CN100563645C - A kind of Beisalutin sustained-release implantation agent for the treatment of entity tumor - Google Patents
A kind of Beisalutin sustained-release implantation agent for the treatment of entity tumor Download PDFInfo
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- CN100563645C CN100563645C CNB2007102028872A CN200710202887A CN100563645C CN 100563645 C CN100563645 C CN 100563645C CN B2007102028872 A CNB2007102028872 A CN B2007102028872A CN 200710202887 A CN200710202887 A CN 200710202887A CN 100563645 C CN100563645 C CN 100563645C
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- tumor
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- bud salol
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Abstract
A kind of Beisalutin sustained-release implantation agent for the treatment of entity tumor is characterized in that this sustained-release implant contains the bud salol fourth of effective anticancer, slow-release auxiliary material and a certain amount of slow release regulator.Entity tumor comprises pulmonary carcinoma, the esophageal carcinoma, gastric cancer, hepatocarcinoma, breast carcinoma, ovarian cancer, carcinoma of prostate, bladder cancer, colorectal cancer.Slow-release auxiliary material is mainly a kind of or its combination in the copolymer, polifeprosan of glycolic and hydroxyacetic acid, poly-(L-lactide-co-etherophosphoric acid), poly-(the L-lactide-co-phosphoric acid propyl ester), in the process of its degraded and absorbed, bud salol fourth slowly can be released to tumor by local, therefore when obviously reducing its general toxic reaction, also can keep active drug concentration in tumor by local.Tumor by local is placed the general toxic reaction that this anti-sustained-release implant not only can reduce bud salol fourth, can also optionally improve the drug level of tumor by local simultaneously, strengthens the therapeutic effect of non-operative treatment such as chemotherapeutics and radiotherapy.
Description
(1) technical field
The present invention relates to a kind of Beisalutin sustained-release implantation agent 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.
Bud salol fixed (Bexarotene, Targretin, tower leather thunder spit of fland) the energy fissional retinal of activation control (vitamin A) receptor is mainly treated the lymphoma (lymphoma) of some type, as is grown in the skin T-cell lymphoma on the skin.Bud salol fourth belongs to retinoid, can be optionally in conjunction with and activate retinoid X receptor hypotype (RXR α, RXR β, RXR γ).RXRs can with retinoic acid receptors (RARs), vitamin D receptor, pth receptor, PPARs etc. form heterodimer.In case be activated, these receptors can be used as transcription factor and regulate control cell differentiation and outgrowth expression of gene.In vitro tests confirms that bud salol fourth can suppress the growth of some tumor cell line; Zoopery finds that also bud salol fourth can cause some tumor regression.Behind the oral bud salol fourth capsule, reached peak serum concentration in about 2 hours, the half-life is about 7 hours.Bud salol fourth can combine (99%) with the plasma protein height.
Bud salol fourth it be unclear that the inhibitory action of other tumors, particularly other solid tumors.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 bud salol fourth has comparatively significantly action effect to 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.Discover that further bud salol fourth local sustained release also has good therapeutical effect to 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.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 this sustained-release implant contains the bud salol fourth of effective anticancer, slow-release auxiliary material and a certain amount of slow release regulator, and wherein the weight ratio of each constituent is:
(1) bud salol fourth 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 10-2000 milligram/patient, is ideal with 100-800 milligram/patient, with 200-500 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) the bud salol fourth of 1%-5% and the polylactic acid of 95%-99%;
(B) the bud salol fourth of 5%-10% and the polylactic acid of 90%-95%;
(C) the bud salol fourth of 10%-15% and the polylactic acid of 85%-90%;
(D) the bud salol fourth of 15%-25% and the polylactic acid of 75%-85%;
(E) the bud salol fourth of 25%-40% and the polylactic acid of 60%-75%;
(F) glycolic of the bud salol fourth of 1%-10% and 90%-99% and the copolymer of hydroxyacetic acid;
(G) glycolic of the bud salol fourth of 10%-20% and 80%-90% and the copolymer of hydroxyacetic acid;
(H) glycolic of the bud salol fourth of 20%-30% and 70%-80% and the copolymer of hydroxyacetic acid;
(I) glycolic of the bud salol fourth of 30%-40% and 60%-70% and the copolymer of hydroxyacetic acid;
(J) the bud salol fourth of 5%-15% and the polifeprosan of 85%-95%;
(K) the bud salol fourth of 15%-35% and the polifeprosan of 65%-85%;
(L) 5% bud salol fourth and 95% poly-(L-lactide-co-etherophosphoric acid);
(M) 10% bud salol fourth and 90% poly-(L-lactide-co-etherophosphoric acid);
(N) 20% bud salol fourth and 80% poly-(L-lactide-co-etherophosphoric acid);
(O) 30% bud salol fourth and 70% poly-(L-lactide-co-etherophosphoric acid);
(P) 5% bud salol fourth and 95% poly-(L-lactide-co-phosphoric acid propyl ester);
(Q) 10% bud salol fourth and 90% poly-(L-lactide-co-phosphoric acid propyl ester);
(R) 20% bud salol fourth and 80% poly-(L-lactide-co-phosphoric acid propyl ester);
(S) 30% bud salol fourth and 70% poly-(L-lactide-co-phosphoric acid propyl ester).
Each component and the weight percentage in compositions thereof are one of further preferred following in the sustained-release implant:
(A) polylactic acid of the bud salol fourth of 1%-5% and 85%-98% and the mannitol of 0.5%-15%;
(B) polylactic acid of the bud salol fourth of 5%-10% and 90%-95% and the sorbitol of 0.5%-10%;
(C) polylactic acid of the bud salol fourth of 10%-15% and 85%-90% and the sodium chloride of 0.5%-10%;
(D) polylactic acid of the bud salol fourth of 15%-25% and 75%-85% and the mannitol of 0.25%-5%;
(E) sorbitol of the polylactic acid 0.1%-8% of the bud salol fourth of 25%-40% and 60%-75%;
(F) copolymer of the glycolic of the bud salol fourth of 1%-10% and 90%-99% and hydroxyacetic acid and the mannitol of 0.5%-15%;
(G) copolymer of the glycolic of the bud salol fourth of 10%-20% and 80%-90% and hydroxyacetic acid and the sorbitol of 0.5%-10%;
(H) copolymer of the glycolic of the bud salol fourth of 20%-30% and 70%-80% and hydroxyacetic acid and the sodium chloride of 0.5%-10%;
(I) copolymer of the glycolic of the bud salol fourth of 30%-40% and 60%-70% and hydroxyacetic acid and the mannitol of 0.25%-5%;
(J) polifeprosan of the bud salol fourth of 5%-15% and 85%-95% and the mannitol of 1%-5%;
(K) polifeprosan of the bud salol fourth of 15%-35% and 65%-85% and the mannitol of 0.25%-7.5%;
(L) 5% bud salol fourth and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(M) 10% bud salol fourth and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(N) 20% bud salol fourth and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(O) 30% bud salol fourth and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(P) 5% bud salol fourth and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(Q) 10% bud salol fourth and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(R) 20% bud salol fourth and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(S) 30% bud salol fourth and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol.
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, bud salol fourth are to the inhibitory action of growth of tumour cell.
Be the inhibitory action of checking bud salol fourth to other growth of tumour cell, this test is added to bud salol fourth (15ug/ml) in 24 hours the various tumor cells of In vitro culture (table 1), continue 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
The result of test one shows that compare with matched group, bud salol fourth all has obvious inhibitory action (P＜0.05) 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.
The sustained-release implant that contains bud salol fourth can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing of implanting.
The preparation method of sustained-release implant of the present invention is as follows:
1, 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.
2, 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.
3, remove organic solvent.Vacuum drying or cold drying all can.
4, dried solid composite is made different shape as required.
5, ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
(4) specific embodiment
Embodiment one,
The slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 10000-20000) of (60mg) of will weighing is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 40 milligrams of bud salol fourths, 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 40% bud salol fourth.The drug release time of this sustained-release implant in external normal saline is 20-26 days, is 24-28 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% bud salol fourth and and 99% polylactic acid;
(B) 5% bud salol fourth and and 95% polylactic acid;
(C) 10% bud salol fourth and 90% polylactic acid;
(D) 15% bud salol fourth and 85% polylactic acid;
(E) 20% bud salol fourth and 80% polylactic acid.
Embodiment three
(molecular weight is the PLGA of 15000-25000 to the slow-release auxiliary material of (75mg) of will weighing, 50: 50) put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion), add 25mg bud salol fourth, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 25% bud salol fourth.The drug release time of this sustained-release implant in external normal saline is 18-24 days, is 16-24 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) glycolic of the bud salol fourth of 1%-10% and 90%-99% and the copolymer of hydroxyacetic acid;
(2) glycolic of the bud salol fourth of 10%-20% and 80%-90% and the copolymer of hydroxyacetic acid;
(3) glycolic of the bud salol fourth of 20%-30% and 70%-80% and the copolymer of hydroxyacetic acid;
(4) glycolic of the bud salol fourth of 30%-40% and 60%-70% and the copolymer of hydroxyacetic acid;
(5) 5% bud salol fourth and 95% the glycolic and the copolymer of hydroxyacetic acid;
(6) 10% bud salol fourth and 90% the glycolic and the copolymer of hydroxyacetic acid;
(7) 20% bud salol fourth and 80% the glycolic and the copolymer of hydroxyacetic acid;
(8) 30% bud salol fourth and 70% the glycolic 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 bud salol fourth and 5mg mannitol, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 10% bud salol fourth.The drug release time of this sustained-release implant in external normal saline is 20-24 days, is 20-28 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) copolymer of the glycolic of the bud salol fourth of 1%-10% and 90%-99% and hydroxyacetic acid and the mannitol of 0.5%-15%;
(2) copolymer of the glycolic of the bud salol fourth of 10%-20% and 80%-90% and hydroxyacetic acid and the sorbitol of 0.5%-10%;
(3) copolymer of the glycolic of the bud salol fourth of 20%-30% and 70%-80% and hydroxyacetic acid and the sodium chloride of 0.5%-10%;
(4) copolymer of the glycolic of the bud salol fourth of 30%-40% and 60%-70% and hydroxyacetic acid and the mannitol of 0.25%-5%;
The copolymer of (5) 5% bud salol fourth and 92% glycolic and hydroxyacetic acid and 2% sodium chloride;
The copolymer of (6) 10% bud salol fourth and 85% glycolic and hydroxyacetic acid and 5% mannitol;
The copolymer of (7) 20% bud salol fourth and 75% glycolic and hydroxyacetic acid and 5% mannitol;
The copolymer of (8) 30% bud salol fourth and 75% glycolic and hydroxyacetic acid and 5% mannitol.
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 bud salol fourth, 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% Beisalutin sustained-release implantation agent.The drug release time of this sustained-release implant in external normal saline is 16-26 days, is 16-28 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) the bud salol fourth of 1%-15% and the polifeprosan of 85%-95%;
(2) the bud salol fourth of 15%-35% and the polifeprosan of 65%-85%;
(3) 5% bud salol fourth and 95% polifeprosan;
(4) 10% bud salol fourth and 90% polifeprosan;
(5) 15% bud salol fourth and the polifeprosan of 85%-95%;
(6) 20% bud salol fourth and 80% polifeprosan.
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 bud salol fourth, 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% Beisalutin sustained-release implantation agent.The drug release time of this sustained-release implant in external normal saline is 18-26 days, is 19-24 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) polifeprosan of the bud salol fourth of 5%-15% and 85%-95% and the mannitol of 1%-5%; Or
(2) polifeprosan of the bud salol fourth of 15%-35% and 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 bud salol fourths, 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% bud salol fourth.The drug release time of this sustained-release implant in external normal saline is 16-24 days, is 20-26 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% bud salol fourth and and 95% polylactic acid and 4% mannitol;
(B) 5% bud salol fourth and and 93% polylactic acid and 2% mannitol;
(C) 10% bud salol fourth and 85% polylactic acid and 5% mannitol;
(D) 15% bud salol fourth and 82% polylactic acid and 3% sodium chloride;
(E) 20% bud salol fourth and 78% polylactic acid 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 bud salol fourth 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, skin carcinoma, lymphoma, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate are 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 bud salol fourth respectively, shake up the sustained-release implant that the preparation of after drying method contains 30%, 20%, 10% and 5% bud salol fourth again.The drug release time of this slow releasing agent in external normal saline is 22-26 days, is about 25-30 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% bud salol fourth;
(2) 5%-10% bud salol fourth;
(3) 10%-20% bud salol fourth;
(4) 20%-40% bud salol fourth;
(5) 5% bud salol fourth and 92% p (LAEG-EOP) and 2% sodium chloride;
(6) 10% bud salol fourth and 85% p (LAEG-EOP) and 5% mannitol;
(7) 20% bud salol fourth and 75% p (LAEG-EOP) and 5% mannitol;
(8) 30% bud salol fourth and 75% p (LAEG-EOP) 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 bud salol fourth respectively, shake up the sustained-release implant that the preparation of after drying method contains 30%, 20%, 10% and 5% bud salol fourth again.The drug release time of this slow releasing agent in external normal saline is 16-22 days, is about 22-28 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% bud salol fourth;
(2) 5%-10% bud salol fourth;
(3) 10%-20% bud salol fourth;
(4) 20%-40% bud salol fourth;
(5) 5% bud salol fourth and 92% p (DAPG-EOP) and 2% sodium chloride;
(6) 10% bud salol fourth and 85% p (DAPG-EOP) and 5% mannitol;
(7) 20% bud salol fourth and 75% p (DAPG-EOP) and 5% mannitol;
(8) 30% bud salol fourth and 75% p (DAPG-EOP) and 5% mannitol.
Embodiment 18, tumor are implanted into the inhibitory action of bud salol fourth 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, bud salol fourth lumbar injection group (hereinafter to be referred as bud salol fourth abdominal cavity group), bud salol fourth local injection group (being called for short bud salol fourth partial groups), high molecular polymer group (being called for short high poly-group), Beisalutin sustained-release implantation agent group with (5% group, 10% group of the made sustained-release implant of embodiment four, 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 with in the bud salol fourth implant implantation tumour tissue, not pastille high molecular polymer, bud salol fourth implant 5%, bud salol fourth implant 10%, bud salol fourth implant 20%.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 the tumor-inhibiting action of bud salol fourth spit of fland sustained-release implant to mice lung cancer
Check the tumor-inhibiting action of Beisalutin sustained-release implantation agent according to embodiment 18 described methods and step to mice lung cancer.Used implant adjuvant is PLGA (molecular weight is 15000-30000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50), is derived from embodiment four.The bud salol fourth implant of this experimental result proof various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Bud salol fourth implant tumor control rate is respectively 58%, 68%, 84%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Repeated experiments: tumor control rate is respectively 52%, 64%, 80%, compares with the local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bud salol fourth lumbar injection group and bud salol fourth local injection group and normal saline group comparison of tumor suppression ratio are 14% and 12%, and repeated experiments: tumor control rate is 18% and 13%.The tumour inhibiting rate of bud salol fourth implant obviously surpasses bud salol fourth lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 20 tumors are implanted into the tumor-inhibiting action of Beisalutin sustained-release implantation agent to mouse breast cancer
Check the tumor-inhibiting action of Beisalutin sustained-release implantation agent to mouse breast cancer according to embodiment 18 described methods and step, used implant is from embodiment one.Experimental result shows that the tumor control rate of 1%, 10% and 25% bud salol fourth implant is respectively 40%, 52%, 78%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 42%, 60%, 82%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bud salol fourth lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 12% and 14%, and repeated experiments: tumor control rate is 13% and 14%.The tumour inhibiting rate of bud salol fourth implant obviously surpasses bud salol fourth lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 21, tumor are implanted into the tumor-inhibiting action of Beisalutin sustained-release implantation agent to the mouse ovarian cancer
Check the tumor-inhibiting action of Beisalutin 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.The bud salol fourth implant of experimental result proof various dose is implanted in the mouse ovarian cancer and can obviously be suppressed tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Bud salol fourth implant tumor control rate is respectively 44%, 54%, 76%, compares with bud salol fourth local injection group, 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 40%, 56%, 78%, compares with bud salol fourth local injection group, 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.Bud salol fourth lumbar injection group and bud salol fourth local injection group and normal saline group comparison of tumor suppression ratio are 18% and 22%, and repeated experiments: tumor control rate is 25% and 16%.The tumour inhibiting rate of bud salol fourth implant obviously surpasses bud salol fourth lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 22 tumors are implanted into the tumor-inhibiting action of Beisalutin sustained-release implantation agent to the mice esophageal carcinoma
Check the tumor-inhibiting action of Beisalutin sustained-release implantation agent to the mice esophageal carcinoma according to embodiment 18 described methods and step, used implant is selected from embodiment six.The bud salol fourth implant of experimental result proof various dose is implanted in nude mice model human esophagus cancer (9706) entity tumor, all can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Bud salol fourth implant tumor control rate is respectively 48%, 56%, 78%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Repeated experiments finds that tumor control rate is respectively 50%, 72%, 80%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bud salol fourth lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 10% and 8%, and repeated experiments shows that tumor control rate is 12% and 10%.The tumour inhibiting rate of bud salol fourth implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 23, tumor are implanted into the tumor-inhibiting action of Beisalutin sustained-release implantation agent to mouse pancreas cancer
Check the tumor-inhibiting action of Beisalutin sustained-release implantation agent to mouse pancreas 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 content of bud salol fourth in sustained-release implant is 2.5%, 7.5% and 12.5%.The bud salol fourth implant of experimental result proof various dose is implanted in 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.Bud salol fourth implant tumor control rate is respectively 38%, 52%, 78%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 38%, 54%, 68%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bud salol fourth lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 21% and 14%.Repeated experiments finds that tumor control rate is 10% and 14%.The tumour inhibiting rate of bud salol fourth implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 24, tumor are implanted into the tumor-inhibiting action of Beisalutin sustained-release implantation agent to the mice rectal cancer
Check the tumor-inhibiting action of Beisalutin 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 content of bud salol fourth in sustained-release implant is 7.5%, 15% and 25%.The bud salol fourth implant of experimental result proof various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Bud salol fourth implant tumor control rate is respectively 40%, 72%, 80%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 50%, 60%, 75%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bud salol fourth lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 21% and 18%.Repeated experiments finds that tumor control rate is 12% and 10%.The tumour inhibiting rate of bud salol fourth implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 25, tumor are implanted into the tumor-inhibiting action of Beisalutin sustained-release implantation agent to the mice carcinoma of prostate
Check the tumor-inhibiting action of Beisalutin 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 content of bud salol fourth in sustained-release implant is 5%, 10% and 20% (from embodiment 14).The bud salol fourth implant of experimental result proof various dose is implanted in the nude mice model human prostata cancer entity tumor, can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Bud salol fourth implant tumor control rate is respectively 38%, 52%, 74%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 40%, 68%, 78%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bud salol fourth lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 21% and 14%.Repeated experiments finds that tumor control rate is 12% and 14%.The tumour inhibiting rate of bud salol fourth implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 26, tumor are implanted into the tumor-inhibiting action of Beisalutin sustained-release implantation agent to rat liver cancer
Check the tumor-inhibiting action of Beisalutin 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 content of bud salol fourth in sustained-release implant is 5%, 10% and 20% (from embodiment 16).The content of bud salol fourth in sustained-release implant is 7.5%, 15% and 25%.The bud salol fourth implant of experimental result proof various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Bud salol fourth implant tumor control rate is respectively 30%, 50%, 60%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 32%, 48%, 68%, compares with bud salol fourth local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bud salol fourth lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 16% and 8%.Repeated experiments finds that tumor control rate is 8% and 10%.The tumour inhibiting rate of bud salol fourth implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
In addition, tumor is implanted into Beisalutin 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, and its effect obviously surpasses bud salol fourth 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 (3)
1. a Beisalutin sustained-release implantation agent for the treatment of entity tumor is characterized in that this sustained-release implant contains the bud salol fourth and the slow-release auxiliary material of effective anticancer, and wherein the weight ratio of each constituent is:
(1) anticancer effective component is 30% bud salol fourth, and slow-release auxiliary material is that 70% molecular weight peak value is poly-(the L-lactide-co-etherophosphoric acid) of 10000-25000;
(2) anticancer effective component is 20% bud salol fourth, and slow-release auxiliary material is that 80% molecular weight peak value is poly-(the L-lactide-co-etherophosphoric acid) of 10000-25000;
(3) anticancer effective component is 10% bud salol fourth, and slow-release auxiliary material is that 90% molecular weight peak value is poly-(the L-lactide-co-etherophosphoric acid) of 10000-25000;
(4) anticancer effective component is 5% bud salol fourth, and slow-release auxiliary material is that 95% molecular weight peak value is poly-(the L-lactide-co-etherophosphoric acid) of 10000-25000;
(5) anticancer effective component is 30% bud salol fourth, 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;
(6) anticancer effective component is 20% bud salol fourth, 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;
(7) anticancer effective component is 10% bud salol fourth, 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; Or
(8) anticancer effective component is 5% bud salol fourth, 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.
2. the sustained-release implant according to claim 1 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.
3. 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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