CN101019828A - Anticancer composition containing both phosphoinositide-3-kinase inhibitor and hormone medicine - Google Patents

Anticancer composition containing both phosphoinositide-3-kinase inhibitor and hormone medicine Download PDF

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CN101019828A
CN101019828A CNA2007102003184A CN200710200318A CN101019828A CN 101019828 A CN101019828 A CN 101019828A CN A2007102003184 A CNA2007102003184 A CN A2007102003184A CN 200710200318 A CN200710200318 A CN 200710200318A CN 101019828 A CN101019828 A CN 101019828A
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eop
release
sustained
chdm
octadecyl
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张红军
邹会凤
俞建江
张婕
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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

The slow released anticancer injection containing both phosphoinositide-3-kinase inhibitor and/or hormone medicine consists of slow released microsphere and solvent. The slow released microsphere includes effective anticancer component and slow releasing supplementary material, and the solvent is common solvent or special solvent containing suspending agent. The suspending agent is sodium carboxymethyl cellulose, etc. and has viscosity of 100-3000 cp at 20-30 deg.c. The slow releasing supplementary material is p(LAEG-EOP), p(DAPG-EOP), p(BHET-EOP/TC), p(BHET-EOP/TC), p(BHDPT-EOP/TC), p(BHDPT-EOP/TC), p(CHDM-HOP), p( CHDM-EOP), etc. The anticancer composition may be also prepared into slow released implanting agent for use alone or together with chemotherapeutic and/or radiotherapeutic medicine to strengthen the treatment effect.

Description

Anticancer composition containing phosphoinositide 3-kinase inhibitor and hormone medicine
(I) technical field
The invention relates to an anticancer composition containing phosphoinositide 3-kinase inhibitor and/or hormone medicine, which is an anticancer sustained-release injection and sustained-release implant and belongs to the technical field of medicines.
(II) background of the invention
As a common chemotherapeutic medicament, phosphoinositide 3-kinase inhibitor is widely applied to the treatment of various malignant tumors, and has obvious effect. However, its significant toxic effects greatly limit the wide use of this class of drugs.
Due to the fact that solid tumors are excessively expanded and proliferated, the interstitial pressure, the tissue elastic pressure, the fluid pressure and the interstitial viscosity of the solid tumors are higher than those of surrounding normal tissues, and therefore, effective drug concentration is difficult to form locally on the tumors through conventional chemotherapy. 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 anti-cancer medicine composition containing a phosphoinositide 3-kinase inhibitor and hormone medicines aiming at the defects of the prior art, and particularly relates to an anti-cancer sustained-release injection or sustained-release implant containing the phosphoinositide 3-kinase inhibitor and the hormone medicines.
Phosphoinositide 3-kinase inhibitors have been 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 the drug in the circulatory system, a drug sustained-release system containing phosphoinositide 3-kinase inhibitor 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 nano-particles (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 phosphoinositide 3-kinase inhibitors, and are susceptible to development of resistance during treatment.
The invention discovers that the anticancer effect of the hormone medicine and the phosphoinositide 3-kinase inhibitor can be mutually strengthened by combining the hormone medicine and the phosphoinositide 3-kinase inhibitor; in addition, the anticancer drug sustained release preparation (mainly sustained release injection and sustained release implant) prepared by combining the phosphoinositide 3-kinase inhibitor and the hormone drug not only can greatly improve the local drug concentration of the tumor, reduce the drug concentration of the drug in the circulatory system and reduce the toxicity of the drug to normal tissues, but also can greatly facilitate the drug injection, reduce the complications of the operation and reduce the cost of patients. The above unexpected findings constitute the subject of the present invention.
The present invention also found that not all sustained-release excipients can achieve sustained-release effect of effective release in terms of ingredients having anticancer activity such as phosphoinositide 3-kinase inhibitors and hormonal drugs. 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 phosphoinositide 3-kinase inhibitor sustained release preparation 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:
0.5-70% of anticancer active ingredient
Sustained release auxiliary materials 30-99%
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 component is phosphoinositide 3-kinase inhibitor and/or hormone medicine.
Phosphoinositide 3-kinase (abbreviated as PI3K) inhibitor (PI3Ki) is selected from 7-hydroxy-staurosporine (7-hydroxy-staurosporine, UCN-01), 7-O-alkyl-staurosporine (UCN-02), beta-methoxystaurosporine, alkylphosphocholines (alkylphosphocholines), hexadecylphosphocholine (hexadecylphosphocholines, MIL, HPC, Miltefosine), Octadecyl- (1, 1-dimethyl-4-piperidine) phosphate (octadecoyl- (1, 1-dimethyl-4-piperidino) phosphate, perifosine, D-21266), 1-O-hexadecyl-2-O-methyl-rac-propyl-3-phosphocholine (AMG-PC, 1-O-hexa-2-phosphocholine-3-phosphate, ET-16-OCH3), 1-O-Octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine (1-O-Octadecyl-2-O-methyl-rac-glycerylphosphocholine, ET-18-OCH3, edelfosine), 1-O-Octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine (1-O-octacycloalkyl-2-O-methyl-methylon-glycerylphosphine-3-phosphocholine, ilmofosine, L-ET-18-OCH (3)), inositol polyphosphates (inositols), cyclosporin A (Cyclosporine A), tetradecyl phosphocholine (Tetradecylphosphine, Hexadecylphosphine (N-N-trimethyl-hexylethanolamine (N-trimethyl-methoamine), HPC6), Octadecyl Phosphorylcholine (OPC) or octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate (octadecyl- [2- (N-methylpiperidino) ethyl ] -phosphate, D-20133 or OMPEP).
7-hydroxyl-astrosporin, 7-O-alkyl-astrosporin, beta-methoxystaurosporine, alkyl phosphorylcholine, hexadecyl phosphorylcholine (Miltefosine), octadecyl- (1, 1-dimethyl-4-piperidine) phosphate (perifosine), 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine (edelfosine), 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphorylcholine (inositol), inositol polyphosphate, cyclosporin A, tetradecyl phosphorylcholine, Hexadecylphosphonic acid (N-N-trimethyl) hexanolamine, octadecylphosphocholine or octadecylphosphonic acid [2- (N-methylpiperidine) ethyl ] -phosphate are preferred.
The content of the phosphoinositide 3-kinase inhibitor in the composition is 0.01-60%, preferably 1-40%, and most preferably 2-30%, all of which are weight percentages.
Hormonal anticancer drugs are mainly steroid hormones and hormone antagonists including, but not limited to, anastrozole (anastrozole), idoxifene (idoxifene), milbexifene (Miproxifene), tamoxifen (tamoxifen ), 4-monohydroxytamoxifen (trans-4-monohydroxytamoxifen, OH-TAM), moxifene (keoxifene, LY156758), steroidal anti-estra (ICI164384, 7- α -alkylamide analogue of estradiol), 7- α - [9- (4, 4, 5, 5-pentafluoropentylsulfinyl) nonyl ] estra-1, 3, 5(10) -triene-3, 17 β -diol (anticancer sterenol, fulvestrant, 7- [9- (4, 4, 5, 5, 5-pentafluoropentylsulene) finyl ] beta-1, 3, 5, 17-alpha-diol (anticancer sterenol, fulvestrant, 7- [9- (4, 4, 5, 5, 5-pentafluoropentylsulene) triene ] 1, 3, 17-alpha-1, 3, 17-alpha-diol, ICI 182780), 4-hydroxytamoxifen (4-hydroxytetramoxifen), gamma-linoleic acid (gamma-linolenic acid), 2-methoxyestradiol (2-methoxyestradiol), methoxynorgestrienediol (moxystrol), 4-hydroxytamoxifen (4-hydroxytetramoxifen), hexachlorocyclohexane (hexachlorobenzene, hexachlorocyclohexane, beta-hexachlorocyclohexocyclohexane, beta-HCH), raloxifene (raloxifene), diethylstilbestrol (diethylstilbestrol), estradiol (estrol), zearalenone (zearalenone), estrone (estrone), 17alpha-estradiol (17-estradiol), estradiol (2-hydroxyestrone), 5, 7, 4-trihydroxy isoestrogen (trihydroxy), pyrrolidone (fludroxyquinone), fludroxynil (fludroxynil), fludroxynil (fludroxynil, Bicalutamide (Casodex), Aminoglutethimide (aminomeptylimide), betamethasone benzoate, carroterone, triptorelin, goserelin, leuprorelin, megestrol, medroxyprogesterone, dartikoside, epithioandrostanol, estrene with ethyl bromide, hesfen, clomiphene, toremifene, letrozole, anastrozole and exemestane or testolactone.
The hormone anticancer drug can be selected singly or in multiple, preferably triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirimimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane or bicalutamide.
The hormone anticancer drugs can be used for various hormone-dependent tumors, but different drugs have relative tumor selectivity, such as tamoxifen, pirimid, rubitecan, and toremifene, which are mainly used for treating estrogen-dependent tumors, such as breast cancer and endometrial cancer; flutamide, quart monosilicon blue, and bicalutamide are used primarily to treat androgen dependent tumors, such as prostate cancer; triptorelin, goserelin, leuprorelin, tamoxifen, raloxifene, aminoglutethimide, clomiphene, toremifene, letrozole, anastrozole and exemestane are used to treat breast cancer, prostate cancer and endometrial cancer.
The content of the hormone anticancer drug in the composition is 0.01-60%, preferably 1-40%, and most preferably 2-30%, by weight.
The weight percentage of the anti-tumor drug in the drug sustained-release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. When used in combination, the weight ratio of phosphoinositide 3-kinase inhibitor to hormonal agent is 1-9: 1 to 1: 1-9, preferably 1-4: 1 and 4-1: 1, and most preferably 1-2: 1 and 2-1: 1.
The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
(a) 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine;
(b) 1-40% triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, milbexifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, antiestrogen, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide; or
(c) 1-40% of 7-hydroxide radical astrosporin, 7-O-alkyl-astrosporin, beta-methoxystaurosporin, alkyl phosphorylcholine, hexadecyl phosphorylcholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphorylcholine with 1-40% of triptorelin, goserelin, leuprorelin, anastrozole, A combination of idoxifene, mircopoxifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide.
The viscosity range IV (dl/g) of the slow release auxiliary material is 0.05-1.8, preferably 0.1-1.4, and most preferably 0.1-1.4. The sustained-release excipients used in the present invention are selected from the group consisting of polyphosphates, polyphosphonates, polycycloalkylphosphates, ethyl phosphate (EOP), poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester, 80/20) (p (BHET-EOP/TC, 80/20)), p (BHET-EOP/TC, 50/50), poly (L-lactide-co-ethyl phosphate (p (LAEG-EOP)), poly (L-lactide-co-propyl phosphate) (p (DAPG-EOP)), trans (formula) -1, 4-dimethylcyclohexane (trans-1, 4-cyclohexanedimethanil, CHDM), hexyldichlorophosphate (hexyldichlorophosphate), HOP), 4-dimethylaminopyridine (4-dimethylaminopyridine, DMAP), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate hydrochloride, 80/20) (p (BHDPT-EOP/TC, 80/20)), p (BHDPT-EOP/TC, 50/50), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) (p (CHDM-HOP)), poly (trans) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)), or a combination thereof.
Among the above phosphates, p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) and p (CHDM-EOP) are preferable.
The sustained-release auxiliary material used by the invention is also selected from the phosphate ester, the racemic polylactic acid (D, L-PLA), the racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), the monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), the monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), the polyethylene glycol/polylactic acid (PLA-PEG-PLA), the polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), the carboxyl-terminated polylactic acid (PLA-COOH), the carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), the polifeprosan, the copolymer of difatty acid and sebacic acid (PFAD-SA), the poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], the poly (fumaric acid-sebacic acid) [ P (FA-SA) ], the polymer, Ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), Polydioxanone (PDO), polytrimethylene carbonate (PTMC), xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin or a blend or copolymer of protein glue. Wherein the phosphate accounts for 1-99% by weight, preferably 40-80% by weight, and most preferably 50-60% by weight.
The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. The sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.
In addition to the above-mentioned adjuvants, other substances may be used as described in detail in U.S. Pat. No. 4757128 (4857311) (4888176 (4789724)) and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luomingsheng and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.
The content of the suspending agent depends on the composition, nature and required amount of the medicine suspended in the solvent, the sustained-release microsphere (or microcapsule), the preparation method of the injection, the kind and composition of the suspending agent, for example, the content of the sodium carboxymethylcellulose can be 0.5-5%, but is preferably 1-3%, the content of mannitol and/or sorbitol is 5-30%, but is preferably 10-20%, and the content of tween 20, tween 40 or tween 80 is 0.05-2%, but is preferably 0.10-0.5%. In most cases, the sustained-release particles are composed of active ingredients and sustained-release excipients, and the solvent is a special solvent. When the solvent is common solvent, the suspended drug or sustained release microsphere (or microcapsule) is composed of effective components, sustained release adjuvant and/or suspending agent. In other words, when the suspending agent in sustained release particle (A) is "0", solvent (B) is a special solvent, and when the suspending agent in sustained release particle (A) is not "0", solvent (B) can be a common solvent or a special solvent. The viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃).
The common solvent can be, but is not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared from various salts, and the pharmacopoeia has corresponding regulations; the special solvent in the invention is a common solvent containing a suspending agent, and the suspending agent can be, but is not limited to, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, a surfactant, tween 20, tween 40 and tween 80 or a combination thereof. The content of the suspending agent in the special solvent is 0.1-30% by volume weight, preferably as follows:
(a) 0.5-5% sodium carboxymethylcellulose; or
(b) 0.5-5% sodium carboxymethylcellulose and 0.1-0.5% tween 80; or
(c) 5-20% mannitol; or
(d) 5-20% mannitol and 0.1-0.5% tween 80; or (b).
(e) 0.5-5% of sodium carboxymethylcellulose, 5-20% of sorbitol and 0.1-0.5% of tween 80.
The above-mentioned all are volume weight percentages, and the weight of suspending agent contained in 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. If the medicine is mixed with different auxiliary materials to prepare the sustained-release microspheres containing different medicines, the sustained-release microspheres can be independently packaged and stored, and can be injected into the body simultaneously or sequentially when in use; the sustained release microspheres can also be further formed by various methods to prepare sustained release implants with various shapes.
The clinically applicable dose of the active ingredient may vary depending on the patient's condition and may range from 0.01 to 1000mg/kg body weight, with 0.1 to 800mg/kg being preferred and 1 to 500mg/kg being most preferred.
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% of 7-hydroxide-astrosporin, 7-O-alkyl-astrosporin, beta-methoxystaurosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine with 1-40% of triptorelin, goserelin, leuprorelin, A combination of anastrozole, idoxifene, mirtaoxifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide.
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:
experiment 1 comparison of local drug concentrations after different modes of application of 7-hydroxy-astrosporin
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 1 cm in diameter. The dose of each group was 5 mg/kg. The results of the determination of the content (%) of the medicament in the tumors at different times show that the concentration difference of the local medicaments of the 7-hydroxyl-astrosporin applied in different modes is obvious, the effective medicament concentration of the part where the tumors are located can be obviously improved and effectively maintained by local administration, and the effect of placing the sustained-release implant in the tumors and injecting the sustained-release injection in the tumors 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 related tumor inhibition assayOne point.
Experiment 2 comparison of in vivo tumor suppression Effect after different modes of application of 7-O-alkyl-Astrosporine
Using white rat as test object, 2X 105Individual breast tumor cells were injected subcutaneously into the quaternary costal region and grouped after tumors grew to 0.5 cm diameter. The dose of each group was 15 mg/kg. The volume of the tumor was measured on the 20 th day after treatment, and the therapeutic effect was compared. The results show that the tumor inhibition effect difference of the 7-O-alkyl-astrosporin applied by different modes is obvious, the effective drug concentration of the tumor part can be obviously improved and effectively maintained by local administration, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. Not only has good curative effect, but also has little toxic and side effect.
Test 3. tumor inhibition of drugs containing choline hexadecylphosphate and hormones
Using white rat as test object, 2X 105Individual pancreatic tumor cells were subcutaneously injected into the quaternary costal region, and were divided into control and treatment groups (1-11) after the tumors had grown for 14 days. The treatment components are hexa-decyl phosphoryl choline group, hormone medicine group, hexa-decyl phosphoryl choline and hormone medicine group. The dosage of the hexa-decyl choline phosphate group and the hormone drug is respectively 25mg/kg and 5mg/kg, and the hexa-decyl choline phosphate group and the hormone drug are injected into tumors. Tumor volume was measured on day 20 after treatment and the effect was compared (see table 1).
TABLE 1
Group of UCN-1 Synergist Tumor inhibition ratio (%) P value
1 + - 64 *
2 - Triptorelin 46 *
3 - Goserelin 42 *
4 - Leuprorelin 38 *
5 - Anastrozole 48 *
6 - Idoxifene 36 *
7 + Triptorelin 86 **
8 + Goserelin 82 **
9 + Leuprorelin 88 **
10 + Anastrozole 86 **
11 + Idoxifene 82 **
The above results show that both phosphoinositide 3-kinase inhibitors (hexadecylphosphocholine) and the hormonal drugs used (triptorelin, goserelin, leuprolide, anastrozole, idoxifene) show significant inhibition of tumor growth at these concentrations alone (P value < 0.05) and when used in combination show very significant synergy (P value < 0.001).
Test 4. tumor inhibition Effect of UCN-1 and hormone drugs (sustained release injection)
The tumor cells include CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), etc. UCN-1 and hormone drugs are added into various tumor cells cultured in vitro for 24 hours according to the concentration of 10ug/ml, and the total number of the cells is counted after the culture is continued for 48 hours. The tumor cell growth inhibitory effect (%) is shown in Table 2.
TABLE 2
Tumor cell PI3Ki A B C D E PI3Ki+A PI3Ki+B PI3Ki+C PI3Ki+D PI3Ki+E
CNS 52 50 48 38 58 42 88 88 82 78 88
C6 54 52 46 36 64 40 90 80 84 84 90
SA 52 58 36 42 62 48 88 84 86 82 82
BC 58 54 40 42 64 54 88 80 74 74 80
BA 68 46 38 48 60 56 80 80 92 92 80
LH 66 56 40 52 58 60 90 82 94 78 94
PAT 60 48 46 50 54 68 82 76 82 80 80
The results show that the PI3Ki (UCN-1) and the hormone drugs (wherein A: milbexifene, B: tamoxifen, C: tamoxifen, D: raloxifene and E: steroidal antiandrogen) have obvious inhibition effects on the growth of various tumor cells when being singly used at the concentration, and can show obvious synergistic effects when being used in combination.
Test 5. tumor inhibition Effect of UCN-2 and hormonal drugs (sustained-release injection)
The tumor cells include CNS-1, C6, 9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), and liver cancer. UCN-2 and hormone drugs are added into various tumor cells cultured in vitro for 24 hours according to the concentration of 10ug/ml, and the total number of the cells is counted after the culture is continued for 48 hours. The tumor cell growth inhibition effect shows that the UCN-2 and hormone drugs (anticancer sterenol, flutamide, aminoglutethimide, pirglutethimide and megestrol) have obvious inhibition effect (P is less than 0.05) on the growth of various tumor cells when being used independently, and can show obvious synergistic effect (P is less than 0.01) when being used in combination.
Test 6, tumor inhibition of PI3Ki and hormonal drugs
Using white rat as test object, 2X 105Individual pancreatic tumor cells were subcutaneously injected into the quaternary costal region, and were divided into control and treatment groups (1-11) after the tumors had grown for 14 days. The treatment components are PI3Ki group, hormone drug group, PI3Ki and hormone drug group. The doses of the PI3Ki group drug and the hormone drug are respectively 25mg/kg and 5mg/kg, and the injection is performed intratumorally. Tumor volume was measured on day 20 after treatment and the treatment effect was compared (see table 3).
TABLE 3
Group of PI3Ki Synergist Tumor inhibition ratio (%) P value
1 + - 62 *
2 - Triptorelin 46 *
3 - Goserelin 42 *
4 - Leuprorelin 38 *
5 - Anastrozole 48 *
6 - Idoxifene 36 *
7 + Triptorelin 78 **
8 + Goserelin 72 **
9 + Leuprorelin 68 **
10 + Anastrozole 80 **
11 + Idoxifene 84 **
The above results show that both PI3Ki (Perifosine) and the hormonal drugs used (triptorelin, goserelin, leuprolide, anastrozole, idoxifene) showed significant inhibition of tumor growth at these concentrations alone (P value less than 0.05) and showed very significant synergy when used in combination (P value less than 0.001).
Test 7, PI3Ki and hormonal drugs (sustained release injection) for their anti-tumor effects
The tumor cells include CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), etc. Phosphoinositide 3-kinase inhibitors and hormonal drugs were added to each tumor cell cultured in vitro for 24 hours at a concentration of 10ug/ml, and the total number of cells was counted after further culturing for 48 hours. The tumor cell growth inhibitory effect (%) is shown in Table 4.
TABLE 4
Tumor cell UCN-2 A B C D E UCN-2+A UCN-2+B UCN-2+C UCN-2+D UCN-2+E
CNS 52 50 48 38 58 42 88 88 82 78 88
C6 54 52 46 36 64 40 90 80 84 84 90
SA 52 58 36 42 62 48 88 84 86 82 82
BC 58 54 40 42 64 54 88 80 74 74 80
BA 68 46 38 48 60 56 80 80 92 92 80
LH 66 56 40 52 58 60 90 82 94 78 94
PAT 60 48 46 50 54 68 82 76 82 80 80
The above results indicate that the hormone drugs used are A: mirbexifene, B: tamoxifen, C: domoxifene, D: raloxifene, E: can be used for resisting female. The medicine has obvious inhibition effect on the growth of various tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used jointly.
Experiment 8, Edelfosine and hormone drug (sustained release injection) tumor inhibition
The tumor cells include CNS-1, C6, 9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), and liver cancer. Edelfosine and hormonal drugs were added to each of the tumor cells cultured in vitro for 24 hours at a concentration of 10ug/ml, and the total number of cells was counted after culturing for another 48 hours. The tumor cell growth inhibition effect shows that the Edelfosine and hormone drugs (anticancer sterenol, flutamide, aminoglutethimide, pirglutethimide and megestrol) have obvious inhibition effect (P is less than 0.05) on the growth of various tumor cells when being used independently, and can show obvious synergistic effect (P is less than 0.01) when being used in combination.
The above results show that when used in combination, the weight ratio of PI3Ki to the hormonal agent is 1-9: 1 to 1: 1-9, preferably 1-4: 1 and 4-1: 1, and most preferably 1-2: 1 and 2-1: 1.
Further research shows that hormone medicines such as goserelin, triptorelin, leuprorelin, tamoxifen, semustine and the like and UCN-1 or UCN-2 have obvious synergistic effect when used together with tumors such as cervical tumor, thyroid cancer, colorectal cancer, ovarian cancer and the like (P is less than 0.05).
In conclusion, the PI3Ki and/or various hormone drugs have obvious inhibition effects on the growth of various tumor cells when being used independently, and can show obvious synergistic effect when being used in combination. Therefore, the active ingredient of the invention is any combination of PI3Ki and/or any hormone medicine. 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 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 UCN-1, 20mg of triptorelin, 10mg of UCN-1 and 10mg of triptorelin are respectively added, after shaking up again, injection microspheres containing 20% of UCN-1, 20% of triptorelin, 10% of UCN-1 and 10% of triptorelin 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 a release time of 40-50 days in vitro physiological saline, and a release time of more than 50 days in mouse subcutaneous liver cancer.
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) 1-40% of UCN-1 or UCN-2;
(2) 1-30% triptorelin, goserelin, leuprorelin, tamoxifen, toremifene, letrozole, anastrozole, exemestane, or bicalutamide; or
(3) 1-40% UCN-1 or UCN-2 in combination with 1-30% triptorelin, goserelin, leuprorelin, tamoxifen, toremifene, letrozole, anastrozole, exemestane or bicalutamide.
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 polyene UCN-2, 30mg of triptorelin, 20mg of UCN-2 and 10mg of triptorelin are respectively added into the three containers, after shaking up again, the microspheres for injection containing 30% of UCN-2, 30% of triptorelin, 20% of UCN-2 and 10% of triptorelin 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 a release time of 55-65 days in vitro physiological saline and a release time of about 60 days in mouse lung cancer.
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% triptorelin, goserelin or leuprorelin; or
(2) 5-40% of UCN-1 or UCN-2; or
(3) 5-30% of UCN-1 or UCN-2 in combination with 5-30% of triptorelin, goserelin or leuprorelin.
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 UCN-1 and 10mg of leuprorelin are added to the mixture, the mixture is shaken again and evenly, and then the spray drying method is used for preparing the microspheres for injection containing 30% of UCN-1 and 10% of leuprorelin. 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 a release time of 50-55 days in vitro physiological saline and a release time of about 55 days in subcutaneous gastric cancer of mice.
Example 6.
The steps of the method for processing the sustained-release injection are the same as the example 5, but the difference is that the molecular weight peak value of the used auxiliary materials is 25000-:
(1) 5-40% of UCN-1; or
(2) 1-20% leuprorelin; or
(3) 5-30% of UCN-1 and 1-20% of leuprorelin.
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 dissolving and mixing uniformly, 25mg of Perifosine and 5mg of tamoxifen are added, after shaking uniformly again, the injection microspheres containing 25% of Perifosine and 5% of tamoxifen are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has a release time of 40-45 days in vitro physiological saline and a release time of about 50 days in subcutaneous esophageal cancer of mice.
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% tamoxifen;
(2) 10-25% UCN-1 or Perifosine; or
(3) 10-20% tamoxifen in combination with 10-25% UCN-1 or Perifosine.
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 Edelfosine, 30mg of toremifene, 5mg of Edelfosine and 25mg of toremifene are respectively added, after the mixture is shaken again, the microspheres for injection containing 30% of Edelfosine, 30% of toremifene, 5% of Edelfosine and 25% of toremifene 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 a release time of 40-45 days in vitro physiological saline and a release time of about 45 days in mouse colorectal cancer.
Example 10.
The steps of the method for processing the sustained-release injection are the same as the example 9, but the difference is that the ratio of the p-carboxyphenylpropane to the sebacic acid in the polifeprosan is 50: 50, the molecular weight peak value of p (DAPG-EOP) is 40000-65000, and the anticancer active ingredients are:
(1) 5-30% of polyene UCN-1;
(2) 20-40% toremifene;
(3) a combination of 5-20% of polyene UCN-1 and 10-40% of toremifene.
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 goserelin and 20mg of Ilmofosine are added, the mixture is shaken again and uniformly, and then the spray drying method is used for preparing the microspheres for injection containing 10% of goserelin and 20% of Ilmofosine. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the release time of 40-45 days in-vitro physiological saline and the release time of 45 days in subcutaneous breast cancer of mice.
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% goserelin; or
(2) 10-20% of Ilmofosine; or
(3) 10-20% goserelin in combination with 10-20% Ilmofosine.
Example 13
40mg of polylactic acid (PLGA, 50: 50) with a molecular weight peak of 15000-35000 and 30 (LAEG-EOP) with a molecular weight peak of 20000-45000p are placed in a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of triptorelin and 20mg of Milefosine are added, after re-shaking uniformly, the injection microspheres containing 10% of triptorelin and 20% of Milefosine 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 in subcutaneous pancreatic cancer 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% UCN-1 or miltefosine; or
(2) 10-20% triptorelin, goserelin or leuprorelin; or
(3) 10-20% of UCN-1 or Milefosine in combination with 10-20% of triptorelin, goserelin or leuprorelin.
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) 1-40% goserelin, triptorelin, leuprorelin, toremifene, or tamoxifen; or
(2) 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine; or
(3) 20-40% of 7-hydroxide-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine with 1-20% of goserelin, triptorelin, A combination of leuprorelin, toremifene, or tamoxifen; or
(4) 1-20% of 7-hydroxide-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine with 20-40% of goserelin, triptorelin, A combination of leuprorelin, toremifene, or tamoxifen.
Example 18 comparison of drug Release characteristics of different Release excipients and their combination (Table 5)
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 5
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: 1 (2): (4) ═ 1: (2) } 4 ═ 1-1: 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 UCN-1 (20%) UCN-1 (20%) UCN-1 (20%) UCN-1 (20%) UCN-1 (20%) UCN-1 (20%) UCN-1 (20%) goserelin (20%) 2228104842444226251054504846 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 molecular polymers such as p (LAEG-EOP) and p (DAPG-EOP) are slow and stable in drug release, and when the polyphosphate ester high molecular polymers are combined with the sugar anhydride high molecular polymers such as PLA, PLGA and polifeprosan, the burst release caused by the sugar anhydride high molecular polymers can be reduced, but the stable and slow drug release characteristics are not greatly influenced. This unexpected finding constitutes a further main technical feature of the present invention. Because the polyphosphate ester high molecular polymer is expensive, the cost of the sustained-release preparation can be reduced, and the drug release characteristic of the sustained-release preparation can be improved.
Example 19 comparison of drug Release characteristics of different Release excipients and their combinations (Table 6)
The procedure of the method for manufacturing the sustained-release implant is the same as that of example 11, and the release characteristics of different sustained-release excipients and the combined sustained-release excipients are compared. The first day of drug release (in vitro) exceeds 20% of the total is burst release.
TABLE 6
Sustained release excipients Molecular weight Medicine and content Time of release (Tian) Whether there is a burst release
(1) PLA (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 UCN-2 (20%) triptorelin (10%) 2532114843454227251357555250 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 10-13 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.
This release profile is also seen for other drug combinations such as triptorelin in combination with UCN-1 and goserelin or leuprorelin in combination with UCN-2.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (10)

1. An anticancer composition containing phosphoinositide 3-kinase inhibitor and hormone medicine, which is characterized in that the anticancer composition is a slow release injection and comprises the following components:
(A) a sustained release microsphere comprising:
0.5-70% of anticancer active ingredient
Sustained release auxiliary materials 30-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active ingredient is phosphoinositide 3-kinase inhibitor and/or hormone medicine;
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 phosphoinositide 3-kinase inhibitor is selected from 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine;
the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), and is selected from one or more of sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40 and Tween-80.
2. The anti-cancer composition according to claim 1, wherein the hormonal agent is selected from the group consisting of triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, anti-cancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, and bicalutamide.
3. The anticancer composition according to claim 1, wherein the anticancer sustained release injection comprises the following anticancer active ingredients:
(1) 5-35% goserelin, triptorelin, leuprorelin, toremifene, or tamoxifen; or
(2) 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine; or
(3) 1-40% of 7-hydroxide-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine with 5-30% of goserelin, triptorelin, A combination of leuprorelin, toremifene, or tamoxifen.
The above are all weight percentages.
The slow release auxiliary material is one or the combination of the following materials:
a) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP);
b) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer of polyglycolic acid and glycolic acid with a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) with polylactic acid having a molecular weight peak of 10000-;
d) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or a combination of p (CHDM-EOP) and polifeprosan, wherein the ratio of p-carboxyphenylpropane to sebacic acid in the polifeprosan is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer of di-fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or egg gelatin.
4. The sustained-release anticancer injection according to claim 1, wherein the suspending agent is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20; or
f) Glycerin, dimethicone, propylene glycol, or carbomer.
5. The sustained-release anticancer injection according to claim 1, wherein the suspending agent is one of the following:
A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;
B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
6. The anticancer composition according to claim 1, which is a sustained-release implant.
7. The sustained-release anticancer implant according to claim 6, characterized in that the anticancer active ingredients are:
(1) 1-40% goserelin, triptorelin, leuprorelin, toremifene, or tamoxifen; or
(2) 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine; or
(3) 20-40% of 7-hydroxide-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine with 1-20% of goserelin, triptorelin, A combination of leuprorelin, toremifene, or tamoxifen; or
(4) 1-20% of 7-hydroxide-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine with 20-40% of goserelin, triptorelin, A combination of leuprorelin, toremifene, or tamoxifen.
The slow release auxiliary material is selected from phosphate ester high molecular polymer or the mixture or copolymer of phosphate ester high molecular polymer and polysaccharide anhydride high molecular polymer.
8. The sustained-release anticancer implant according to claim 6, characterized in that the sustained-release excipients are selected from one of the following:
a) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP);
b) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer of polyglycolic acid and glycolic acid with a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) with polylactic acid having a molecular weight peak of 10000-;
d) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or a combination of p (CHDM-EOP) and polifeprosan, wherein the ratio of p-carboxyphenylpropane to sebacic acid in the polifeprosan is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer of di-fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or egg gelatin.
9. The sustained-release anticancer injection according to claim 1, wherein the active ingredients of the sustained-release anticancer injection are used for preparing a pharmaceutical preparation for treating primary or secondary cancer, sarcoma or carcinosarcoma originated from brain, central nervous system, kidney, liver, gallbladder, head and neck, oral cavity, thyroid, skin, mucosa, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon or rectum of human and animal.
10. The sustained-release injection and sustained-release injection as claimed in claims 1 and 6, wherein the sustained-release injection is administered by intratumoral or peritumoral injection or placement and is sustained-released in vivo for more than 40 days.
CNA2007102003184A 2007-03-23 2007-03-23 Anticancer composition containing both phosphoinositide-3-kinase inhibitor and hormone medicine Pending CN101019828A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017502989A (en) * 2014-01-15 2017-01-26 ノバルティス アーゲー Combination medicine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017502989A (en) * 2014-01-15 2017-01-26 ノバルティス アーゲー Combination medicine

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