CN1299674C - Slow released combination of anticancer drugs embedded in vivo - Google Patents
Slow released combination of anticancer drugs embedded in vivo Download PDFInfo
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- CN1299674C CN1299674C CNB2004100758415A CN200410075841A CN1299674C CN 1299674 C CN1299674 C CN 1299674C CN B2004100758415 A CNB2004100758415 A CN B2004100758415A CN 200410075841 A CN200410075841 A CN 200410075841A CN 1299674 C CN1299674 C CN 1299674C
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- paclitaxel
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- tumor
- anticancer
- ramulus
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a slow released composition of anticancer drugs embedded internally, which belongs to the technical field of drugs. The present invention comprises pharmaceutic supplementary materials and anticancer drugs, wherein the anticancer drugs are docetaxel and /or docetaxel ramifications; the pharmaceutic supplementary materials are high molecular biologic polymers which have capacitability and /or can be degraded and absorbed, and in a degradation and absorption process, the anticancer drugs can be slowly released at part of a tumor, so the systemic toxicity reactions of the drugs are reduced obviously; simultaneously, the present invention is favourable for the maintenance of the effective drug concentration of part of the tumor. The composition is put at part of the tumor, the drug concentration of part of the tumor can be enhanced in a selective mode, and the treatment effect of non-operative treatments, such as chemotherapeutics, radiotherapy, etc., can be enhanced.
Description
(1) technical field
The present invention relates to a kind of anticancer pharmaceutical composition, be mainly the combination of anticancer drugs embedded in vivo of slow release, belong to technical field of pharmaceuticals.
(2) background technology
As chemotherapeutics commonly used, docetaxel and derivant thereof have been widely used in the treatment of multiple malignant tumor, and have obtained comparatively significantly action effect.Yet, discover that further the treatment of multiple malignant tumor, particularly entity tumor remains in more problem.Entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level (referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer pharmaceutical composition is provided.The effective ingredient that comprises pharmaceutic adjuvant and effective anticancer, wherein effective ingredient is docetaxel (docetaxel) and/or docetaxel derivant.
The docetaxel derivant be selected from 2 '-hydroxyl paclitaxel (paclitaxel-2 '-hydroxy), 10-removes acetyl Baccatine III (10-deacetylbaccatin III, DAB), 14 beta-hydroxies-10-removes acetyl Baccatine III (14beta-hydroxy-10-deacetylbaccatin III, 14-OH-DAB), 9-dihydro-13-Baccatine III (DHB), 13-(N-three-butoxy carbonyl-β-isobutyl group Isoserinol)-14-hydroxy baccatin gibberellins-1,14-carbonate (13-(N-tert.-butoxycarbonyl-beta-isobutylisoserinyl)-14-hydroxybaccatin-1,14-carbonate, DN5109), IDN5111 IDN 5111 (IDN5111), IDN5127 IDN 5127. (IDN5127), 3 '-(2-methyl isophthalic acid-acrylic) paclitaxel (3 '-(2-methyl-1-propenyl)), 3 '-(2-methyl-propyl) paclitaxel (3 '-(2-methylpropyl) taxoids, SB-T-1213), 4a-paclitaxel (SB-T-1213 (4a)), 4b-paclitaxel (SB-T-1214 (4b)), 5a-paclitaxel (SB-T-1102 (5a)), 10-removes acetyl paclitaxel (10-deacetyl taxol), 7-table-paclitaxel (7-epi-taxol), Tetraol, Baccatine III (baccatin III), Tetraol V, Semen Caesalpiniae Ramulus et folium taxi cuspidatae (Taxus brevifolia), ground hemlock (Taxus Canadensis), yew (Taxus baccata) and Chinese Ramulus et folium taxi cuspidatae (Taxus chinensis), pointed tooth Ramulus et folium taxi cuspidatae (Taxus cuspidata), cultivate Ramulus et folium taxi cuspidatae (Taxus X media cultivars), Yunnan Ramulus et folium taxi cuspidatae (Taxus yunnanensis) and Florida Ramulus et folium taxi cuspidatae (Taxus floridana).
Anticancer effective component of the present invention also comprises the salt of docetaxel derivant, and the salt of docetaxel derivant is selected from sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine salt, pyrimidine salt, succinate or maleate.
One of the salt of docetaxel, docetaxel derivant or docetaxel derivant can singly select or multiselect, preferred following:
Docetaxel, 2 '-hydroxyl paclitaxel, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, 9-dihydro-13-Baccatine III, 13-(N-three-butoxy carbonyl-β-isobutyl group Isoserinol)-14-hydroxy baccatin gibberellins-1,14-carbonate, IDN5111 IDN 5111, IDN5127 IDN 5127., 3 '-(2-methyl isophthalic acid-acrylic) paclitaxel, 3 '-(2-methyl-propyl) paclitaxel, the 4a-paclitaxel, the 4b-paclitaxel, the 5a-paclitaxel, 10-removes the acetyl paclitaxel, 7-table-paclitaxel, Tetraol, Baccatine III or Tetraol V.
Above-mentioned active ingredient shared percentage by weight in compositions is 0.01%-60%, is good with 1%-40%, is best with 5%-30%.
Pharmaceutic adjuvant comprises one of following or its combination:
(1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacic acid), polifeprosan (to the copolymer of carboxy phenyl propane and certain herbaceous plants with big flowers diacid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin etc.
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description in other United States Patent (USP) that (US 4857311; 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of mixture, glycolic and the hydroxy carboxylic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid; When PLA and PLGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.The molecular weight of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 1000-100,000, but with 10,000-50000 is preferred; With 10,000-20000 is for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or certain herbaceous plants with big flowers diacid or copolymer for most preferably, as, but be not limited to, molecular weight is 5000 to 10000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 20000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 5000 to 10000 polylactic acid mixes with the certain herbaceous plants with big flowers diacid, molecular weight is that 30000 to 80000 PLGA mixes with the certain herbaceous plants with big flowers diacid.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change anticancer pharmaceutical composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt and sodium salt etc.
The used pharmaceutic adjuvant of anticancer pharmaceutical composition of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of composition for treating solid tumor of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The effective ingredient of anticancer pharmaceutical composition can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.In addition, the effective ingredient of anticancer pharmaceutical composition also can be packaged in the liposome equably, or makes microsphere with art methods.
Characteristics of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Anticancer pharmaceutical composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule and slow releasing agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and mould shape.In various dosage forms, be implanted into agent, agent for slow releasing and implant agent for slow releasing based on body.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Because anticancer pharmaceutical composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
Route of administration
Anticancer pharmaceutical composition of the present invention can be used through various approach, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, tumor week or tumor chamber be placed as preferably, the form that local slow discharges is implanted into agent, slow releasing agent and implantation slow release agent etc. for most preferably as selecting various slow-releasing pump, slow releasing capsule, body for use.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But effective dose commonly used is 0.01-60 milligram/kg body weight, is ideal with 1-40 milligram/kg body weight, with 2-10 milligram/kg body weight for the most desirable.Ratio shared in compositions is decided because of concrete condition, can be good with 1%-40% from 0.01%-60%, is best with 5%-30%.Below all be weight percentage.
Anticancer pharmaceutical composition of the present invention can be used to prepare the various entity tumors for the treatment of the people, comprises former or the cancer of transfer or the medicine of sarcoma or carcinosarcoma originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Anticancer pharmaceutical composition of the present invention also can be used for the treatment of the various entity tumors of house pet and animal, and when being used for the treatment of the various entity tumor of house pet and animal, the material of species specificity is preferably selected in the active ingredient of anticancer pharmaceutical composition of the present invention for use.
Also can add other medicinal ingredient in the anticancer pharmaceutical composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Anticancer pharmaceutical composition of the present invention can be used in the following manner.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can be through various administrations, with topical, as selective arterial injection and directly injection or be placed as goodly in the tumor body, wherein are released to the best with local slow again.When used the part, anticancer pharmaceutical composition of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Anticancer pharmaceutical composition Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
Anticancer pharmaceutical composition of the present invention can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be good with 1%-40% from 0.1%-60%, be best with 5%-30%.This anticancer pharmaceutical composition can be made into various dosage forms, as, but be not limited to, injection, muddy suspension, ointment, capsule, implant, slow releasing agent and implantation slow release agent etc. serve as preferred with implant, slow releasing agent and implantation slow release agent wherein; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and apperance; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Most preferred dosage form of the present invention is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and composition for treating solid tumor also can be packed in the liposome.
The characteristics of anticancer pharmaceutical composition technology of preparing of the present invention are in the docetaxel or derivatives thereof one or more are planted and are packaged in the pharmaceutic adjuvant, proportionally with active ingredient and pharmaceutic adjuvant dissolving, wait to fill part mixing after the universe dry.Treat that the universe is shaped immediately after dry and sterilizes packing.The local placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
The present invention be processed into anticancer pharmaceutical composition preparation method as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. add the anticancer active ingredient of weighing and shake up the percentage by weight 0.1%-60% of anticancer active ingredient and pharmaceutic adjuvant again.
3. removal organic solvent.Vacuum drying or cold drying all can.
4. dried solid composite is made different shape as required.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
In a word, the anticancer pharmaceutical composition that contains above effective ingredient can be made into any dosage form or shape, and effective ingredient is any one (or multiple) plant alkaloid kind anti-cancer drugs, but is preferred with the agent for slow releasing.
(4) specific embodiment
The present invention is processed into anticancer pharmaceutical composition and further is illustrated by following examples, but is not limited thereto.
Embodiment 1.
It with the 90mg molecular weight 10000 the PLGA (copolymer of hydroxyacetic acid and glycolic, hydroxyacetic acid and glycolic weight ratio 25: 75) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 10mg docetaxel, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% docetaxel.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-30 days, is 30-45 days at the subcutaneous drug release time of mice.
Embodiment 2. is as described in the embodiment 1, and different is, and that contained effective ingredient is is one of following:
2 '-hydroxyl paclitaxel, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, 9-dihydro-13-Baccatine III, 13-(N-three-butoxy carbonyl-β-isobutyl group Isoserinol)-14-hydroxy baccatin gibberellins-1,14-carbonate, IDN5111 IDN 5111, IDN5127 IDN 5127., 3 '-(2-methyl isophthalic acid-acrylic) paclitaxel, 3 '-(2-methyl-propyl) paclitaxel, the 4a-paclitaxel, the 4b-paclitaxel, the 5a-paclitaxel, 10-removes the acetyl paclitaxel, 7-table-paclitaxel, Tetraol, Baccatine III, Tetraol V, the Semen Caesalpiniae Ramulus et folium taxi cuspidatae, ground hemlock, yew, China's Ramulus et folium taxi cuspidatae, the pointed tooth Ramulus et folium taxi cuspidatae, cultivate Ramulus et folium taxi cuspidatae, Yunnan Ramulus et folium taxi cuspidatae or Florida Ramulus et folium taxi cuspidatae, the percentage by weight of effective ingredient in anticancer pharmaceutical composition is 5-30%.
Embodiment 3.
90mg pharmaceutic adjuvant ethylene vinyl acetate copolymer (EVAc) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg7-table-paclitaxel, shake up the dry removal of final vacuum organic solvent again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10%7-table-paclitaxel.The drug release time of this anticancer pharmaceutical composition in external normal saline is 14-24 days, is 20-35 days at the subcutaneous drug release time of mice.
Embodiment 4. is as described in the embodiment 3, and different is, and that contained effective ingredient is is one of following:
2 '-hydroxyl paclitaxel, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, 9-dihydro-13-Baccatine III, 13-(N-three-butoxy carbonyl-β-isobutyl group Isoserinol)-14-hydroxy baccatin gibberellins-1,14-carbonate, IDN5111 IDN 5111, IDN5127 IDN 5127., 3 '-(2-methyl isophthalic acid-acrylic) paclitaxel, 3 '-(2-methyl-propyl) paclitaxel, the 4a-paclitaxel, the 4b-paclitaxel, the 5a-paclitaxel, 10-removes the acetyl paclitaxel, Tetraol, Baccatine III, Tetraol V, the Semen Caesalpiniae Ramulus et folium taxi cuspidatae, ground hemlock, yew, China's Ramulus et folium taxi cuspidatae, the pointed tooth Ramulus et folium taxi cuspidatae, cultivate Ramulus et folium taxi cuspidatae, Yunnan Ramulus et folium taxi cuspidatae or Florida Ramulus et folium taxi cuspidatae, the percentage by weight of effective ingredient in anticancer pharmaceutical composition is 1-40%.
Embodiment 5.
With the 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer) put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 20mg docetaxel, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 20% docetaxel.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-25 days, is 25-40 days at the subcutaneous drug release time of mice.
Embodiment 6. is as described in the embodiment 5, and different is, and that contained effective ingredient is is one of following:
2 '-hydroxyl paclitaxel, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, 9-dihydro-13-Baccatine III, 13-(N-three-butoxy carbonyl-β-isobutyl group Isoserinol)-14-hydroxy baccatin gibberellins-1,14-carbonate, IDN5111 IDN 5111, IDN5127 IDN 5127., 3 '-(2-methyl isophthalic acid-acrylic) paclitaxel, 3 '-(2-methyl-propyl) paclitaxel, the 4a-paclitaxel, the 4b-paclitaxel, the 5a-paclitaxel, 10-removes the acetyl paclitaxel, 7-table-paclitaxel, Tetraol, Baccatine III, Tetraol V, the Semen Caesalpiniae Ramulus et folium taxi cuspidatae, ground hemlock, yew, China's Ramulus et folium taxi cuspidatae, the pointed tooth Ramulus et folium taxi cuspidatae, cultivate Ramulus et folium taxi cuspidatae, Yunnan Ramulus et folium taxi cuspidatae or Florida Ramulus et folium taxi cuspidatae, the percentage by weight of effective ingredient in anticancer pharmaceutical composition is 5-30%.
Embodiment 7.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 1,3 or 5, but used pharmaceutic adjuvant be following one of a)-e) or its combination:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan), wherein to carboxy phenyl propane (p-CPP): the weight ratio of certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 8.
With the 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer) put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 10mg IDN5111 IDN 5111 and 10mg docetaxel, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% IDN5111 IDN 5111 and 10% docetaxel.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-25 days, is 30-40 days at the subcutaneous drug release time of mice.
Tumor-inhibiting action in the body of embodiment 9. docetaxels and docetaxel derivant.
With the white mice is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 7 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is docetaxel, and the 5th to 7 group is 2 '-hydroxyl paclitaxel, and the 8th to 10 group is 7-table-paclitaxel.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.The local docetaxel of placing is selected from embodiment 1, and the percentage by weight of medicine in implant is 10%; And 2 '-hydroxyl paclitaxel and 7-table-paclitaxel all are selected from embodiment 2, and the percentage by weight of medicine in implant is respectively 10% and 30%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 70.5±12.5 | |
| 2(6) | Docetaxel (ip) | 28±6.0 | ＜0.05 |
| 3(6) | Docetaxel (it) | 16±4.5 | ＜0.01 |
| 4(6) | Docetaxel itp) | 11±1.8 | ＜0.01 |
| 5(6) | 2 '-hydroxyl paclitaxel (ip) | 20±4.0 | ＜0.01 |
| 6(6) | 2 '-hydroxyl paclitaxel (it) | 18±4.6 | ＜0.01 |
| 7(6) | 2 '-hydroxyl paclitaxel (itp) | 10±1.8 | ＜0.001 |
| 8(6) | 7-table-paclitaxel (ip) | 16±1.6 | ＜0.001 |
| 9(6) | 7-table-paclitaxel (it) | 12±1.4 | ＜0.001 |
| 10(6) | 7-table-paclitaxel (itp) | 6±0.4 | ＜0.001 |
Tumor-inhibiting action in the body of embodiment 10. docetaxel derivants
EXPERIMENTAL DESIGN is with embodiment 9, and local 4a-paclitaxel, 4b-paclitaxel and the 5a-paclitaxel of placing is selected from embodiment 3,4 and 5 respectively, and the percentage by weight of medicine in implant is respectively 10%, 20% and 30%, (seeing Table 2).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is the 4a-paclitaxel, and the 5th to 7 group is the 4b-paclitaxel, and the 8th to 10 group is the 5a-paclitaxel.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 10th day.
Table 2
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 74±13.5 | |
| 2(6) | 4a-paclitaxel (ip) | 44±6.4 | ＜0.05 |
| 3(6) | 4a-paclitaxel (it) | 38±3.8 | ＜0.01 |
| 4(6) | 4a-paclitaxel (itp) | 28±2.8 | ＜0.01 |
| 5(6) | 4b-paclitaxel (ip) | 40±4.0 | ＜0.01 |
| 6(6) | 4b-paclitaxel (it) | 32±3.0 | ＜0.01 |
| 7(6) | 4b-paclitaxel (itp) | 18±2.2 | ＜0.001 |
| 8(6) | 5a-paclitaxel (ip) | 33±5.8 | ＜0.001 |
| 9(6) | 5a-paclitaxel (it) | 18±2.0 | ＜0.001 |
| 10(6) | 5a-paclitaxel (itp) | 10±1.6 | ＜0.001 |
Tumor-inhibiting action in the body of embodiment 11. docetaxel derivants.
EXPERIMENTAL DESIGN is with embodiment 9, and the local medicine of placing is 10% Tetraol, 20% Baccatine III and 30% Tetraol V, is selected from embodiment 2,4 and 6 respectively.First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is Tetraol, and the 5th to 7 group is Baccatine III, and the 8th to 10 group is Tetraol V.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 74±10 | |
| 2(6) | Tetraol (ip) | 48±6.6 | ＜0.05 |
| 3(6) | Tetraol (it) | 39±4.1 | ＜0.01 |
| 4(6) | Tetraol (itp) | 28±2.2 | ＜0.01 |
| 5(6) | Baccatine III (ip) | 54±7.0 | ＜0.01 |
| 6(6) | Baccatine III (it) | 36±3.0 | ＜0.01 |
| 7(6) | Baccatine III (itp) | 17±2.2 | ＜0.001 |
| 8(6) | Tetraol V (ip) | 42±6.6 | ＜0.001 |
| 9(6) | Tetraol V (it) | 20±2.6 | ＜0.001 |
| 10(6) | Tetraol V (itp) | 12±1.6 | ＜0.001 |
The result of embodiment 9 to 11 shows that used docetaxel and multiple derivant thereof all have the obvious suppression effect to growth of tumour cell when this concentration, but comparatively obvious with local application's effect, and wherein local placement is the most obvious.Local placement not only can suppress tumor growth effectively, and can significantly reduce the general toxic reaction of medicine, and selected docetaxel and derivant thereof are of universal significance.
The result of embodiment 9 to 11 shows, tumor by local is placed medicine and is had obvious superiority, be further clear and definite slow release effect of the present invention, selected the copolymer (PLGA of polyglycolic acid and hydroxyacetic acid respectively for use, molecular weight is 10000), ethylene vinyl acetate copolymer (EVAc) and polifeprosan (to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA) copolymer) be that pharmaceutic adjuvant, gravimetry percentage ratio are the release conditions of docetaxel derivant used among 20% docetaxel and the embodiment 9 to 11.The result shows that the drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is about 30-40 days at the subcutaneous drug release time of mice.Therefore the obvious tumor-inhibiting action that this anticancer pharmaceutical composition is described is mainly from its medicament slow release characteristic, and the latter is apparent at the superiority of keeping aspect the local drug concentration, and to selected docetaxel and derivant tool universal meaning thereof.Wherein PLGA is excellent than EVAc or polifeprosan.
As mentioned above, the preparation method of anticancer pharmaceutical composition of the present invention can be selected as the case may be.Anticancer pharmaceutical composition can be made various dosage forms with existing method, and being implanted into agent, slow releasing agent and implantation slow release agent with body is first-selection.Above embodiment only is used for explanation, and is not limitation application of the present invention.Said composition except that independent application, also can with many treatment measure use in conjunction: as with use in conjunction such as radiotherapy, high thermal therapeutical, immunization therapy, phototherapy, electrotherapy.Said composition is used in local placement such as implant, slow releasing agent and implantation slow release agent can be used as synergist, has unique advantage and very high clinical value.
Claims (3)
1, a kind of anticancer pharmaceutical composition, comprise pharmaceutic adjuvant and anticancer effective component, it is characterized in that this pharmaceutical composition is a sustained-release implant, described anticancer effective component is docetaxel and/or docetaxel derivant, the percentage by weight of anticancer effective component in anticancer pharmaceutical composition is 5-30%, the docetaxel derivant is selected from 2 '-hydroxyl paclitaxel, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, 9-dihydro-13-Baccatine III, 13-(N-three-butoxy carbonyl-β-isobutyl group Isoserinol)-14-hydroxy baccatin gibberellins-1,14-carbonate, IDN5111 IDN 5111, IDN5127 IDN 5127., 3 '-(2-methyl isophthalic acid-acrylic) paclitaxel, 3 '-(2-methyl-propyl) paclitaxel, the 4a-paclitaxel, the 4b-paclitaxel, the 5a-paclitaxel, 10-removes the acetyl paclitaxel, 7-table-paclitaxel, ground hemlock, China's Ramulus et folium taxi cuspidatae, the pointed tooth Ramulus et folium taxi cuspidatae, cultivate Ramulus et folium taxi cuspidatae, Yunnan Ramulus et folium taxi cuspidatae or Florida Ramulus et folium taxi cuspidatae;
The used pharmaceutic adjuvant of anti-cancer composition is one of following:
1) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid;
2) ethylene vinyl acetate copolymer;
3) to carboxy phenyl propane: the decanedioic acid copolymer, to carboxy phenyl propane: decanedioic acid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40; Be weight ratio.
2, the anticancer pharmaceutical composition according to claim 1 is characterized in that in this anti-cancer composition tumor or all placements of tumor.
3, the anticancer pharmaceutical composition according to claim 1 is characterized in that this anticancer pharmaceutical composition makes granular, lamellar, sphere, bulk, needle-like, bar-shaped and mould shape.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275377A (en) * | 2000-04-29 | 2000-12-06 | 孔庆忠 | Anticancer medicine composition |
| CN1404830A (en) * | 2002-10-29 | 2003-03-26 | 李昕跃 | Method for preparing controllable complex of taxiol and polylactic acid |
| CN1561988A (en) * | 2004-03-18 | 2005-01-12 | 山东居仁生物医药技术研究所 | Method for preparing taxol micro ball anti-cancer medicine |
| CN1631362A (en) * | 2004-11-26 | 2005-06-29 | 中国科学院上海药物研究所 | Anti cancer sustained releasing composition and its preparation method |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275377A (en) * | 2000-04-29 | 2000-12-06 | 孔庆忠 | Anticancer medicine composition |
| CN1404830A (en) * | 2002-10-29 | 2003-03-26 | 李昕跃 | Method for preparing controllable complex of taxiol and polylactic acid |
| CN1561988A (en) * | 2004-03-18 | 2005-01-12 | 山东居仁生物医药技术研究所 | Method for preparing taxol micro ball anti-cancer medicine |
| CN1631362A (en) * | 2004-11-26 | 2005-06-29 | 中国科学院上海药物研究所 | Anti cancer sustained releasing composition and its preparation method |
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