CN101204367A - Axitinib sustained-release implplant treating for solid tumor - Google Patents
Axitinib sustained-release implplant treating for solid tumor Download PDFInfo
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- CN101204367A CN101204367A CNA2007102027615A CN200710202761A CN101204367A CN 101204367 A CN101204367 A CN 101204367A CN A2007102027615 A CNA2007102027615 A CN A2007102027615A CN 200710202761 A CN200710202761 A CN 200710202761A CN 101204367 A CN101204367 A CN 101204367A
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Abstract
The invention relates to an Axitinib sustained-release implant for treating a solid tumor, which is characterized in that: the sustained-release implant contains an effective anticancer amount of Axitinib and sustained-release excipients and a certain amount of sustained-release regulator. The solid tumors include the liver cancer, the lung cancer, the esophageal canner, the gastric canner, the breast canner, the ovarian canner, the prostate canner, the bladder canner and the rectum canner. The sustained-release excipients are mainly a copolymer of polylactic acid, glycollic acid and hydroxyacetic acid and one of the three materials, polifeprosan, poly-(L-lactide-co-ethyl phosphonate) and Poly(L-lactide-co-propyl phosphonate) or a combination of the three materials, in the degradation and absorption process of which the Axitinib is sustainedly released to part of the tumor, thus the entire toxicity of the Axitinib is significantly reduced while an effective medicine consistency is maintained on part of the tumor. That the sustained-release implant is implanted inside part of the tumor can not only reduce the entire toxicity of the Axitinib, but also enhance the medicine consistency on part of the tumor, thereby increasing the curing effect of non-operative therapeutics such as chemotherapeutic drugs and radiotherapy.
Description
(1) technical field
The present invention relates to a kind of sustained-release implant for the treatment of entity tumor, belong to technical field of pharmaceuticals.
(2) background technology
Though the research about cancer has obtained bigger progress, its mortality rate still occupies the prostatitis of the various common causes of the death.Up-to-date data show that China had 3,000,000 people to die from cancer in 2006.Cancer morbidity rises year by year and is rejuvenation trend, has data to show that in less than the time in 20 years, China's cancer morbidity has risen 69%, and mortality rate has increased by 29.4%.According to World Health Organization's recent statistics, will increase by 50 percent to the year two thousand twenty whole world cancer morbidity, number of the infected increases to 15,000,000.Estimate that the year two thousand twenty China will have 4,000,000 people to die from cancer therefore every year, inquire into the focus that a kind of effective treatment method for cancer or medicine have become present research.
A Xi is a kind of oral cancer therapy drug for Buddhist nun (Axitinib), have active selective depressant for first, second and third type of vascular endothelial growth factor receptor, and be proved and effectively had activity antithyroid, pancreatic cancer and metastatic renal cell tumor.Yet the inhibitory action to other tumors, particularly other solid tumors it be unclear that.Though unite separately or with other anticarcinogen some tumor may be had certain effect by tool, limited its clinical practice by the caused whole body toxic and side effects of conventional route administration.
(3) summary of the invention
Based on above examination to prior art, the present invention compares other tumor, found that A Xi replaces the Buddhist nun that entity tumors such as the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer and rectal cancer are had comparatively significantly action effect.Discover that further A Xi replaces Buddhist nun's local sustained release that the outer entity tumor of other craniums such as thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate is also had good therapeutical effect.Yet conventional method is difficult to bring into play its anti-tumor effect.Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.
The present invention is directed to the deficiencies in the prior art, a kind of sustained-release implant is provided, be used for the treatment of entity tumor, not only effect is obvious, and its general toxicity obviously alleviates.
The present invention treats the sustained-release implant of entity tumor, it is characterized in that A Xi that this sustained-release implant contains effective anticancer for Buddhist nun, slow-release auxiliary material and a certain amount of slow release regulator, and wherein the weight ratio of each constituent is:
(1) A Xi is for Buddhist nun 0.1%-60%
(2) slow-release auxiliary material 40%-99%
(3) slow release regulator 0-15%
Decanedioic acid (SA) copolymer), a kind of or its combination among poly-(L-lactide-co-etherophosphoric acid) (p (LAEG-EOP)), poly-(L-lactide-co-phosphoric acid propyl ester) (p (DAPG-EOP)) slow-release auxiliary material of the present invention mainly is selected from the copolymer (PLGA), polifeprosan of polylactic acid (PLA), glycolic and hydroxyacetic acid (to carboxy phenyl propane (p-CPP):.
Wherein the molecular weight peak value of polylactic acid (PLA) is 5000-15000,10000-20000,20000-35000 or 30000-50000; Serve as preferred wherein with 5000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.
The molecular weight peak value of the copolymer of glycolic and hydroxyacetic acid (PLGA) is 5000-15000,15000-35000,35000-45000 or 45000-80000; Serve as preferred wherein with 5000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.The percentage by weight of glycolic and hydroxyacetic acid is 90: 10,80: 20, and 70: 30,60: 40,50: 50 or 40: 60; Wherein with 80: 20,70: 30,60: 40, be preferred at 50: 50, with 60: 40 and 50: 50 for most preferably.
Polifeprosan (to carboxy phenyl propane (p-CPP): the percentage by weight to carboxy phenyl propane (p-CPP) and decanedioic acid (SA) decanedioic acid (SA) copolymer) is 10: 90,20: 80, and 30: 70,40: 60,50: 50 or 60: 40; Wherein with 80: 20,70: 30,60: 40, be preferred at 50: 50, with 60: 40 and 50: 50 for most preferably.
The molecular weight peak value of poly-(L-lactide-co-etherophosphoric acid) is 5000-15000,10000-20000,20000-35000 or 30000-50000, serve as preferred wherein with 5000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.
In " slow-release auxiliary material complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor), slow-release auxiliary material is had a detailed description.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 slow-release auxiliary material.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above slow-release auxiliary material 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 slow-release auxiliary material, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The slow release regulator is selected from a kind of or its combination in xylitol, oligosaccharide, chitin, potassium salt, sodium salt, mannitol, sorbitol, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
For regulating other characteristic of drug releasing rate or change anti-cancer sustained-released implantation agent of the present invention, can change the monomer component of polymer or the composition and the proportioning of molecular weight, interpolation or adjusting slow-release auxiliary material, 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.
Characteristics of the present invention are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other slow-release auxiliary material.The slow-release auxiliary material of adding 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.
Slow-release auxiliary material 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 slow-release auxiliary material is applicable to the compositions that contains or do not contain additive.
The consumption of sustained-release implant 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 its principle is at the repair ability that can reduce tumor cell, when increasing the chemotherapy action effect and the toxic reaction of not obvious increase medicine.Effective dose is 0.01-100 milligram/patient, is ideal with 1-50 milligram/patient, with 2-30 milligram/patient for the most desirable.
The present invention can be made into different shape, and wherein the content of active ingredient is decided because of different needs.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., wherein implant is mainly sustained-release implant, controlled release implant or slowbreak implant; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and apperance; Can be through various administrations, as in tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Whether route of administration depends on multiple factor, as position, tumor place, perform the operation or transfer, gross tumor volume size, tumor classification, patient age, health, bearing status and requirement etc.For obtain active drug concentration in position, tumor place, arterial perfusion optionally, intra-bladder instillation (intracavitary), (intraspinal) administration in abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and the canalis spinalis, but also place in the internal organs, as in the enteric cavity, in the intravesical, uterine cavity, in intravaginal, gastric and the esophagus etc.In various approach, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, to place the form that slowly discharges serve as preferably for tumor week or tumor chamber, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant and sustained-release implant as selecting for use.
Available arbitrary method preparation.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; (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 anti-cancer sustained-released implantation agent also can be packed in the liposome.The effective ingredient of compositions can be packaged in the whole slow-release auxiliary material 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.Each component and the weight percentage in compositions thereof are preferred one of following in the sustained-release implant:
(A) A Xi of 1%-5% is for the polylactic acid of Buddhist nun and 95%-99%;
(B) A Xi of 5%-10% is for the polylactic acid of Buddhist nun and 90%-95%;
(C) A Xi of 10%-15% is for the polylactic acid of Buddhist nun and 85%-90%;
(D) A Xi of 15%-25% is for the polylactic acid of Buddhist nun and 75%-85%;
(E) A Xi of 25%-40% is for the polylactic acid of Buddhist nun and 60%-75%;
(F) A Xi of 1%-10% is for Buddhist nun and the glycolic of 90%-99% and the copolymer of hydroxyacetic acid;
(G) A Xi of 10%-20% is for Buddhist nun and the glycolic of 80%-90% and the copolymer of hydroxyacetic acid;
(H) A Xi of 20%-30% is for Buddhist nun and the glycolic of 70%-80% and the copolymer of hydroxyacetic acid;
(I) A Xi of 30%-40% is for Buddhist nun and the glycolic of 60%-70% and the copolymer of hydroxyacetic acid;
(J) A Xi of 5%-15% is for the polifeprosan of Buddhist nun and 85%-95%;
(K) A Xi of 15%-35% is for the polifeprosan of Buddhist nun and 65%-85%;
(L) 5% A Xi is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 95%;
(M) 10% A Xi is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 90%;
(N) 20% A Xi is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 80%;
(O) 30% A Xi is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 70%;
(P) 5% A Xi is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 95%;
(Q) 10% A Xi is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 90%;
(R) 20% A Xi is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 80%;
(S) 30% A Xi is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 70%.
Each component and the weight percentage in compositions thereof are one of further preferred following in the sustained-release implant:
(A) A Xi of 1%-5% is for Buddhist nun and the polylactic acid of 85%-98% and the mannitol of 0.5%-15%;
(B) A Xi of 5%-10% is for Buddhist nun and the polylactic acid of 90%-95% and the sorbitol of 0.5%-10%;
(C) A Xi of 10%-15% is for Buddhist nun and the polylactic acid of 85%-90% and the sodium chloride of 0.5%-10%;
(D) A Xi of 15%-25% is for Buddhist nun and the polylactic acid of 75%-85% and the mannitol of 0.25%-5%;
(E) A Xi of 25%-40% is for the sorbitol of the polylactic acid 0.1%-8% of Buddhist nun and 60%-75%;
(F) A Xi of 1%-10% is for glycolic and the copolymer of hydroxyacetic acid and the mannitol of 0.5%-15% of Buddhist nun and 90%-99%;
(G) A Xi of 10%-20% is for glycolic and the copolymer of hydroxyacetic acid and the sorbitol of 0.5%-10% of Buddhist nun and 80%-90%;
(H) A Xi of 20%-30% is for glycolic and the copolymer of hydroxyacetic acid and the sodium chloride of 0.5%-10% of Buddhist nun and 70%-80%;
(I) A Xi of 30%-40% is for glycolic and the copolymer of hydroxyacetic acid and the mannitol of 0.25%-5% of Buddhist nun and 60%-70%;
(J) A Xi of 5%-15% is for Buddhist nun and the polifeprosan of 85%-95% and the mannitol of 1%-5%;
(K) A Xi of 15%-35% is for Buddhist nun and the polifeprosan of 65%-85% and the mannitol of 0.25%-7.5%;
(L) 5% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 2% the sodium chloride of Buddhist nun and 92%;
(M) 10% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 85%;
(N) 20% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%;
(O) 30% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%;
(P) 5% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 2% the sodium chloride of Buddhist nun and 92%;
(Q) 10% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 85%;
(R) 20% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%;
(S) 30% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%.
Sustained-release implant is used for the treatment of entity tumor, comprise the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma, tumor of head and neck and come from gallbladder, oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, eyes, former or cancer, sarcoma or the carcinosarcoma of secondary.Therefore, application of the present invention is the above-mentioned various pharmaceutical preparatioies that are used to make the above-mentioned tumor of treatment, serve as preferred wherein with injection, muddy suspension, ointment, capsule, implant, slow releasing agent and sustained-release implant, with sustained-release implant, controlled release implant or slowbreak implant for most preferably.
Also can add other medicinal ingredient in this anti-cancer sustained-released implantation agent, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Because anti-cancer sustained-released implantation agent 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.When share with above-mentioned non-operative treatment, anti-cancer sustained-released implantation agent of the present invention can be used simultaneously with non-operative treatment, also can in implementing a few days ago, non-operative treatment use, its purpose is to strengthen as far as possible the sensitivity of tumor, thereby provide a kind of more effective new method for effecting a radical cure former of various human bodies and animal and shifting entity tumor, have very high clinical value and remarkable economical and social benefit.
When used the part, said composition 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.
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 outer entity tumor of cranium had the obvious treatment effect.
Anti-cancer composition of the present invention can be implemented by many schemes, and its purpose is just in order to further specify, and is not in addition any restriction of enforcement of the present invention.
Test one, A Xi are for the inhibitory action of Buddhist nun to growth of tumour cell.
For checking A Xi replaces the inhibitory action of Buddhist nun to other growth of tumour cell, this test is added to A Xi in 24 hours the various tumor cells of In vitro culture (table 1) for Buddhist nun (15ug/ml), continues to cultivate after 48 hours the counting cells sum and calculates its suppression ratio to growth of tumour cell (%).
The suppression ratio of growth of tumour cell (%)=((cellular control unit number-test group cell number)/cellular control unit number) * 100%
Table 1
| Tumor cell | Suppression ratio (%) |
| Hepatocarcinoma | 70 |
| Pulmonary carcinoma | 78 |
| The esophageal carcinoma | 72 |
| Gastric cancer | 78 |
| Breast carcinoma | 66 |
| Cancer of pancreas | 86 |
| Thyroid carcinoma | 88 |
| Nasopharyngeal carcinoma | 80 |
| Ovarian cancer | 78 |
| Carcinoma of endometrium | 70 |
| Cervical cancer | 80 |
| Renal carcinoma | 82 |
| Carcinoma of prostate | 78 |
| Bladder cancer | 78 |
| Colon cancer | 76 |
| Rectal cancer | 70 |
| Skin carcinoma | 72 |
| Carcinoma of testis | 70 |
The result of test one shows, compares with matched group, and A Xi all has obvious inhibitory action (P＜0.05) for the Buddhist nun to the examination growth of tumor, and is wherein right.This is unexpected finds to constitute major technique feature of the present invention, for the treatment of entity tumor provides new selection.
Contain A Xi and can be made into any dosage form or shape, but serve as preferred with the agent for slow releasing of implanting for Buddhist nun's sustained-release implant.
The preparation method of sustained-release implant of the present invention is as follows:
The slow-release auxiliary material 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.
Adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and slow-release auxiliary material is decided because of specific requirement.
Remove organic solvent.Vacuum drying or cold drying all can.
Dried solid composite is made different shape as required.
Ray sterilizing after the packing (roentgendosis is different because of volume) is standby.Also available other method sterilization.
(4) specific embodiment
Embodiment one,
The slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 10000-20000) of (90mg) of will weighing is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 10 milligrams of A Xi for the Buddhist nun, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 10% A Xi for the Buddhist nun.The drug release time of this sustained-release implant in external normal saline is 14-20 days, is 15-22 days at the subcutaneous drug release time of mice.
Embodiment two
Make sustained-release implant by embodiment one described method, but contained anticancer effective component is one of following:
(A) 1% A Xi for the Buddhist nun and and 99% polylactic acid;
(B) 5% A Xi for the Buddhist nun and and 95% polylactic acid;
(C) 10% A Xi is for the polylactic acid of Buddhist nun and 90%;
(D) 15% A Xi is for the polylactic acid of Buddhist nun and 85%;
(E) 20% A Xi is for the polylactic acid of Buddhist nun and 80%.
Embodiment three
(molecular weight is the PLGA of 15000-25000 to the slow-release auxiliary material of (85mg) of will weighing, 50: 50) put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion), add 15mg A Xi, shake up the dry organic solvent of removing of final vacuum again for the Buddhist nun with abundant dissolving.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 15% A Xi for the Buddhist nun.The drug release time of this sustained-release implant in external normal saline is 14-22 days, is 18-26 days at the subcutaneous drug release time of mice.
Embodiment four
Make sustained-release implant by embodiment three described methods, contained anticancer effective component that different is is one of following:
(1) A Xi of 1%-10% is for Buddhist nun and the glycolic of 90%-99% and the copolymer of hydroxyacetic acid;
(2) A Xi of 10%-20% is for Buddhist nun and the glycolic of 80%-90% and the copolymer of hydroxyacetic acid;
(3) A Xi of 20%-30% is for Buddhist nun and the glycolic of 70%-80% and the copolymer of hydroxyacetic acid;
(4) A Xi of 30%-40% is for Buddhist nun and the glycolic of 60%-70% and the copolymer of hydroxyacetic acid;
(5) 5% A Xi is for the glycolic of Buddhist nun and 95% and the copolymer of hydroxyacetic acid;
(6) 10% A Xi is for the glycolic of Buddhist nun and 90% and the copolymer of hydroxyacetic acid;
(7) 20% A Xi is for the glycolic of Buddhist nun and 80% and the copolymer of hydroxyacetic acid;
(8) 30% A Xi is for the glycolic of Buddhist nun and 70% and the copolymer of hydroxyacetic acid.
Embodiment five
(molecular weight is the PLGA of 25000-30000 to the slow-release auxiliary material of (85mg) of will weighing, 75: 25) put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion), add 10mg A Xi, shake up the dry organic solvent of removing of final vacuum again for Buddhist nun and 5mg mannitol with abundant dissolving.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 10% A Xi for the Buddhist nun.The drug release time of this sustained-release implant in external normal saline is 14-24 days, is 20-30 days at the subcutaneous drug release time of mice.
Embodiment six
Make sustained-release implant by embodiment five described methods, contained anticancer effective component that different is is one of following:
(1) A Xi of 1%-10% is for glycolic and the copolymer of hydroxyacetic acid and the mannitol of 0.5%-15% of Buddhist nun and 90%-99%;
(2) A Xi of 10%-20% is for glycolic and the copolymer of hydroxyacetic acid and the sorbitol of 0.5%-10% of Buddhist nun and 80%-90%;
(3) A Xi of 20%-30% is for glycolic and the copolymer of hydroxyacetic acid and the sodium chloride of 0.5%-10% of Buddhist nun and 70%-80%;
(4) A Xi of 30%-40% is for glycolic and the copolymer of hydroxyacetic acid and the mannitol of 0.25%-5% of Buddhist nun and 60%-70%;
(5) 5% A Xi is for glycolic and the copolymer of hydroxyacetic acid and 2% the sodium chloride of Buddhist nun and 92%;
(6) 10% A Xi is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 85%;
(7) 20% A Xi is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 75%;
(8) 30% A Xi is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 75%.
Embodiment seven
85mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 50: 50) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 15mg A Xi for the Buddhist nun, 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 percentage by weight 15% A Xi for Buddhist nun's sustained-release implant.The drug release time of this sustained-release implant in external normal saline is 17-24 days, is 27-32 days at the subcutaneous drug release time of mice.
Embodiment eight
Make sustained-release implant by embodiment seven described methods, that contained anticancer effective component is is one of following but different is:
(1) A Xi of 1%-15% is for the polifeprosan of Buddhist nun and 85%-95%;
(2) A Xi of 15%-35% is for the polifeprosan of Buddhist nun and 65%-85%;
(3) 5% A Xi is for the polifeprosan of Buddhist nun and 95%;
(4) 10% A Xi is for the polifeprosan of Buddhist nun and 90%;
(5) 15% A Xi is for the polifeprosan of Buddhist nun and 85%-95%;
(6) 20% A Xi is for the polifeprosan of Buddhist nun and 80%.
Embodiment nine
80mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 30: 70) and 5mg sodium chloride are put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 15mg A Xi for the Buddhist nun, 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 percentage by weight 15% A Xi for Buddhist nun's sustained-release implant.The drug release time of this sustained-release implant in external normal saline is 12-20 days, is 16-23 days at the subcutaneous drug release time of mice.
Embodiment ten
Make sustained-release implant by embodiment ten described methods, that contained anticancer effective component is is one of following but different is:
(1) A Xi of 5%-15% is for Buddhist nun and the polifeprosan of 85%-95% and the mannitol of 1%-5%; Or
(2) A Xi of 15%-35% is for Buddhist nun and the polifeprosan of 65%-85% and the mannitol of 0.25%-7.5%.
Embodiment 11
85mg slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 15000-30000) and 10mg mannitol are put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 5 milligrams of A Xi for the Buddhist nun, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 5% A Xi for the Buddhist nun.The drug release time of this sustained-release implant in external normal saline is 18-24 days, is 20-28 days at the subcutaneous drug release time of mice.
Embodiment 12
Make sustained-release implant by embodiment 11 described methods, used slow-release auxiliary material is selected from one of following or its combination:
(A) 1% A Xi for the Buddhist nun and and 95% polylactic acid and 4% mannitol;
(B) 5% A Xi for the Buddhist nun and and 93% polylactic acid and 2% mannitol;
(C) 10% A Xi is for the polylactic acid of Buddhist nun and 85% and 5% mannitol;
(D) 15% A Xi is for the polylactic acid of Buddhist nun and 82% and 3% sodium chloride;
(E) 20% A Xi is for the polylactic acid of Buddhist nun and 78% and 2% sodium chloride.
Embodiment 13
Make sustained-release implant by embodiment 1 to 11 described method, used slow-release auxiliary material is selected from one of following or its combination:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,15000-35000,35000-45000 or 45000-80000 and the copolymer of hydroxyacetic acid (PLGA);
C) polifeprosan is (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) copolymer), be 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to the percentage by weight of carboxy phenyl propane (p-CPP) and decanedioic acid (SA).
On the basis of above-mentioned slow release, the present invention finds that further body is implanted into A Xi and for the Buddhist nun other entity tumors such as the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer, rectal cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate is also had good therapeutical effect.Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.Following in vivo test is used for explanation but not limitation of the present invention.
Embodiment 14
With 70,80,90 and 95mg molecular weight peak value be that the p (LAEG-EOP) of 10000-25000 puts into first, second, third, four containers of fourth respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in four containers, add 30mg, 20mg, 10mg and 5mg A Xi respectively for the Buddhist nun, shake up the preparation of after drying method again and contain the sustained-release implant of 30%, 20%, 10% and 5% A Xi for the Buddhist nun.The drug release time of this slow releasing agent in external normal saline is 22-30 days, is about 28-35 days at the subcutaneous drug release time of mice.
Embodiment 15
The method step that is processed into sustained-release implant is identical with embodiment 14, but the molecular weight peak value of different is p (LAEG-EOP) is 25000-45000, and contained anticancer effective component and percentage by weight thereof are:
(1) 1%-5% A Xi is for the Buddhist nun;
(2) 5%-10% A Xi is for the Buddhist nun;
(3) 10%-20% A Xi is for the Buddhist nun;
(4) 20%-40% A Xi is for the Buddhist nun;
(5) 5% A Xi is for the p (LAEG-EOP) of Buddhist nun and 92% and 2% sodium chloride;
(6) 10% A Xi is for the p (LAEG-EOP) of Buddhist nun and 85% and 5% mannitol;
(7) 20% A Xi is for the p (LAEG-EOP) of Buddhist nun and 75% and 5% mannitol;
(8) 30% A Xi is for the p (LAEG-EOP) of Buddhist nun and 75% and 5% mannitol.
Embodiment 16
With 70,80,90 and 95mg molecular weight peak value be that the p (DAPG-EOP) of 10000-25000 puts into first, second, third, four containers of fourth respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in four containers, add 30mg, 20mg, 10mg and 5mg A Xi respectively for the Buddhist nun, shake up the preparation of after drying method again and contain the sustained-release implant of 30%, 20%, 10% and 5% A Xi for the Buddhist nun.The drug release time of this slow releasing agent in external normal saline is 22-30 days, is about 30-35 days at the subcutaneous drug release time of mice.
Embodiment 17
The method step that is processed into sustained-release implant is identical with embodiment 16, but the molecular weight peak value of different is p (DAPG-EOP) is 25000-45000, and contained anticancer effective component and percentage by weight thereof are:
(1) 1%-5% A Xi is for the Buddhist nun;
(2) 5%-10% A Xi is for the Buddhist nun;
(3) 10%-20% A Xi is for the Buddhist nun;
(4) 20%-40% A Xi is for the Buddhist nun;
(5) 5% A Xi is for the p (DAPG-EOP) of Buddhist nun and 92% and 2% sodium chloride;
(6) 10% A Xi is for the p (DAPG-EOP) of Buddhist nun and 85% and 5% mannitol;
(7) 20% A Xi is for the p (DAPG-EOP) of Buddhist nun and 75% and 5% mannitol;
(8) 30% A Xi is for the p (DAPG-EOP) of Buddhist nun and 75% and 5% mannitol.
Embodiment 18, tumor are implanted into A Xi for the inhibitory action of Buddhist nun to entity tumor
Method and step: tumor cell inoculation is subcutaneous in the right side of mice axillary fossa, and (inoculation back the 8th day) is divided into 7 groups at random with animal, 10 every group when diameter of tumor grows to the 0.8cm left and right sides.Be normal saline group, A Xi for Buddhist nun's lumbar injection group (hereinafter to be referred as A Xi for Buddhist nun abdominal cavity group), A Xi for Buddhist nun's local injection group (being called for short A Xi), high molecular polymer group (being called for short high poly-group), A Xi for Buddhist nun's sustained-release implant group with (5% group, 10% group of the made sustained-release implant of embodiment four for Buddhist nun's partial groups, with 20% group, be called for short implant 5%, implant 10%, implant 20%).With 70% alcohol disinfecting tumor surface skin, selection is apart from tumor lower edge 1cm place, cut off the long otch of 1mm, with puncture needle A Xi is replaced in Buddhist nun's implant implantation tumour tissue, pastille high molecular polymer, A Xi replace Buddhist nun's implant 20% for Buddhist nun's implant 5%, A Xi for Buddhist nun's implant 10%, A Xi.Sew up the incision and prevent that implant from spilling.Put to death animal in 15 days with vernier caliper measurement tumor size after the implant embedding in per 3 days, the back of weighing is complete peels off tumor and claims tumor heavy.Calculate tumor control rate %, DAS.ver1.0 pharmacology software is done statistical procedures.
Tumor control rate=(the average tumor of the average tumor weight/normal saline of 1-administration group group is heavy) * 100%
Embodiment 19, tumor are implanted into A Xi for the tumor-inhibiting action of Buddhist nun spit of fland sustained-release implant to Mice Bearing Lewis Lung Cancer
Replace the tumor-inhibiting action of Buddhist nun's sustained-release implant according to embodiment 18 described methods and step check A Xi to Mice Bearing Lewis Lung Cancer.Used implant adjuvant is PLGA (molecular weight is 15000-30000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50), is derived from embodiment four.The A Xi of this experimental result proof various dose can obviously suppress tumor growth for Buddhist nun's implant, and tumor control rate and drug dose are obvious dose-effect relationship.A Xi is respectively 40%, 58%, 72% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Repeated experiments: tumor control rate is respectively 32%, 56%, 76%, compares with the local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.A Xi is 16% and 12.5% for Buddhist nun's lumbar injection group and A Xi for Buddhist nun's local injection group and normal saline group comparison of tumor suppression ratio, and repeated experiments: tumor control rate is 18% and 14%.A Xi obviously surpasses A Xi for Buddhist nun's lumbar injection group and local injection group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
Embodiment 20 tumors are implanted into A Xi for the tumor-inhibiting action of Buddhist nun's sustained-release implant to mouse breast cancer
Replace the tumor-inhibiting action of Buddhist nun's sustained-release implant to mouse breast cancer according to embodiment 18 described methods and step check A Xi, used implant is from embodiment one.Experimental result shows that 1%, 10% and 25% A Xi is respectively 40%, 52%, 68% for the tumor control rate of Buddhist nun's implant, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 42%, 60%, 72%, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Difference has the height statistical significance.It is 10% and 12% that A Xi replaces Buddhist nun's lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio, and repeated experiments: tumor control rate is 13% and 8%.A Xi obviously surpasses A Xi for Buddhist nun's lumbar injection group and local injection group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
Embodiment 21, tumor are implanted into A Xi for the tumor-inhibiting action of Buddhist nun's sustained-release implant to rat liver cancer
Replace the tumor-inhibiting action of Buddhist nun's sustained-release implant according to embodiment 18 described methods and step check A Xi to rat liver cancer, used implant is 5%, 10% and 20% polifeprosan (percentage by weight to carboxy phenyl propane (p-CPP) and decanedioic acid (SA) is 50: 50), from embodiment eight.The A Xi of experimental result proof various dose implants in rat liver cancer (H22) entity tumor for Buddhist nun's implant and can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.A Xi is respectively 38%, 56%, 70% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with A Xi, and low dose group P value equals 0.001, and middle and high dosage group P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 22%, 50%, 64%, compares for Buddhist nun's local injection group with A Xi, and low dose group P value is less than 0.05, and middle and high dosage group P value is all less than 0.001.Difference has the height statistical significance.A Xi is 28% and 20% for Buddhist nun's lumbar injection group and A Xi for Buddhist nun's local injection group and normal saline group comparison of tumor suppression ratio, and repeated experiments: tumor control rate is 25% and 20%.A Xi obviously surpasses A Xi for Buddhist nun's lumbar injection group and local injection group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
Embodiment 22 tumors are implanted into A Xi for the tumor-inhibiting action of Buddhist nun's sustained-release implant to the mice esophageal carcinoma
Replace the tumor-inhibiting action of Buddhist nun's sustained-release implant to the mice esophageal carcinoma according to embodiment 18 described methods and step check A Xi, used implant is selected from embodiment six.The A Xi of experimental result proof various dose implants in nude mice model human esophagus cancer (9706) entity tumor for Buddhist nun's implant, all can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.A Xi is respectively 42%, 50%, 72% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Repeated experiments finds that tumor control rate is respectively 40%, 62%, 76%, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Difference has the height statistical significance.It is 10% and 8% that A Xi replaces Buddhist nun's lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio, and repeated experiments shows that tumor control rate is 12% and 14%.A Xi obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
Embodiment 23, tumor are implanted into A Xi for the tumor-inhibiting action of Buddhist nun's sustained-release implant to mouse pancreas cancer
Replace the tumor-inhibiting action of Buddhist nun's sustained-release implant to mouse pancreas cancer according to embodiment 18 described methods and step check A Xi, used implant adjuvant is PLGA (molecular weight is 20000-35000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50).A Xi for the content of Buddhist nun in sustained-release implant be 2.5%, 7.5% and the A Xi of 12.5%. experimental result proof various dose implant in nude mice model human pancreas cancer (JF305) entity tumor for Buddhist nun's implant, can obviously suppress tumor growth, tumor control rate and drug dose are obvious dose-effect relationship.A Xi is respectively 36%, 48%, 78% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 58%, 68%, 82%, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Difference has the height statistical significance.It is 21% and 10.6% that A Xi replaces Buddhist nun's lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio.Repeated experiments finds that tumor control rate is 12% and 14%.A Xi obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
Embodiment 24, tumor are implanted into A Xi for the tumor-inhibiting action of Buddhist nun's sustained-release implant to the mice rectal cancer
Replace the tumor-inhibiting action of Buddhist nun's sustained-release implant to the mice rectal cancer according to embodiment 18 described methods and step check A Xi, used implant adjuvant is PLGA (molecular weight is 20000-35000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50).A Xi is 7.5%, 15% and 25% for the content of Buddhist nun in sustained-release implant.The A Xi of experimental result proof various dose can obviously suppress tumor growth for Buddhist nun's implant, and tumor control rate and drug dose are obvious dose-effect relationship.A Xi is respectively 56%, 78%, 86% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 52%, 68%, 86%, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Difference has the height statistical significance.It is 21% and 8% that A Xi replaces Buddhist nun's lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio.Repeated experiments finds that tumor control rate is 12% and 13%.A Xi obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
Embodiment 25, tumor are implanted into A Xi for the tumor-inhibiting action of Buddhist nun's sustained-release implant to the mice carcinoma of prostate
Replace the tumor-inhibiting action of Buddhist nun's sustained-release implant to the mice carcinoma of prostate according to embodiment 18 described methods and step check A Xi, used implant adjuvant is p (LAEG-EOP) (molecular weight is 10000-25000).A Xi is 5%, 10% and 20% (from embodiment 14) for the content of Buddhist nun in sustained-release implant.The A Xi of experimental result proof various dose implants in the nude mice model human prostata cancer entity tumor for Buddhist nun's implant, can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.A Xi is respectively 32%, 58%, 72% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 50%, 64%, 68%, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Difference has the height statistical significance.It is 21% and 11% that A Xi replaces Buddhist nun's lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio.Repeated experiments finds that tumor control rate is 12% and 12%.A Xi obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
Embodiment 26, tumor are implanted into A Xi for the tumor-inhibiting action of Buddhist nun's sustained-release implant to the mouse ovarian cancer
Replace the tumor-inhibiting action of Buddhist nun's sustained-release implant to the mouse ovarian cancer according to embodiment 18 described methods and step check A Xi, used implant adjuvant is p (DAPG-EOP) (molecular weight is 10000-25000).A Xi is 5%, 10% and 20% (from embodiment 16) for the content of Buddhist nun in sustained-release implant.A Xi is 7.5%, 15% and 25% for the content of Buddhist nun in sustained-release implant.The A Xi of experimental result proof various dose can obviously suppress tumor growth for Buddhist nun's implant, and tumor control rate and drug dose are obvious dose-effect relationship.A Xi is respectively 46%, 62%, 76% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 50%, 68%, 82%, compares for Buddhist nun's local injection group with A Xi, and the P value is all less than 0.001.Difference has the height statistical significance.It is 16% and 10% that A Xi replaces Buddhist nun's lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio.Repeated experiments finds that tumor control rate is 8% and 9%.A Xi obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
In addition, tumor is implanted into A Xi and for Buddhist nun's sustained-release implant other entity tumors such as gastric cancer, bladder cancer, carcinoma of testis, colon cancer, carcinoma of endometrium, lymphoma, the cerebral tumor, cervical cancer, renal carcinoma is also had good therapeutical effect, and its effect obviously surpasses A Xi for Buddhist nun's lumbar injection group and local injection group.This is unexpected finds to constitute another major technique feature of the present invention, for the treatment of entity tumor provides another new selection.
Claims (10)
1. sustained-release implant for the treatment of entity tumor is characterized in that A Xi that this sustained-release implant contains effective anticancer for Buddhist nun, slow-release auxiliary material and a certain amount of slow release regulator, and wherein the weight ratio of each constituent is:
(1) A Xi is for Buddhist nun 0.1%-60%
(2) slow-release auxiliary material 40%-99%
(3) slow release regulator 0-15%
Wherein,
Slow-release auxiliary material is selected from a kind of or its combination in the copolymer, polifeprosan of polylactic acid, polyglycolic acid and hydroxyacetic acid, poly-(L-lactide-co-etherophosphoric acid), poly-(the L-lactide-co-phosphoric acid propyl ester);
The slow release regulator is selected from a kind of or its combination in xylitol, oligosaccharide, chitin, potassium salt, sodium salt, mannitol, sorbitol, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
2. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) A Xi of 1%-5% is for the polylactic acid of Buddhist nun and 95%-99%;
(B) A Xi of 5%-10% is for the polylactic acid of Buddhist nun and 90%-95%;
(C) A Xi of 10%-15% is for the polylactic acid of Buddhist nun and 85%-90%;
(D) A Xi of 15%-25% is for the polylactic acid of Buddhist nun and 75%-85%;
(E) A Xi of 25%-40% is for the polylactic acid of Buddhist nun and 60%-75%;
(F) A Xi of 1%-10% is for Buddhist nun and the glycolic of 90%-99% and the copolymer of hydroxyacetic acid;
(G) A Xi of 10%-20% is for Buddhist nun and the glycolic of 80%-90% and the copolymer of hydroxyacetic acid;
(H) A Xi of 20%-30% is for Buddhist nun and the glycolic of 70%-80% and the copolymer of hydroxyacetic acid;
(I) A Xi of 30%-40% is for Buddhist nun and the glycolic of 60%-70% and the copolymer of hydroxyacetic acid;
(J) A Xi of 5%-15% is for the polifeprosan of Buddhist nun and 85%-95%;
(K) A Xi of 15%-35% is for the polifeprosan of Buddhist nun and 65%-85%.
3. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) A Xi of 1%-5% is for Buddhist nun and the polylactic acid of 85%-98% and the mannitol of 0.5%-15%;
(B) A Xi of 5%-10% is for Buddhist nun and the polylactic acid of 90%-95% and the sorbitol of 0.5%-10%;
(C) A Xi of 10%-15% is for Buddhist nun and the polylactic acid of 85%-90% and the sodium chloride of 0.5%-10%;
(D) A Xi of 15%-25% is for Buddhist nun and the polylactic acid of 75%-85% and the mannitol of 0.25%-5%;
(E) A Xi of 25%-40% is for the sorbitol of the polylactic acid 0.1%-8% of Buddhist nun and 60%-75%;
(F) A Xi of 1%-10% is for glycolic and the copolymer of hydroxyacetic acid and the mannitol of 0.5%-15% of Buddhist nun and 90%-99%;
(G) A Xi of 10%-20% is for glycolic and the copolymer of hydroxyacetic acid and the sorbitol of 0.5%-10% of Buddhist nun and 80%-90%;
(H) A Xi of 20%-30% is for glycolic and the copolymer of hydroxyacetic acid and the sodium chloride of 0.5%-10% of Buddhist nun and 70%-80%;
(I) A Xi of 30%-40% is for glycolic and the copolymer of hydroxyacetic acid and the mannitol of 0.25%-5% of Buddhist nun and 60%-70%;
(J) A Xi of 5%-15% is for Buddhist nun and the polifeprosan of 85%-95% and the mannitol of 1%-5%; Or
(K) A Xi of 15%-35% is for Buddhist nun and the polifeprosan of 65%-85% and the mannitol of 0.25%-7.5%.
4. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) 1% A Xi for the Buddhist nun and and 99% polylactic acid;
(B) 5% A Xi for the Buddhist nun and and 95% polylactic acid;
(C) 10% A Xi is for the polylactic acid of Buddhist nun and 90%;
(D) 15% A Xi is for the polylactic acid of Buddhist nun and 85%;
(E) 20% A Xi is for the polylactic acid of Buddhist nun and 80%;
(F) 5% A Xi is for the glycolic of Buddhist nun and 95% and the copolymer of hydroxyacetic acid;
(G) 10% A Xi is for the glycolic of Buddhist nun and 90% and the copolymer of hydroxyacetic acid;
(H) 20% A Xi is for the glycolic of Buddhist nun and 80% and the copolymer of hydroxyacetic acid;
(I) 30% A Xi is for the glycolic of Buddhist nun and 70% and the copolymer of hydroxyacetic acid;
(J) 5% A Xi is for the polifeprosan of Buddhist nun and 95%;
(K) 15% A Xi is for the polifeprosan of Buddhist nun and 85%;
(L) 5% A Xi is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 95%;
(M) 10% A Xi is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 90%;
(N) 20% A Xi is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 80%;
(O) 30% A Xi is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 70%;
(P) 5% A Xi is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 95%;
(Q) 10% A Xi is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 90%;
(R) 20% A Xi is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 80%;
(S) 30% A Xi is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 70%.
5. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) 1% A Xi for the Buddhist nun and and 95% polylactic acid and 4% mannitol;
(B) 5% A Xi for the Buddhist nun and and 93% polylactic acid and 2% mannitol;
(C) 10% A Xi is for the polylactic acid of Buddhist nun and 85% and 5% mannitol;
(D) 15% A Xi is for the polylactic acid of Buddhist nun and 82% and 3% sodium chloride;
(E) 20% A Xi is for the polylactic acid of Buddhist nun and 78% and 2% sodium chloride;
(F) 5% A Xi is for glycolic and the copolymer of hydroxyacetic acid and 2% the sodium chloride of Buddhist nun and 92%;
(G) 10% A Xi is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 85%;
(H) 20% A Xi is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 75%;
(I) 30% A Xi is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 75%;
(J) 5% A Xi is for the polifeprosan of Buddhist nun and 92.5% and 2.5% mannitol;
(K) 15% A Xi is for the polifeprosan of Buddhist nun and 75% and 10% mannitol;
(L) 5% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 2% the sodium chloride of Buddhist nun and 92%;
(M) 10% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 85%;
(N) 20% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%;
(O) 30% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%;
(P) 5% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 2% the sodium chloride of Buddhist nun and 92%;
(Q) 10% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 85%;
(R) 20% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%;
(S) 30% A Xi is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%.
6. according to the described anti-cancer sustained-released implantation agent of claim 1-5, the molecular weight peak value that it is characterized in that polylactic acid is 5000-15000,10000-20000,20000-35000 or 30000-50000.
7. according to the described anti-cancer sustained-released implantation agent of claim 1-5, the molecular weight peak value that it is characterized in that the copolymer of glycolic and hydroxyacetic acid is 5000-15000,15000-35000,35000-45000 or 45000-80000; The percentage by weight of glycolic and hydroxyacetic acid is 90: 10,80: 20, and 70: 30,60: 40,50: 50 or 40: 60.
8. according to the described anti-cancer sustained-released implantation agent of claim 1-5, it is characterized in that the percentage by weight to carboxy phenyl propane and decanedioic acid is 10: 90 in the polifeprosan (to carboxy phenyl propane-decanedioic acid copolymer), 20: 80,30: 70,40: 60,50: 50 or 60: 40.
9. the described sustained-release implant of claim 1-5 is characterized in that this sustained-release implant is in the tumor or the slow releasing injection and the solid sustained-release implant of all injections of tumor or placement.
10. the sustained-release implant according to claim 1 is characterized in that described sustained-release implant is used to prepare the treatment cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma, tumor of head and neck and originates from the pharmaceutical preparation of cancer, sarcoma or the carcinosarcoma of gallbladder, oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, eyes former or secondary.
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| CNA2007102027615A CN101204367A (en) | 2007-11-29 | 2007-11-29 | Axitinib sustained-release implplant treating for solid tumor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601682A (en) * | 2013-09-22 | 2014-02-26 | 浙江理工大学 | Preparation method of 3-alkenyl-1H-indazole compound |
| CN103917234A (en) * | 2011-11-11 | 2014-07-09 | 辉瑞大药厂 | N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide for the treatment of chronic myelogenous leukemia |
| WO2022111379A1 (en) * | 2020-11-26 | 2022-06-02 | 成都康弘药业集团股份有限公司 | Axitinib intraocular implant |
-
2007
- 2007-11-29 CN CNA2007102027615A patent/CN101204367A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103917234A (en) * | 2011-11-11 | 2014-07-09 | 辉瑞大药厂 | N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide for the treatment of chronic myelogenous leukemia |
| CN103601682A (en) * | 2013-09-22 | 2014-02-26 | 浙江理工大学 | Preparation method of 3-alkenyl-1H-indazole compound |
| WO2022111379A1 (en) * | 2020-11-26 | 2022-06-02 | 成都康弘药业集团股份有限公司 | Axitinib intraocular implant |
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