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or gelatin.
Example 16.
The procedure for preparing a sustained release injection is the same as in examples 1 to 15, except that the suspending agent used is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20.
Example 17
The procedure for manufacturing the sustained-release implant was the same as in examples 11 and 13, except that the anticancer active ingredient contained:
(1) 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine; or
(2) 10-40% fluorouracil, tegafur, capecitabine, methotrexate, pemetrexed, carmofur or gemcitabine; or
(3) A combination of 5-25% fluorouracil, tegafur or capecitabine with 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine; or
(4) 5-25% methotrexate, carmofur, pemetrexed or gemcitabine in combination with 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine.
Example 18 comparison of drug Release characteristics of different Release excipients and their combination (Table 7)
The procedure of the method for manufacturing the sustained-release implant is the same as that of example 11, and the release characteristics of different sustained-release excipients and the combined sustained-release excipients are compared. The first day of drug release (in vitro) exceeds 20% of the total is burst release.
TABLE 7
Sustained release excipients Molecular weight Medicine and content Time of release (Tian) Whether there is a burst release
(1)PLA 10000-25000 Carmustine (20%) 22 Is free of
(2)PLGA(50/50) 20000-40000 Carmustine (20%) 28 Is free of
(3) Polifeprosan (20/80) 20000-40000 Carmustine (20%) 10 Is provided with
(4)p(LAEG-EOP) 15000-35000 Carmustine (20%) 66 Is free of
(1)∶(4)＝1∶1 Carmustine (20%) 64 Is free of
(2)∶(4)＝1∶1 Carmustine (20%) 62 Is free of
(3)∶(4)＝1∶1 Carmustine (20%) 56 Is free of
(5)PLA 25000-45000 Fluorouracil (40%) 26 Is free of
(6)PLGA(75/25) 10000-20000 Fluorouracil (40%) 25 Is free of
(7) Polifeprosan (50/50) 10000-20000 Fluorouracil (40%) 10 Is provided with
(8)p(DAPG-EOP) 35000-55000 Fluorouracil (40%) 56 Is free of
(5)∶(8)＝6∶4 Fluorouracil (40%) 54 Is free of
(6)∶(8)＝7∶3 Fluorouracil (40%) 52 Is free of
(7)∶(8)＝5∶5 Fluorouracil (40%) 50 Is free of
The data in the table show that when the anhydroglucose high-molecular polymers such as PLA, PLGA (50/50), polifeprosan (20/80) and the like are independently applied, the drug release is fast, wherein the drug release time of the polifeprosan is 8-10 days and the polifeprosan has obvious burst release. The polyphosphate ester high molecular polymers such as p (LAEG-EOP) and p (DAPG-EOP) are slow and stable in drug release, and when the polyphosphate ester high molecular polymers are combined with the sugar anhydride high molecular polymers such as PLA, PLGA and polifeprosan, the burst release caused by the sugar anhydride high molecular polymers can be reduced, but the stable and slow drug release characteristics are not greatly influenced. 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 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 20000-35000 Nimustine (20%) 24 Is free of
(2)PLGA(50/50) 30000-45000 Nimustine (20%) 32 Is free of
(3) Polifeprosan (20/80) 20000-40000 Nimustine (20%) 12 Is provided with
(4)p(LAEG-EOP) 25000-45000 Nimustine (20%) 60 Is free of
(1)∶(4)＝1∶1 Nimustine (20%) 58 Is free of
(2)∶(4)＝1∶1 Nimustine (20%) 56 Is free of
(3)∶(4)＝1∶1 Nimustine (20%) 52 Is free of
(5)PLA 25000-45000 Carbone fluoride (30%) 26 Is free of
(6)PLGA(75/25) 20000-40000 Carbone fluoride (30%) 26 Is free of
(7) Polifeprosan (50/50) 20000-40000 Carbone fluoride (30%) 12 Is provided with
(8)p(DAPG-EOP) 35000-55000 Carbone fluoride (30%) 58 Is free of
(5)∶(8)＝6∶4 Carbone fluoride (30%) 54 Is free of
(6)∶(8)＝7∶3 Carbone fluoride (30%) 52 Is free of
(7)∶(8)＝5∶5 Carbone fluoride (30%) 50 Is free of
The data in the table show that when the anhydroglucose high-molecular polymers such as PLA, PLGA (50/50), polifeprosan (20/80) and the like are independently applied, the drug release is fast, wherein the drug release time of the polifeprosan is 8-10 days and the polifeprosan has obvious burst release. The polyphosphate ester high molecular polymers such as p (LAEG-EOP) and p (DAPG-EOP) are slow and stable in drug release, and when the polyphosphate ester high molecular polymers are combined with the sugar anhydride high molecular polymers such as PLA, PLGA and polifeprosan, the burst release caused by the sugar anhydride high molecular polymers can be reduced, but the stable and slow drug release characteristics are not greatly influenced. This unexpected finding constitutes a further main technical feature of the present invention. Because the polyphosphate ester high molecular polymer is expensive, the cost of the sustained-release preparation can be reduced, and the drug release characteristic of the sustained-release preparation can be improved.
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 (10)

1. An anticancer sustained-release injection containing antimetabolite is characterized in that the sustained-release injection consists of the following components:
(A) a sustained release microsphere comprising:
0.5-60% of anticancer active ingredient
Sustained release auxiliary materials 40-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active ingredients are antimetabolites and/or alkylating agents;
the slow release auxiliary material is selected from phosphate ester high molecular polymer or the mixture or copolymer of the phosphate ester high molecular polymer and the polysaccharide anhydride high molecular polymer:
the antimetabolites are mainly selected from 6-mercaptopurine, pemetrexed disodium, methotrexate, 5-fluorouracil, folic acid, lumitrexed, doxifluridine, fluorouracil, mercaptopurine, thioguanine, carmofur, tegafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoletabine, mitoquinone, mitotane, cytarabine, hydroxyurea, capecitabine, gemcitabine, fludarabine, raltitrexed, dexrazoxane, cladribine, nolatrexed and pentoside;
the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), and is selected from one or more of sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40 and Tween-80.
2. The sustained-release injection of anticancer drug according to claim 1, characterized in that the alkylating agent is selected from carmustine, nimustine, carmustine, denatoplatin, ennimostine, epithioplatin, cis-spiroplatin, fotemustine, iproplatin, nimustine, fotemustine, lomustine, bendamustine, spiroplatin or zeniplatin.
3. The sustained-release anticancer injection according to claim 1, wherein the anticancer active ingredients of the sustained-release anticancer injection are:
(1) 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine; or
(2) 10-40% fluorouracil, tegafur, capecitabine, methotrexate, pemetrexed, carmofur or gemcitabine; or
(3) A combination of 5-25% fluorouracil, tegafur or capecitabine with 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine; or
(4) 5-25% methotrexate, carmofur, pemetrexed or gemcitabine in combination with 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine.
The above are all weight percentages.
The slow release auxiliary material is one or the combination of the following materials:
a) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate), or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP));
b) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)) with a copolymer of polyglycolic acid and glycolic acid, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) a combination of poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate), or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)) with polylactic acid;
d) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans) -1, 4-dimethylcyclohexane-hexylphosphorodiamidate (p (CHDM-EOP)) with polifeprosan, wherein the ratio of p-carboxyphenylpropane to sebacic acid in polifeprosan is 10: 90, 20: 80, 30: 70, p-xylylene-p-hexylphosphorate (p (CHDM-EOP)) and polifeprosan, 40: 60, 50: 50 or 60: 40; or
e) Poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans) -1, 4-dimethylcyclohexane-hexyldichlorophosphate (p (CHDM-EOP)) with a copolymer of di-fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), Xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or egg gelatin.
4. The sustained-release anticancer injection according to claim 1, wherein the suspending agent is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20; or
f) Glycerin, dimethicone, propylene glycol, or carbomer.
5. The sustained-release anticancer injection according to claim 1, wherein the suspending agent is one of the following:
A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;
B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
6. The anticancer sustained release microspheres of claim 1, used for preparing sustained release implant.
7. The sustained-release anticancer implant according to claim 6, characterized in that the anticancer active ingredients are:
(1) 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine; or
(2) 10-40% fluorouracil, tegafur, capecitabine, methotrexate, pemetrexed, carmofur or gemcitabine; or
(3) A combination of 5-25% fluorouracil, tegafur or capecitabine with 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine; or
(4) 5-25% methotrexate, carmofur, pemetrexed or gemcitabine in combination with 5-20% carmustine, nimustine, fotemustine, lomustine or bendamustine.
The slow release auxiliary material is selected from phosphate ester high molecular polymer or the mixture or copolymer of phosphate ester high molecular polymer and polysaccharide anhydride high molecular polymer.
8. The sustained-release anticancer implant according to claim 6, characterized in that the sustained-release excipients are selected from one of the following:
a) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate), or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP));
b) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)) with a copolymer of polyglycolic acid and glycolic acid, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) a combination of poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate), or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)) with polylactic acid;
d) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans) -1, 4-dimethylcyclohexane-hexylphosphorodiamidate (p (CHDM-EOP)) with polifeprosan, wherein the ratio of p-carboxyphenylpropane to sebacic acid in polifeprosan is 10: 90, 20: 80, 30: 70, p-xylylene-p-hexylphosphorate (p (CHDM-EOP)) and polifeprosan, 40: 60, 50: 50 or 60: 40; or
e) Poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans) -1, 4-dimethylcyclohexane-hexyldichlorophosphate (p (CHDM-EOP)) with a copolymer of di-fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), Xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or egg gelatin.
9. The sustained-release anticancer injection according to claim 1, wherein the active ingredients of the sustained-release anticancer injection are used for preparing a pharmaceutical preparation for treating primary or secondary cancer, sarcoma or carcinosarcoma originated from brain, central nervous system, kidney, liver, gallbladder, head and neck, oral cavity, thyroid, skin, mucosa, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon or rectum of human and animal.
10. The sustained-release injection and sustained-release injection as claimed in claims 1 and 6, wherein the sustained-release injection is administered by intratumoral or peritumoral injection or placement, and is sustained-released in vivo for more than 50 days.
CNA2007102001884A 2007-02-12 2007-02-12 Slow release injection containing anti-metabolism medicament and alkylating agent Pending CN101011343A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111840547A (en) * 2020-06-15 2020-10-30 山西振东泰盛制药有限公司 Preparation method of pemetrexed magnetic self-assembly nano composite particles for injection

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111840547A (en) * 2020-06-15 2020-10-30 山西振东泰盛制药有限公司 Preparation method of pemetrexed magnetic self-assembly nano composite particles for injection
CN111840547B (en) * 2020-06-15 2023-04-28 山西振东泰盛制药有限公司 Preparation method of pemetrexed magnetic self-assembled nano composite particles for injection

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