CN1311818C - Pharmaceutical composition for solid tumour - Google Patents
Pharmaceutical composition for solid tumour Download PDFInfo
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- CN1311818C CN1311818C CNB2004100360982A CN200410036098A CN1311818C CN 1311818 C CN1311818 C CN 1311818C CN B2004100360982 A CNB2004100360982 A CN B2004100360982A CN 200410036098 A CN200410036098 A CN 200410036098A CN 1311818 C CN1311818 C CN 1311818C
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 18
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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- Medicinal Preparation (AREA)
Abstract
The present invention relates to a medical composition for anti-entity tumors, which comprises anticancer effective components and pharmaceutic supplementary materials, wherein the anticancer effective components are platinum compounds; the pharmaceutic supplementary materials are mainly high molecular biologic capacitability polymers which can be degraded and absorbed, and in a degradation and absorption process, anticancer drugs can be slowly released at part of at a tumor, so the systemic toxicity reactions of the drugs are reduced obviously; simultaneously, the effective drug concentration can be kept at part of the tumor. The composition is put at part of the tumor, the systemic toxicity reactions of the drugs can be reduced, and simultaneously, the drug concentration of part of the tumor can be enhanced in a selective mode. 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 pharmaceutical composition of anti entity tumour, belong to technical field of pharmaceuticals.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of platinum-like compounds is comparatively obvious, has been widely used in multiple malignant tumor.Yet, further discover, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Because 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) (KongQ 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.Therefore, keep high drug level and increase tumor cell at tumor by local the sensitivity of medicine is just become an important subject.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of pharmaceutical composition of anti entity tumour is provided.
Entity-tumor-resistant medicine composition of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is a platinum-like compounds.
Above-mentioned platinum-like compounds is selected from platinum in heptan, DNA-2114, enloplatin (Enloplatin), sulfatodiamino cyclohexane platinum (ring ethylenediamine platinic sulfate), Spiroplatin (spiral shell sulphur platinum amine), dexormaplatin (Dexormaplatin), iproplatin (Iproplatin), lobaplatin (Lobaplatin), rice platinum (Miboplatin), nedaplatin (Nedaplatin), ormaplatin (Ormaplatin), oxaliplatin (Oxaliplatin, Oxaloplatin, 02), sebriplatin (Sebriplatin), spiroplatin (Spiroplatin) and zeniplatin (Zeniplatin) etc.
Above-mentioned platinum-like compounds can singly select or multiselect.
One or more of above-mentioned platinum-like compounds platinum in preferred heptan, enloplatin, dexormaplatin, lobaplatin, ormaplatin or oxaliplatin.
The percentage by weight of above-mentioned platinum-like compounds (anticancer active ingredient) in compositions is 0.1%-99.9%, is good with 0.1%-80%, and 5%-40% is best.
Above-mentioned 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 (sebacicacid) 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 but comparatively desirable, referring to United States Patent (USP) 4757128.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), sees 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 is, but is not limited to, 5000-100, and 000, 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, 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 that polylactic acid and the molecular weight of 5000-10000 is that the polylactic acid that polylactic acid mixes, molecular weight is 10000-20000 and the molecular weight of 20000-50000 is that the PLGA that the polylactic acid that PLGA mixes, molecular weight is 5000-10000 mixes with the certain herbaceous plants with big flowers diacid, molecular weight is 30000-80000 of 30000-80000 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 entity-tumor-resistant medicine 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 entity-tumor-resistant medicine 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 preferred, 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 adjuvants.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 entity-tumor-resistant medicine 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 composition for treating solid tumor 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.
Entity-tumor-resistant medicine composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, suspension, ointment, capsule, slow releasing agent, implant, implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, based on agent for slow releasing in the body or implant.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
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.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and entity-tumor-resistant medicine composition also can be packaged in the liposome.
Because entity-tumor-resistant medicine 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
Entity-tumor-resistant medicine composition of the present invention can be through various administrations, as in vein, 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, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump and slow releasing capsule or sustained release profile in vivo test implant as selecting for use.With the tremulous pulse approach is good, directly is placed as the best in the tumor body.
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, can be 0.01-80 milligram/kg body weight, is ideal with 1-50 milligram/kg body weight, with 2-10 milligram/kg body weight for the most desirable.
The application of entity-tumor-resistant medicine composition of the present invention is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal 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 or rectum former or secondary.
Entity-tumor-resistant medicine composition of the present invention also can be used for the treatment of the medicine of the various entity tumors of house pet and animal, 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 entity-tumor-resistant medicine composition of the present invention for use.
Also can add other medicinal ingredient in the entity-tumor-resistant medicine 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.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can with topical, wherein be released to the best with local slow again as injection in selective arterial injection and the direct tumor body for good through various administrations.When used the part, composition for treating solid tumor 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.
Entity-tumor-resistant medicine 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.
The characteristics of entity-tumor-resistant medicine composition technology of preparing of the present invention are platinum-like compounds is packaged in the pharmaceutic adjuvant, in proportion with the dissolving of active ingredient and pharmaceutic adjuvant, treat after the abundant mixing dryly, are shaped immediately after to be dried and sterilize packing.
Above platinum-like compounds is local to be placed, not only can overcome the toxic reaction that the whole body administration brings, and has solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
The external tumor-inhibiting action of test one, platinum-like compounds.
Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Following platinum-like compounds is added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continues to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 1.
Table 1
| Oncocyte | Sebriplatin | DNA-2114 | Lobaplatin | Heptan platinum | Dexormaplatin | Enloplatin | Rice platinum | Nedaplatin | Oxaliplatin |
| CNS | 68％ | 64％ | 66％ | 64％ | 90％ | 56％ | 58％ | 49％ | 56％ |
| C6 | 62％ | 64％ | 60％ | 64％ | 96％ | 60％ | 68％ | 64％ | 54％ |
| SA | 58％ | 60％ | 56％ | 60％ | 86％ | 56％ | 62％ | 62％ | 62％ |
| BC | 54％ | 64％ | 54％ | 54％ | 94％ | 64％ | 64％ | 60％ | 62％ |
| BA | 54％ | 62％ | 62％ | 52％ | 98％ | 62％ | 62％ | 58％ | 60％ |
| LH | 60％ | 58％ | 62％ | 68％ | 90％ | 62％ | 58％ | 56％ | 64％ |
| PAT | 54％ | 56％ | 66％ | 66％ | 94％ | 56％ | 58％ | 59％ | 58％ |
Tumor-inhibiting action in the body of test two, platinum-like compounds.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 2).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of platinum-like compounds is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 30th day.
Table 2
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 82.5±23cm 3 | |
| 2(6) | Dexormaplatin | 64±5.3cm 3 | ＜0.05 |
| 3(6) | Oxaliplatin | 61±2.3cm 3 | ＜0.01 |
| 4(6) | Lobaplatin | 54±3.6cm 3 | ＜0.01 |
| 5(6) | Heptan platinum | 58±3.4cm 3 | ＜0.01 |
| 6(6) | Enloplatin | 56±3.8cm 3 | ＜0.01 |
| 7(6) | Rice platinum | 38±3.6cm 3 | ＜0.001 |
| 8(6) | Spiroplatin | 36±3.6cm 3 | ＜0.001 |
| 9(6) | Zeniplatin | 34±3.6cm 3 | ＜0.001 |
| 10(6) | Sebriplatin | 28±3.6cm 3 | ＜0.001 |
Explain: above platinum-like compounds all has obvious tumor-inhibiting action (P＜0.05).
Tumor-inhibiting action relatively in the body of test three, different approaches platinum-like compounds.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (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 oxaliplatin, and the 5th to 7 group is platinum in heptan, and the 8th to 10 group is enloplatin.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.Dosage is 5mg/kg.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 | 88±2 | |
| 2(6) | Oxaliplatin (ip) | 48±5.3 | ＜0.05 |
| 3(6) | Oxaliplatin (it) | 58±2.3 | ＜0.01 |
| 4(6) | Oxaliplatin (itp) | 56±3.4 | ＜0.01 |
| 5(6) | Platinum in heptan (ip) | 48±3.0 | ＜0.01 |
| 6(6) | Platinum in heptan (it) | 44±3.0 | ＜0.01 |
| 7(6) | Platinum in heptan (itp) | 33±3.0 | ＜0.001 |
| 8(6) | Enloplatin (ip) | 32±3.6 | ＜0.001 |
| 9(6) | Enloplatin (it) | 24±3.6 | ＜0.001 |
| 10(6) | Enloplatin (itp) | 18±3.6 | ＜0.001 |
Above result shows that used various medicines 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 (implant) is the most obvious.Local placement not only can suppress tumor growth effectively, and can significantly reduce the general toxic reaction of medicine.Therefore, the effective ingredient of entity-tumor-resistant medicine composition of the present invention is any one (or multiple).The entity-tumor-resistant medicine composition that contains above effective ingredient can be made into any dosage form or shape, but serves as preferred with agent for slow releasing (or implant) type.
The preparation method of entity-tumor-resistant medicine composition of the present invention is as follows:
1. the pharmaceutic adjuvant of weighing is put into container, it is even to add organic dissolution with solvents, and the not strict qualification of the amount of organic solvent is suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing by above-mentioned percentage by weight shakes up 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.
(4) specific embodiment
Embodiment 1.
With the 90mg molecular weight is that 10000 polylactic acid (PLGA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 10mg oxaliplatin, shakes 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 entity-tumor-resistant medicine composition of percentage by weight 10% oxaliplatin.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 2. is as described in the embodiment 1, and different is that contained anticancer effective component is: the platinum in heptan of 0.1-30%, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, sebriplatin, spiroplatin or zeniplatin.All be weight percentage.
Embodiment 3.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 20mg oxaliplatin, 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 entity-tumor-resistant medicine composition of 20% oxaliplatin.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
As described in embodiment 3, different is that anticancer effective component is:
The platinum in heptan of 0.1-30%, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, sebriplatin, spiroplatin or zeniplatin.All be weight percentage.
Embodiment 5.
(EVAc) puts into container with the 90mg ethylene vinyl acetate copolymer, add 100 milliliters of dichloromethane dissolving mixings after, adds 10 milligrams of dexormaplatins, 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 10% dexormaplatin entity-tumor-resistant medicine composition.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 6. is as described in the embodiment 5, and different is that anticancer effective component is:
The platinum in heptan of 0.1-30%, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, sebriplatin, spiroplatin or zeniplatin.All be weight percentage.
Embodiment 7. is as described in the embodiment 5, and different is that anticancer effective component is:
10% platinum in heptan, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin or lobaplatin.All be weight percentage.
Embodiment 8. is as described in embodiment 1,3 or 5, and different is, and that used pharmaceutic adjuvant is respectively is one of following:
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 the copolymer (polifeprosan) of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA), to carboxy phenyl propane: certain herbaceous plants with big flowers diacid percentage by weight is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
Test four, composition for treating solid tumor extracorporeal releasing characteristic are relatively
Pastille complex in the foregoing description 7 is placed in the room temperature normal saline soaks, survey the different time release amount of medicine, and calculate accumulative total and discharge percent (%).Be shown in Table 4.
Table 4
| Embodiment 7 | 1 day | 3 days | 5 days | 7 days | 14 |
| A B C D E F G H | 20 19 21 23 22 23 22 20 | 40 39 41 42 38 39 40 41 | 60 61 63 62 59 59 61 61 | 70 78 79 78 76 72 81 81 | 89 88 92 90 90 90 85 86 |
Release characteristics relatively in test five, the composition for treating solid tumor body
It is subcutaneous that pastille complex in the foregoing description 7 is put in white mice, regularly takes out and survey medicament contg, according to the residual drug amount, and calculates accumulative total and discharge percent (%).Be shown in Table 5.
Table 5
| Embodiment 7 | 1 day | 3 days | 5 days | 7 days | 14 | 21 | 28 days |
| A B C D E F G H | 10 9 11 13 12 13 12 10 | 20 29 21 22 21 19 20 21 | 30 31 33 32 29 29 31 31 | 50 48 49 58 56 52 51 51 | 79 78 72 73 70 70 5 66 | 96 94 96 96 94 94 93 93 | 98 98 99 99 98 99 98 98 |
As can be seen from Table 4, the different pharmaceutical release in vitro no significant difference that tries discharged the about 20%, the 14th day and discharges 85-90% in first day.
As can be seen from Table 5, try to discharge in the different pharmaceutical body also no significant difference, discharged the about 10%, 28th day and discharge more than 98% in first day.But the inside and outside discharges notable difference is arranged, release in vitro is fast than being released in the body.Can keep one month in vivo.
Because the used platinum-like compounds of the present invention is of universal significance, and inside and outside release is comparatively slow and steady, so platinum-like compounds is arbitrarily in the composition for treating solid tumor of the present invention.Composition for treating solid tumor can be made various dosage forms with existing method, and therefore, above embodiment only is used for explanation, and is not limitation application of the present invention.
Claims (5)
1. entity-tumor-resistant medicine composition, comprise anticancer effective component and pharmaceutic adjuvant, it is characterized in that this pharmaceutical composition is a sustained-release implant, described anticancer effective component is platinum in heptan, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin or the zeniplatin in the platinum-like compounds;
Described pharmaceutic adjuvant is a slow-release auxiliary material, is selected from one of following or its combination:
A) molecular weight is the polylactic acid 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;
C) ethylene vinyl acetate copolymer; Or
D) to the copolymer of carboxy phenyl propane and certain herbaceous plants with big flowers diacid, to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
2. the entity-tumor-resistant medicine composition according to claim 1 is characterized in that the percentage by weight of platinum-like compounds in pharmaceutical composition is 0.1%-80%.
3. the entity-tumor-resistant medicine composition according to claim 1 is characterized in that the percentage by weight of platinum-like compounds in pharmaceutical composition is 5%-40%.
4. the entity-tumor-resistant medicine composition according to claim 1 is characterized in that, the interior or all placements of tumor of this anticancer pharmaceutical composition tumor.
5. the purposes of the described entity-tumor-resistant medicine composition of claim 1 is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal 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 or rectum former or secondary.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1361693A (en) * | 1999-05-19 | 2002-07-31 | 金子升 | Use of 1,4-benzothiazepine derivatives as drugs overcoming carcinostatic tolerance |
| CN1089582C (en) * | 1996-08-28 | 2002-08-28 | 孔庆忠 | Agent for slow releasing medicine |
| US6673805B2 (en) * | 2001-12-06 | 2004-01-06 | Pharmacia Italia S.P.A. | Platinum derivative pharmaceutical formulations |
| CN1133464C (en) * | 1995-03-01 | 2004-01-07 | 耶达研究及发展有限公司 | Pharmaceutical compositions for controlled release of soluble receptors |
| CN1170533C (en) * | 1999-08-30 | 2004-10-13 | 德比奥法姆股份有限公司 | Pharmaceutically stable oxaliplatinum preparation for parenteral administration |
-
2004
- 2004-11-22 CN CNB2004100360982A patent/CN1311818C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1133464C (en) * | 1995-03-01 | 2004-01-07 | 耶达研究及发展有限公司 | Pharmaceutical compositions for controlled release of soluble receptors |
| CN1089582C (en) * | 1996-08-28 | 2002-08-28 | 孔庆忠 | Agent for slow releasing medicine |
| CN1361693A (en) * | 1999-05-19 | 2002-07-31 | 金子升 | Use of 1,4-benzothiazepine derivatives as drugs overcoming carcinostatic tolerance |
| CN1170533C (en) * | 1999-08-30 | 2004-10-13 | 德比奥法姆股份有限公司 | Pharmaceutically stable oxaliplatinum preparation for parenteral administration |
| US6673805B2 (en) * | 2001-12-06 | 2004-01-06 | Pharmacia Italia S.P.A. | Platinum derivative pharmaceutical formulations |
Non-Patent Citations (4)
| Title |
|---|
| 回顾铂的应用及铂族金属抗癌药物的研究进展 杨一昆，普绍平，高文桂，中国新药杂志，第8卷第12期 1999 * |
| 回顾铂的应用及铂族金属抗癌药物的研究进展 杨一昆，普绍平，高文桂，中国新药杂志，第8卷第12期 1999;回顾铂类化合物的发展历程及临床评价 宋慧忠，张石革，中国医院用药评价与分析，第4卷第1期 2004;药物控释体系的研究与控释技术进展 李良，李国明，江苏化工，第30卷第6期 2002 * |
| 回顾铂类化合物的发展历程及临床评价 宋慧忠，张石革，中国医院用药评价与分析，第4卷第1期 2004 * |
| 药物控释体系的研究与控释技术进展 李良，李国明，江苏化工，第30卷第6期 2002 * |
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