CN101181232B - Marseilledinun sustained-release implantation agent for curing entity tumour - Google Patents
Marseilledinun sustained-release implantation agent for curing entity tumour Download PDFInfo
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- CN101181232B CN101181232B CN2007102031998A CN200710203199A CN101181232B CN 101181232 B CN101181232 B CN 101181232B CN 2007102031998 A CN2007102031998 A CN 2007102031998A CN 200710203199 A CN200710203199 A CN 200710203199A CN 101181232 B CN101181232 B CN 101181232B
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Abstract
The invention relates to a masitinib sustained-release implant for the treatment of solid tumors, which is characterized in that the sustained-release implant contains anti-cancer effective amount of masitinib, sustained-release excipient and certain amount of sustained-release regulator. The solid tumors include lung cancer, esophageal cancer, stomach cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, bladder cancer and colorectal cancer. The sustained-release excipient mainly comprises one or the combination of the copolymer of glycolic acid and hydroxyacetic acid, polifeprosan, poly (L-lactide-co-ethyl phosphate) and poly (L-lactide-co-propyl phosphate). The invention can slowly release the masitinib in the local part of the tumor during the degradation and absorption process, so the invention can maintain the effective drug concentration at the local part of the tumor at the same time of significantly reducing systemic toxic reaction. The sustained-release implant is arranged at the local part of the tumor, which can not only reduce the systemic toxic reaction of masitinib, but can also selectively improve the drug concentration at the local part of the tumor and strengthen the treatment effects of chemotherapy drugs, radiation therapy and other non-surgical therapies.
Description
(1) technical field
The present invention relates to a kind of Marseilledinun sustained-release implantation agent for the treatment of entity tumor, belong to technical field of pharmaceuticals.
(2) background technology
Malignant entity tumor accounts for more than 70% of all malignant tumor, yet, being different from non-entity tumor such as blood and lymph tumor, conventional chemotherapy is difficult in and obtains long-time active drug concentration in the entity tumor.Though diffusion can occur in the tumor growth process, expansive growth is still the main growth pattern of most of malignant entity tumors.Therefore, the organizational stress in the tumor is apparently higher than normal structure.Moreover, the blood vessel that causes in tumor growth process chemotherapeutics disorderly and that intermittent blood flow usually causes whole body to be used is many to distribute at other normal structure organs, seldom enters in the solid tumor.The low concentration medicine not only can not effectively kill and wound cancerous cell, also can promote tumor diffusion and chemical sproof generation.Therefore, be not difficult to explain why for many years cancer chemotherapy is not obtained bigger progress always.
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.
The Marseille is for Buddhist nun (Masitinib), chemical structural formula is [4-[(4-methyl piperazine-1-yl) methyl] nitrogen-(4-methyl-3-([4-(pyridin-3-yl)-1, the 3-thiazol-2-yl] amino) phenyl) Benzoylamide], English is: [4-[(4-methylpiperazin-1-yl) methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl] amino}phenyl) benzamide].In vitro tests shows, the Marseille can suppress vascular endothelial growth for the Buddhist nun, yet it is unclear to be used for the treatment of the effect of other tumor separately.Though unite some tumors may be had certain effect by tool, limited its clinical practice by the caused whole body toxic and side effects of conventional route administration with other anticarcinogen.
(3) summary of the invention
Based on above examination to prior art, the present invention compares other tumor, found that the Marseille replaces the Buddhist nun that entity tumors such as 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 certain action 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 adjuvant that can be used for the slow thing of medicine at present is a lot, it is not the equal effect that can play slow release, decanedioic acid (SA) copolymer), poly-(L-lactide-co-etherophosphoric acid) (p (LAEG-EOP)), poly-(L-lactide-co-phosphoric acid propyl ester) slow-release auxiliary material such as (p (DAPG-EOP)) can discharge the Marseille preferably for the Buddhist nun find that through a large amount of creative researches the copolymer (PLGA) of polylactic acid (PLA), glycolic and hydroxyacetic acid, polifeprosan are (to carboxy phenyl propane (p-CPP):.
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 Marseille 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) Marseille is for Buddhist nun 0.1%-50%
(2) slow-release auxiliary material 50%-99%
(3) slow release regulator 0-15%
Marseille of the present invention serve as preferably for the percentage by weight of Buddhist nun in sustained-release implant with 0.1 to 50%, with 5%-30% for most preferably.The Marseille can be various salt for the Buddhist nun, serves as preferred with phosphate or hydrochlorate (Marseille is for the Buddhist nun).
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, and 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 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.
The molecular weight peak value of poly-(L-lactide-co-etherophosphoric acid) is 10000-15000,15000-25000,25000-35000 or 35000-60000, serve as preferred wherein with 10000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.
The molecular weight peak value of poly-(L-lactide-co-phosphoric acid propyl ester) is 8000-20000,20000-30000,30000-40000 or 40000-80000.Serve as preferred wherein with 10000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.
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.
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 10-1000 milligram/patient, is ideal with 50-700 milligram/patient, with 100-500 milligram/patient for the most desirable.
The present invention can be made into various dosage forms, as, but be not limited to injection, muddy suspension, ointment, capsule, implant, slow releasing agent, implantation slow release agent or slow releasing injection etc.; 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, be first-selected with the topical, it is swollen, in the tumor, all injections of tumor or be placed as most preferably.
Each component and the weight percentage in compositions thereof are preferred one of following in the sustained-release implant:
(A) Marseille of 1%-5% is for the polylactic acid of Buddhist nun and 95%-99%;
(B) Marseille of 5%-10% is for the polylactic acid of Buddhist nun and 90%-95%;
(C) Marseille of 10%-15% is for the polylactic acid of Buddhist nun and 85%-90%;
(D) Marseille of 15%-25% is for the polylactic acid of Buddhist nun and 75%-85%;
(E) Marseille of 25%-40% is for the polylactic acid of Buddhist nun and 60%-75%;
(F) Marseille of 1%-10% is for Buddhist nun and the glycolic of 90%-99% and the copolymer of hydroxyacetic acid;
(G) Marseille of 10%-20% is for Buddhist nun and the glycolic of 80%-90% and the copolymer of hydroxyacetic acid;
(H) Marseille of 20%-30% is for Buddhist nun and the glycolic of 70%-80% and the copolymer of hydroxyacetic acid;
(I) Marseille of 30%-40% is for Buddhist nun and the glycolic of 60%-70% and the copolymer of hydroxyacetic acid;
(J) Marseille of 5%-15% is for the polifeprosan of Buddhist nun and 85%-95%;
(K) Marseille of 15%-35% is for the polifeprosan of Buddhist nun and 65%-85%;
(L) 5% Marseille is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 95%;
(M) 10% Marseille is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 90%;
(N) 20% Marseille is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 80%;
(O) 30% Marseille is for poly-(the L-lactide-co-etherophosphoric acid) of Buddhist nun and 70%;
(P) 5% Marseille is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 95%;
(Q) 10% Marseille is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 90%;
(R) 20% Marseille is for poly-(the L-lactide-co-phosphoric acid propyl ester) of Buddhist nun and 80%;
(S) 30% Marseille 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) Marseille of 1%-5% is for Buddhist nun and the polylactic acid of 85%-98% and the mannitol of 0.5%-15%;
(B) Marseille of 5%-10% is for Buddhist nun and the polylactic acid of 90%-95% and the sorbitol of 0.5%-10%;
(C) Marseille of 10%-15% is for Buddhist nun and the polylactic acid of 85%-90% and the sodium chloride of 0.5%-10%;
(D) Marseille of 15%-25% is for Buddhist nun and the polylactic acid of 75%-85% and the mannitol of 0.25%-5%;
(E) Marseille of 25%-40% is for the sorbitol of the polylactic acid 0.1%-8% of Buddhist nun and 60%-75%;
(F) Marseille 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) Marseille 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) Marseille 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) Marseille 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) Marseille of 5%-15% is for Buddhist nun and the polifeprosan of 85%-95% and the mannitol of 1%-5%;
(K) Marseille of 15%-35% is for Buddhist nun and the polifeprosan of 65%-85% and the mannitol of 0.25%-7.5%;
(L) 5% Marseille is for poly-(L-lactide-co-etherophosphoric acid) and 2% the sodium chloride of Buddhist nun and 93%;
(M) 10% Marseille is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 85%;
(N) 20% Marseille is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%;
(O) 30% Marseille is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 65%;
(P) 5% Marseille is for poly-(L-lactide-co-etherophosphoric acid) and 2% the sodium chloride of Buddhist nun and 93%;
(Q) 10% Marseille is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 85%;
(R) 20% Marseille is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 75%;
(S) 30% Marseille is for poly-(L-lactide-co-etherophosphoric acid) and 5% the mannitol of Buddhist nun and 65%.
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, lymphoma, 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, Marseille are for the inhibitory action of Buddhist nun to growth of tumour cell.
For replacing the inhibitory action of Buddhist nun in the checking Marseille to other growth of tumour cell, this test is added to the Marseille 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 (%) |
| Pulmonary carcinoma | 50 |
| The esophageal carcinoma | 58 |
| Gastric cancer | 60 |
| Breast carcinoma | 70 |
| Cancer of pancreas | 62 |
| Thyroid carcinoma | 68 |
| Nasopharyngeal carcinoma | 70 |
| Ovarian cancer | 66 |
| Carcinoma of endometrium | 72 |
| Cervical cancer | 68 |
| Renal carcinoma | 70 |
| Carcinoma of prostate | 76 |
| Bladder cancer | 60 |
| Colon cancer | 70 |
| Rectal cancer | 78 |
| Skin carcinoma | 74 |
| Lymphoma | 72 |
| Hepatocarcinoma | 76 |
| Carcinoma of testis | 72 |
The result of test one shows, compares with matched group, and the Marseille 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 the Marseille 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 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.
(4) specific embodiment
Embodiment one,
80mg slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 15000-30000) is put into container, add certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving after, adds 20 milligrams of Marseilles for the Buddhist nun, shake up the dry removal of final vacuum organic solvent again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 20% Marseille for the Buddhist nun.The drug release time of this sustained-release implant in external normal saline is 22-26 days, is 20-26 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% Marseille for the Buddhist nun and and 99% polylactic acid;
(B) 5% Marseille for the Buddhist nun and and 95% polylactic acid;
(C) 10% Marseille is for the polylactic acid of Buddhist nun and 90%;
(D) 15% Marseille is for the polylactic acid of Buddhist nun and 85%;
(E) 20% Marseille is for the polylactic acid of Buddhist nun and 80%.
Embodiment three
85mg slow-release auxiliary material (molecular weight is the PLGA of 15000-25000,50: 50) is put into container, add certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving after, add the 15mg Marseille 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 15% Marseille for the Buddhist nun.The drug release time of this sustained-release implant in external normal saline is 25-32 days, is 23-28 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) Marseille of 1%-10% is for Buddhist nun and the glycolic of 90%-99% and the copolymer of hydroxyacetic acid;
(2) Marseille of 10%-20% is for Buddhist nun and the glycolic of 80%-90% and the copolymer of hydroxyacetic acid;
(3) Marseille of 20%-30% is for Buddhist nun and the glycolic of 70%-80% and the copolymer of hydroxyacetic acid;
(4) Marseille of 30%-40% is for Buddhist nun and the glycolic of 60%-70% and the copolymer of hydroxyacetic acid;
(5) 5% Marseille is for the glycolic of Buddhist nun and 95% and the copolymer of hydroxyacetic acid;
(6) 10% Marseille is for the glycolic of Buddhist nun and 90% and the copolymer of hydroxyacetic acid;
(7) 20% Marseille is for the glycolic of Buddhist nun and 80% and the copolymer of hydroxyacetic acid;
(8) 30% Marseille is for the glycolic of Buddhist nun and 70% and the copolymer of hydroxyacetic acid.
Embodiment five
(molecular weight is the PLGA of 15000-30000 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 the 10mg Marseille, 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% Marseille for the Buddhist nun.The drug release time of this sustained-release implant in external normal saline is 26-32 days, is 26-34 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) Marseille 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) Marseille 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) Marseille 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) Marseille 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% Marseille is for glycolic and the copolymer of hydroxyacetic acid and 2% the sodium chloride of Buddhist nun and 93%;
(6) 10% Marseille is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 85%;
(7) 20% Marseille is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 75%;
(8) 30% Marseille is for glycolic and the copolymer of hydroxyacetic acid and 5% the mannitol of Buddhist nun and 65%.
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 the 15mg Marseille 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% Marseilledinun sustained-release implantation agent.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is 12-16 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) Marseille of 1%-15% is for the polifeprosan of Buddhist nun and 85%-95%;
(2) Marseille of 15%-35% is for the polifeprosan of Buddhist nun and 65%-85%;
(3) 5% Marseille is for the polifeprosan of Buddhist nun and 95%;
(4) 10% Marseille is for the polifeprosan of Buddhist nun and 90%;
(5) 15% Marseille is for the polifeprosan of Buddhist nun and 85%-95%;
(6) 20% Marseille 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 the 15mg Marseille 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% Marseilledinun sustained-release implantation agent.The drug release time of this sustained-release implant in external normal saline is 12-16 days, is 14-20 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) Marseille of 5%-15% is for Buddhist nun and the polifeprosan of 85%-95% and the mannitol of 1%-5%; Or
(2) Marseille 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 Marseilles 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% Marseille for the Buddhist nun.The drug release time of this sustained-release implant in external normal saline is 18-25 days, is 20-27 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% Marseille for the Buddhist nun and and 95% polylactic acid and 4% mannitol;
(B) 5% Marseille for the Buddhist nun and and 93% polylactic acid and 2% mannitol;
(C) 10% Marseille is for the polylactic acid of Buddhist nun and 85% and 5% mannitol;
(D) 15% Marseille is for the polylactic acid of Buddhist nun and 82% and 3% sodium chloride;
(E) 20% Marseille 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 10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 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 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).
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 Marseille 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% Marseille for the Buddhist nun.The drug release time of this slow releasing agent in external normal saline is 46-52 days, is about 45-54 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) the 1%-5% Marseille is for the Buddhist nun;
(2) the 5%-10% Marseille is for the Buddhist nun;
(3) the 10%-20% Marseille is for the Buddhist nun;
(4) the 20%-40% Marseille is for the Buddhist nun;
(5) 5% Marseille is for the p (LAEG-EOP) of Buddhist nun and 93% and 2% sodium chloride;
(6) 10% Marseille is for the p (LAEG-EOP) of Buddhist nun and 85% and 5% mannitol;
(7) 20% Marseille is for the p (LAEG-EOP) of Buddhist nun and 75% and 5% mannitol;
(8) 30% Marseille is for the p (LAEG-EOP) of Buddhist nun and 65% 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 Marseille 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% Marseille for the Buddhist nun.The drug release time of this slow releasing agent in external normal saline is 46-56 days, is about 54-60 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) the 1%-5% Marseille is for the Buddhist nun;
(2) the 5%-10% Marseille is for the Buddhist nun;
(3) the 10%-20% Marseille is for the Buddhist nun;
(4) the 20%-40% Marseille is for the Buddhist nun;
(5) 5% Marseille is for the p (DAPG-EOP) of Buddhist nun and 93% and 2% sodium chloride;
(6) 10% Marseille is for the p (DAPG-EOP) of Buddhist nun and 85% and 5% mannitol;
(7) 20% Marseille is for the p (DAPG-EOP) of Buddhist nun and 75% and 5% mannitol;
(8) 30% Marseille is for the p (DAPG-EOP) of Buddhist nun and 65% and 5% mannitol.
Embodiment 18, tumor are implanted into the Marseille for the inhibitory action of Buddhist nun to entity tumor
With 10
5Tumor cell inoculation is subcutaneous in the right side of mice axillary fossa, when tumor growth is divided into 5 groups, 5 every group at random with animal during to the 1.2cm left and right sides.Be normal saline group (matched group), Marseilledinun sustained-release implantation agent group, replace Buddhist nun's lumbar injection group (i.p. group) with embodiment four made sustained-release implant (5%, 10%, 20%) and Marseilles, chamber injection group dosage is with low dose of sustained-release implant group.Animal put to death in 25 days with vernier caliper measurement tumor size after the implant embedding in per 3 days in the treatment back, and the back of weighing is complete peels off tumor and claim tumor heavy.Calculate tumor control rate % according to following formula.
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 the Marseille for the tumor-inhibiting action of Buddhist nun spit of fland sustained-release implant to mice lung cancer
Check the tumor-inhibiting action of Marseilledinun sustained-release implantation agent according to embodiment 18 described methods and step to mice lung cancer.Used implant adjuvant is PLGA (molecular weight is 15000-25000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50), is derived from embodiment four.This experimental result sees Table 2.
Table 2
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 16 | ＞0.05 |
| 3 | 5% group | 48 | ＜0.05 |
| 4 | 10% group | 58 | ＜0.01 |
| 5 | 20% group | 76 | ＜0.01 |
The result shows that the Marseille obviously strengthens than the lumbar injection effect for Buddhist nun's implant, and the Marseille of various dose can obviously suppress tumor growth for Buddhist nun's implant, and tumor control rate and drug dose are obvious dose-effect relationship.
Embodiment 20 tumors are implanted into the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to mouse breast cancer
Check the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to mouse breast cancer according to embodiment 18 described methods and step, used implant is from embodiment two.Experimental result sees Table 3
Table 3
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 26 | ＞0.05 |
| 3 | 1% group | 48 | ＜0.05 |
| 4 | 10% group | 58 | ＜0.01 |
| 5 | 20% group | 86 | ＜0.001 |
Show that 1%, 10% and 20% Marseille is respectively 48%, 48%, 86% for the tumor control rate of Buddhist nun's implant, compare for Buddhist nun's local injection group that the P value is all less than 0.001 with the Marseille.Illustrate that the Marseille obviously surpasses the Marseille for Buddhist nun's lumbar injection group group, twice experimental result good reproducibility for the tumour inhibiting rate of Buddhist nun's implant.
Embodiment 21, tumor are implanted into the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to the mouse ovarian cancer
Check the tumor-inhibiting action of Marseilledinun sustained-release implantation agent according to embodiment 18 described methods and step to the mouse ovarian 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.Experimental result sees Table 4.
Table 4
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 24 | ＞0.05 |
| 3 | 5% group | 45 | ＜0.05 |
| 4 | 10% group | 54 | ＜0.01 |
| 5 | 20% group | 72 | ＜0.01 |
Implant in the mouse ovarian cancer for Buddhist nun's implant the Marseille of proof various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.The Marseille is respectively 45%, 54%, 72% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with the Marseille, and low dose group P value equals 0.001, and middle and high dosage group P value is all less than 0.001.
Embodiment 22 tumors are implanted into the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to the mice esophageal carcinoma
Check the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to the mice esophageal carcinoma according to embodiment 18 described methods and step, used implant is selected from embodiment six.Experimental result sees Table 5.
Table 5
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 25 | ＞0.05 |
| 3 | 5% group | 42 | ＜0.05 |
| 4 | 10% group | 55 | ＜0.01 |
| 5 | 20% group | 72 | ＜0.01 |
Implant in nude mice model human esophagus cancer (9706) entity tumor for Buddhist nun's implant the Marseille of proof various dose, all can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.The Marseille is respectively 42%, 55%, 72% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with the Marseille, and the P value is all less than 0.001.
Embodiment 23, tumor are implanted into the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to mouse pancreas cancer
Check the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to mouse pancreas cancer according to embodiment 18 described methods and step, used implant adjuvant is PLGA (molecular weight is 15000-30000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50).The Marseille is 5%, 10% and 30% for the content of Buddhist nun in sustained-release implant, from embodiment six. experimental result sees Table 6.
Table 6
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 36 | ＞0.05 |
| 3 | 5% group | 56 | ＜0.01 |
| 4 | 10% group | 78 | ＜0.01 |
| 5 | 30% group | 88 | ＜0.001 |
The result proves that the Marseille of various dose in Buddhist nun's implant implantation nude mice model human pancreas cancer (JF305) entity tumor, can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Compare for Buddhist nun's local injection group with the Marseille, the P value is all less than 0.001.
Embodiment 24, tumor are implanted into the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to the mice rectal cancer
Check the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to the mice rectal cancer according to embodiment 18 described methods and step, used implant adjuvant is PLGA (molecular weight is 20000-35000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50).The Marseille is that 7.5%, 15% and 25%. experimental results see Table 7 for the content of Buddhist nun in sustained-release implant.
Table 7
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 24 | ＞0.05 |
| 3 | 7.5% group | 44 | ＜0.05 |
| 4 | 15% group | 70 | ＜0.01 |
| 5 | 25% group | 84 | ＜0.01 |
The Marseille of various dose can obviously suppress tumor growth for Buddhist nun's implant, and tumor control rate and drug dose are obvious dose-effect relationship.The Marseille is respectively 44%, 70%, 84% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with the Marseille, and the P value is all less than 0.001.
Embodiment 25, tumor are implanted into the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to the mice carcinoma of prostate
Check the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to the mice carcinoma of prostate according to embodiment 18 described methods and step, used implant adjuvant is p (LAEG-EOP) (molecular weight is 10000-25000).The Marseille is 5%, 10% and 20% (from embodiment 14) for the content of Buddhist nun in sustained-release implant.Experimental result sees Table 8.
Table 8
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 18 | ＞0.05 |
| 3 | 5% group | 36 | ＜0.05 |
| 4 | 10% group | 56 | ＜0.01 |
| 5 | 20% group | 78 | ＜0.001 |
The result shows that implant in the nude mice model human prostata cancer entity tumor for Buddhist nun's implant the Marseille of various dose, can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.The Marseille is respectively 36%, 56%, 78% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with the Marseille, and the P value is all less than 0.001.
Embodiment 26, tumor are implanted into the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to rat liver cancer
Check the tumor-inhibiting action of Marseilledinun sustained-release implantation agent to rat liver cancer according to embodiment 18 described methods and step, used implant adjuvant is p (DAPG-EOP) (molecular weight is 10000-25000).The Marseille is 5%, 10% and 20% (from embodiment 16) for the content of Buddhist nun in sustained-release implant.The Marseille is that 7.5%, 15% and 25%. experimental results see Table 9 for the content of Buddhist nun in sustained-release implant.
Table 9
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 18 | ＞0.05 |
| 3 | 5% group | 46 | ＜0.05 |
| 4 | 10% group | 58 | ＜0.01 |
| 5 | 20% group | 76 | ＜0.01 |
The Marseille of 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.The Marseille is respectively 46%, 58%, 76% for Buddhist nun's implant tumor control rate, compares for Buddhist nun's local injection group with the Marseille, and the P value is all less than 0.001.
In addition, tumor is implanted into Marseilledinun sustained-release implantation agent 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, its effect obviously surpasses the Marseille for Buddhist nun's lumbar injection group, not only curative effect is obvious, and the toxicity of local sustained release obviously alleviates than systemic injection.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 (2)
1. Marseilledinun sustained-release implantation agent for the treatment of entity tumor is characterized in that Marseille that this sustained-release implant contains effective anticancer for Buddhist nun and slow-release auxiliary material, is made up of one of following ingredients:
(1) anticancer effective component is that the Buddhist nun is replaced in 5% Marseille, and slow-release auxiliary material is that 95% molecular weight peak value is poly-(the L-lactide-co-etherophosphoric acid) of 10000-25000;
(2) anticancer effective component is that the Buddhist nun is replaced in 10% Marseille, and slow-release auxiliary material is that 90% molecular weight peak value is poly-(the L-lactide-co-etherophosphoric acid) of 10000-25000;
(3) anticancer effective component is that the Buddhist nun is replaced in 20% Marseille, and slow-release auxiliary material is that 80% molecular weight peak value is poly-(the L-lactide-co-etherophosphoric acid) of 10000-25000;
(4) anticancer effective component is that the Buddhist nun is replaced in 30% Marseille, and slow-release auxiliary material is that 70% molecular weight peak value is poly-(the L-lactide-co-etherophosphoric acid) of 10000-25000;
(5) anticancer effective component is that the Buddhist nun is replaced in 5% Marseille, and slow-release auxiliary material is that 95% molecular weight peak value is poly-(the L-lactide-co-phosphoric acid propyl ester) of 10000-25000;
(6) anticancer effective component is that the Buddhist nun is replaced in 10% Marseille, and slow-release auxiliary material is that 90% molecular weight peak value is poly-(the L-lactide-co-phosphoric acid propyl ester) of 10000-25000;
(7) anticancer effective component is that the Buddhist nun is replaced in 20% Marseille, and slow-release auxiliary material is that 80% molecular weight peak value is poly-(the L-lactide-co-phosphoric acid propyl ester) of 10000-25000;
(8) anticancer effective component is that the Buddhist nun is replaced in 30% Marseille, and slow-release auxiliary material is that 70% molecular weight peak value is poly-(the L-lactide-co-phosphoric acid propyl ester) of 10000-25000.
2. the sustained-release implant according to claim 1 is characterized in that described sustained-release implant is used for the preparation 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, lymphoma, tumor of head and neck and originate from gallbladder, the oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, former or the cancer of secondary of eyes, the pharmaceutical preparation of sarcoma or carcinosarcoma.
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