CN101204365A - Implant agent treating for solid tumor - Google Patents
Implant agent treating for solid tumor Download PDFInfo
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- CN101204365A CN101204365A CNA2007102027598A CN200710202759A CN101204365A CN 101204365 A CN101204365 A CN 101204365A CN A2007102027598 A CNA2007102027598 A CN A2007102027598A CN 200710202759 A CN200710202759 A CN 200710202759A CN 101204365 A CN101204365 A CN 101204365A
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Abstract
The invention relates to a sustained-release implant for treating a solid tumor, which is characterized in that: the sustained-release implant contains an effective anticancer amount of bortezomib and sustained-release excipients. The solid tumor includes brain tumor, liver cancer, lung cancer, oesophagus cancer, gastric cancer, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, ovarian cancer, endometrial cancer, cervical cancer, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, skin cancer, head and neck cancer and primary or secondary cancer, caruncle or carcinosarcoma rooted at a peripheral nervous system, mucosa, glands, blood vessels, bone tissues and lymph nodes. The sustained-release excipients are mainly a biological polymer which is dissoluble and can be degraded and absorbed, in the degradation and absorption process of which carmustine is sustainedly released to part of the tumor, thus the entire toxicity of the carmustine is significantly reduced while an effective medicine consistency is maintained on part of the tumor. That the sustained-release implant is implanted inside part of the tumor can not only reduce the entire toxicity of the carmustine but also enhance the medicine consistency on part of the tumor, thereby increasing the curing effect of non-operative therapeutics such as chemotherapeutic drugs and radiotherapy.
Description
(1) technical field
The present invention relates to a kind of sustained-release implant for the treatment of entity tumor, belong to technical field of pharmaceuticals.
(2) background technology
Though the research about cancer has obtained bigger progress, its mortality rate still occupies the prostatitis of the various common causes of the death.Up-to-date data show that China had 3,000,000 people to die from cancer in 2006.Cancer morbidity rises year by year and is rejuvenation trend, has data to show that in less than the time in 20 years, China's cancer morbidity has risen 69%, and mortality rate has increased by 29.4%.According to World Health Organization's recent statistics, will increase by 50 percent to the year two thousand twenty whole world cancer morbidity, number of the infected increases to 15,000,000.Estimate that the year two thousand twenty China will have 4,000,000 people to die from cancer therefore every year, inquire into the focus that a kind of effective treatment method for cancer or medicine have become present research.
In recent years, bortezomib is used as one of treatment multiple myeloma choice drug.The effect that is used for the treatment of other tumor separately is unclear.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 bortezomib 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 the bortezomib 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.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.
The present invention treats the sustained-release implant of entity tumor, it is characterized in that this sustained-release implant contains the bortezomib of effective anticancer (Bortezomib, ten thousand Mactra sulcatria Deshayess or Velcade), slow-release auxiliary material and a certain amount of slow release regulator, and wherein the weight ratio of each constituent is:
(1) bortezomib 0.1%-60%
(2) slow-release auxiliary material 40%-99%
(3) slow release regulator 0-15%
Slow-release auxiliary material comprises one of following or its combination:
(1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), decanedioic acid (sebacic acid), poly-(L-lactide-co-etherophosphoric acid (p (LAEG-EOP)), poly-(L-lactide-co-phosphoric acid propyl ester) (p (DAPG-EOP)), polifeprosan (to the copolymer of carboxy phenyl propane and decanedioic acid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, chrondroitin, gelatin, albumin etc.
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and decanedioic acid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and decanedioic acid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description in other United States Patent (USP) that (US 4857311; 4888176; 4789724).
Copolymer, polifeprosan, the ethylene vinyl acetate copolymer of the preferred polylactic acid of slow-release auxiliary material, polyglycolic acid and hydroxyacetic acid; 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.
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of mixture, glycolic and the hydroxy carboxylic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid; When PLA and PLGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.The molecular weight of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50,000 is preferred, with 10,000-20,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50,000 is preferred, with 10,000-20,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 1000-100,000, but with 10,000-50,000 is preferred; With 10,000-20,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 5000 to 10000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 20000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 5000 to 10000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change 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.
The used slow-release auxiliary material of sustained-release implant of the present invention can be any or multiple material in the above-mentioned slow-release auxiliary material, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or decanedioic acid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLGA, glycolic and hydroxy carboxylic acid, decanedioic acid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Slow-release auxiliary material has a detailed description 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).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.
Decanedioic acid (SA) copolymer), a kind of or its combination in ethylene vinyl acetate copolymer (EVAc), xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin and the albumin therefore, slow-release auxiliary material of the present invention mainly is selected from the copolymer (PLGA), polifeprosan of polylactic acid (PLA), polyglycolic acid 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; The molecular weight peak value of the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA) is 5000-15000,15000-35000,35000-45000 or 45000-80000; The percentage by weight of polyglycolic acid and hydroxyacetic acid is 10: 90,20: 80, and 30: 70,40: 60,50: 50 or 60: 40; 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.
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
For regulating other characteristic of drug releasing rate or change Anticarcinogenic internal implant 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.
The consumption of sustained-release implant depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But its principle is at the repair ability that can reduce tumor cell, when increasing the chemotherapy action effect and the toxic reaction of not obvious increase medicine.Effective dose is 0.01-100 milligram/patient, is ideal with 1-50 milligram/patient, with 2-30 milligram/patient for the most desirable.
The present invention can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be made into various dosage forms, as, but be not limited to, injection, muddy suspension, ointment, capsule, implant, slow releasing agent and implantation slow release agent etc., wherein implant is mainly sustained-release implant, controlled release implant or slowbreak implant; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and apperance; Can be through various administrations, as in tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Whether route of administration depends on multiple factor, as position, tumor place, perform the operation or transfer, gross tumor volume size, tumor classification, patient age, health, bearing status and requirement etc.For obtain active drug concentration in position, tumor place, arterial perfusion optionally, intra-bladder instillation (intracavitary), (intraspinal) administration in abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and the canalis spinalis, but also place in the internal organs, as in the enteric cavity, in the intravesical, uterine cavity, in intravaginal, gastric and the esophagus etc.In various approach, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, to place the form that slowly discharges serve as preferably for tumor week or tumor chamber, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant and sustained-release implant as selecting for use.
Available arbitrary method preparation.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and anti-cancer sustained-released implantation agent also can be packed in the liposome.The effective ingredient of compositions can be packaged in the whole slow-release auxiliary material equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.
Each component and the weight percentage in compositions thereof are preferred one of following in the sustained-release implant:
(A) polylactic acid of the bortezomib of 1%-5% and 95%-99%;
(B) polylactic acid of the bortezomib of 5%-10% and 90%-95%;
(C) polylactic acid of the bortezomib of 10%-15% and 85%-90%;
(D) polylactic acid of the bortezomib of 15%-25% and 75%-85%;
(E) polylactic acid of the bortezomib of 25%-40% and 60%-75%;
(F) copolymer of the glycolic of the bortezomib of 1%-10% and 90%-99% and hydroxyacetic acid;
(G) copolymer of the glycolic of the bortezomib of 10%-20% and 80%-90% and hydroxyacetic acid;
(H) copolymer of the glycolic of the bortezomib of 20%-30% and 70%-80% and hydroxyacetic acid;
(I) copolymer of the glycolic of the bortezomib of 30%-40% and 60%-70% and hydroxyacetic acid;
(J) polifeprosan of the bortezomib of 5%-15% and 85%-95%; Or
(K) polifeprosan of the bortezomib of 15%-35% and 65%-85%.
Each component and the weight percentage in compositions thereof are one of further preferred following in the sustained-release implant:
(A) mannitol of the polylactic acid of the bortezomib of 1%-5% and 85%-98% and 0.5%-15%;
(B) sorbitol of the polylactic acid of the bortezomib of 5%-10% and 90%-95% and 0.5%-10%;
(C) sodium chloride of the polylactic acid of the bortezomib of 10%-15% and 85%-90% and 0.5%-10%;
(D) mannitol of the polylactic acid of the bortezomib of 15%-25% and 75%-85% and 0.25%-5%;
(E) sorbitol of the polylactic acid 0.1%-8% of the bortezomib of 25%-40% and 60%-75%;
(F) mannitol of the copolymer of the glycolic of the bortezomib of 1%-10% and 90%-99% and hydroxyacetic acid and 0.5%-15%;
(G) sorbitol of the copolymer of the glycolic of the bortezomib of 10%-20% and 80%-90% and hydroxyacetic acid and 0.5%-10%;
(H) sodium chloride of the copolymer of the glycolic of the bortezomib of 20%-30% and 70%-80% and hydroxyacetic acid and 0.5%-10%;
(I) mannitol of the copolymer of the glycolic of the bortezomib of 30%-40% and 60%-70% and hydroxyacetic acid and 0.25%-5%;
(J) mannitol of the polifeprosan of the bortezomib of 5%-15% and 85%-95% and 1%-5%; Or
(K) mannitol of the polifeprosan of the bortezomib of 15%-35% and 65%-85% and 0.25%-7.5%.
Sustained-release implant is used for the treatment of entity tumor, comprise the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma, tumor of head and neck and come from gallbladder, oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, eyes, former or cancer, sarcoma or the carcinosarcoma of secondary.Therefore, application of the present invention is the above-mentioned various pharmaceutical preparatioies that are used to make the above-mentioned tumor of treatment, serve as preferred wherein with injection, muddy suspension, ointment, capsule, implant, slow releasing agent and sustained-release implant, with sustained-release implant, controlled release implant or slowbreak implant for most preferably.
Also can add other medicinal ingredient in this anti-cancer sustained-released implantation agent, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Because anti-cancer sustained-released implantation agent of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.When share with above-mentioned non-operative treatment, anti-cancer sustained-released implantation agent of the present invention can be used simultaneously with non-operative treatment, also can in implementing a few days ago, non-operative treatment use, its purpose is to strengthen as far as possible the sensitivity of tumor, thereby provide a kind of more effective new method for effecting a radical cure former of various human bodies and animal and shifting entity tumor, have very high clinical value and remarkable economical and social benefit.
When used the part, said composition can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.The outer entity tumor of cranium had the obvious treatment effect.
Anti-cancer composition of the present invention can be implemented by many schemes, and its purpose is just in order to further specify, and is not in addition any restriction of enforcement of the present invention.
Test one, bortezomib are to the inhibitory action of growth of tumour cell.
Be the inhibitory action of checking bortezomib to other growth of tumour cell, this test is added to bortezomib (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
| Tumor cell | Suppression ratio (%) |
| Hepatocarcinoma | 90 |
| Pulmonary carcinoma | 82 |
| The esophageal carcinoma | 88 |
| Gastric cancer | 72 |
| Breast carcinoma | 76 |
| Cancer of pancreas | 86 |
| Thyroid carcinoma | 84 |
| Nasopharyngeal carcinoma | 80 |
| Ovarian cancer | 78 |
| Carcinoma of endometrium | 72 |
| Cervical cancer | 80 |
| Renal carcinoma | 88 |
| Carcinoma of prostate | 78 |
| Bladder cancer | 80 |
| Colon cancer | 82 |
| Rectal cancer | 82 |
| Skin carcinoma | 82 |
| Carcinoma of testis | 80 |
The result of test one shows that compare with matched group, bortezomib 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 bortezomib 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:
The slow-release auxiliary material of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
Adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and slow-release auxiliary material is decided because of specific requirement.
Remove organic solvent.Vacuum drying or cold drying all can.
Dried solid composite is made different shape as required.
Ray sterilizing after the packing (roentgendosis is different because of volume) is standby.Also available other method sterilization.
(4) specific embodiment
Embodiment one,
The slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 10000-20000) of (90mg) of will weighing is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 10 milligrams of bortezomibs, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 10% bortezomib.The drug release time of this sustained-release implant in external normal saline is 15-20 days, is 25-30 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% bortezomib and and 99% polylactic acid;
(B) 5% bortezomib and and 95% polylactic acid;
(C) 10% bortezomib and 90% polylactic acid;
(D) 15% bortezomib and 85% polylactic acid;
(E) 20% bortezomib and 80% polylactic acid.
Embodiment three
(molecular weight is the PLGA of 15000-30000 to the slow-release auxiliary material of (85mg) of will weighing, 50: 50) put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion), add the 15mg bortezomib, 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 15% bortezomib.The drug release time of this sustained-release implant in external normal saline is 14-24 days, is 20-28 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) copolymer of the glycolic of the bortezomib of 1%-10% and 90%-99% and hydroxyacetic acid;
(2) copolymer of the glycolic of the bortezomib of 10%-20% and 80%-90% and hydroxyacetic acid;
(3) copolymer of the glycolic of the bortezomib of 20%-30% and 70%-80% and hydroxyacetic acid;
(4) copolymer of the glycolic of the bortezomib of 30%-40% and 60%-70% and hydroxyacetic acid;
The copolymer of (5) 5% bortezomib and 95% glycolic and hydroxyacetic acid;
The copolymer of (6) 10% bortezomib and 90% glycolic and hydroxyacetic acid;
The copolymer of (7) 20% bortezomib and 80% glycolic and hydroxyacetic acid;
The copolymer of (8) 30% bortezomib and 70% glycolic and hydroxyacetic acid.
Embodiment five
(molecular weight is the PLGA of 20000-30000 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 bortezomib 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% bortezomib.The drug release time of this sustained-release implant in external normal saline is 15-25 days, is 25-40 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) mannitol of the copolymer of the glycolic of the bortezomib of 1%-10% and 90%-99% and hydroxyacetic acid and 0.5%-15%;
(2) sorbitol of the copolymer of the glycolic of the bortezomib of 10%-20% and 80%-90% and hydroxyacetic acid and 0.5%-10%;
(3) sodium chloride of the copolymer of the glycolic of the bortezomib of 20%-30% and 70%-80% and hydroxyacetic acid and 0.5%-10%;
(4) mannitol of the copolymer of the glycolic of the bortezomib of 30%-40% and 60%-70% and hydroxyacetic acid and 0.25%-5%;
The copolymer of (5) 5% bortezomib and 92% glycolic and hydroxyacetic acid and 2% sodium chloride;
The copolymer of (6) 10% bortezomib and 85% glycolic and hydroxyacetic acid and 5% mannitol;
The copolymer of (7) 20% bortezomib and 75% glycolic and hydroxyacetic acid and 5% mannitol;
The copolymer of (8) 30% bortezomib 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 the 15mg bortezomib, 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% bortezomib sustained-release implant.The drug release time of this sustained-release implant in external normal saline is 15-25 days, is 25-35 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) polifeprosan of the bortezomib of 1%-15% and 85%-95%;
(2) polifeprosan of the bortezomib of 15%-35% and 65%-85%;
(3) 5% bortezomib and 95% polifeprosan;
(4) 10% bortezomib and 90% polifeprosan;
(5) 15% bortezomib and the polifeprosan of 85%-95%;
(6) 20% bortezomib and 80% polifeprosan.
Embodiment nine
80mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) and 5mg sodium chloride are put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 15mg bortezomib, 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% bortezomib sustained-release implant.The drug release time of this sustained-release implant in external normal saline is 15-25 days, is 25-35 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) mannitol of the polifeprosan of the bortezomib of 5%-15% and 85%-95% and 1%-5%; Or
(2) mannitol of the polifeprosan of the bortezomib of 15%-35% and 65%-85% and 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 bortezomibs, 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% bortezomib.The drug release time of this sustained-release implant in external normal saline is 18-20 days, is 20-30 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% bortezomib and and 95% polylactic acid and 4% mannitol;
(B) 5% bortezomib and and 93% polylactic acid and 2% mannitol;
(C) 10% bortezomib and 85% polylactic acid and 5% mannitol;
(D) 15% bortezomib and 82% polylactic acid and 3% sodium chloride;
(E) 20% bortezomib 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 bortezomib other entity tumors such as the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer, rectal cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate 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, tumor are implanted into the inhibitory action of bortezomib 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, bortezomib lumbar injection group (hereinafter to be referred as bortezomib abdominal cavity group), bortezomib local injection group (being called for short the bortezomib partial groups), high molecular polymer group (being called for short high poly-group), bortezomib sustained-release implant 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 bortezomib implant implantation tumour tissue, not pastille high molecular polymer, bortezomib implant 5%, bortezomib implant 10%, bortezomib 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 15 tumors are implanted into the tumor-inhibiting action of bortezomib spit of fland sustained-release implant to Mice Bearing Lewis Lung Cancer
Check the tumor-inhibiting action of bortezomib sustained-release implant according to embodiment 14 described methods and step to Mice Bearing Lewis Lung Cancer.Used implant adjuvant is PLGA (molecular weight is 15000-30000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50), is derived from embodiment four.The bortezomib 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.Bortezomib implant tumor control rate is respectively 43%, 78%, 92%, compares with bortezomib local injection group, and the P value is all less than 0.001.Repeated experiments: tumor control rate is respectively 44%, 76%, 90%, compares with the local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bortezomib lumbar injection group and bortezomib local injection group and normal saline group comparison of tumor suppression ratio are 16% and 8.5%, and repeated experiments: tumor control rate is 11.8% and 11.2%.The tumour inhibiting rate of bortezomib implant obviously surpasses bortezomib lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 16 tumors are implanted into the tumor-inhibiting action of bortezomib sustained-release implant to mouse breast cancer
Check the tumor-inhibiting action of bortezomib sustained-release implant to mouse breast cancer according to embodiment 14 described methods and step, used implant is from embodiment one.Experimental result shows that the tumor control rate of 1%, 10% and 25% bortezomib implant is respectively 37%, 70%, 90%, compares with bortezomib local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 36%, 77%, 92%, compares with bortezomib local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bortezomib lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 14% and 10%, and repeated experiments: tumor control rate is 13% and 8%.The tumour inhibiting rate of bortezomib implant obviously surpasses bortezomib lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 17 tumors are implanted into the tumor-inhibiting action of bortezomib sustained-release implant to rat liver cancer
Check the tumor-inhibiting action of bortezomib sustained-release implant according to embodiment 15 described methods and step to rat liver cancer, used implant is 5%, 10% and 20% polifeprosan (percentage by weight to carboxy phenyl propane (p-CPP) and decanedioic acid (SA) is 50: 50), from embodiment eight.The bortezomib implant of experimental result proof various dose is implanted in rat liver cancer (H22) entity tumor and can obviously be suppressed tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Bortezomib implant tumor control rate is respectively 50%, 66%, 84%, compares with bortezomib 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 47%, 70%, 82%, compares with bortezomib 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.Bortezomib lumbar injection group and bortezomib local injection group and normal saline group comparison of tumor suppression ratio are 30% and 20%, and repeated experiments: tumor control rate is 27% and 20%.The tumour inhibiting rate of bortezomib implant obviously surpasses bortezomib lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 18 tumors are implanted into the tumor-inhibiting action of bortezomib sustained-release implant to the mice esophageal carcinoma
Check the tumor-inhibiting action of bortezomib sustained-release implant to the mice esophageal carcinoma according to embodiment 15 described methods and step, used implant is selected from embodiment six.The bortezomib 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.Bortezomib implant tumor control rate is respectively 45%, 64%, 76%, compares with bortezomib local injection group, and the P value is all less than 0.001.Repeated experiments finds that tumor control rate is respectively 50%, 80%, 88%, compares with bortezomib local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bortezomib lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 13% and 5.5%, and repeated experiments shows that tumor control rate is 12% and 13%.The tumour inhibiting rate of bortezomib implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 19 tumors are implanted into the tumor-inhibiting action of bortezomib sustained-release implant to mouse pancreas cancer
Check the tumor-inhibiting action of bortezomib sustained-release implant to mouse pancreas cancer according to embodiment 15 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 bortezomib in sustained-release implant be 2.5%, 7.5% and the bortezomib implant of 12.5%. experimental result proof various dose implant in nude mice model human pancreas cancer (JF305) entity tumor, can obviously suppress tumor growth, tumor control rate and drug dose are obvious dose-effect relationship.Bortezomib implant tumor control rate is respectively 34%, 47%, 76%, compares with bortezomib local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 58%, 65%, 72%, compares with bortezomib local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bortezomib lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 21% and 6.6%.Repeated experiments finds that tumor control rate is 12% and 9%.The tumour inhibiting rate of bortezomib implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 20 tumors are implanted into the tumor-inhibiting action of bortezomib sustained-release implant to the mice rectal cancer
Check the tumor-inhibiting action of bortezomib sustained-release implant to the mice rectal cancer according to embodiment 15 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 bortezomib in sustained-release implant is 7.5%, 15% and 25%.The bortezomib implant of experimental result proof various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Bortezomib implant tumor control rate is respectively 54%, 77%, 86%, compares with bortezomib local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 50%, 68%, 82%, compares with bortezomib local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Bortezomib lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 21% and 6.6%.Repeated experiments finds that tumor control rate is 12% and 9%.The tumour inhibiting rate of bortezomib implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
In addition, tumor is implanted into the bortezomib sustained-release implant other entity tumors such as gastric cancer, bladder cancer, carcinoma of testis, colon cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate is also had good therapeutical effect, and its effect obviously surpasses bortezomib lumbar injection group and local injection group.This is unexpected finds to constitute another major technique feature of the present invention, for the treatment of entity tumor provides another new selection.
Claims (10)
1. a sustained-release implant for the treatment of entity tumor is characterized in that this sustained-release implant contains the bortezomib 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) bortezomib 0.1%-60%
(2) slow-release auxiliary material 40%-99%
(3) slow release regulator 0-15%
Wherein,
Slow-release auxiliary material is selected from copolymer, polifeprosan, poly-(a kind of or its combination in L-lactide-co-etherophosphoric acid, poly-(the L-lactide-co-phosphoric acid propyl ester) of polylactic acid, polyglycolic acid and hydroxyacetic acid;
The slow release regulator is selected from a kind of or its combination in xylitol, oligosaccharide, chitin, potassium salt, sodium salt, mannitol, sorbitol, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
2. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) polylactic acid of the bortezomib of 1%-5% and 95%-99%;
(B) polylactic acid of the bortezomib of 5%-10% and 90%-95%;
(C) polylactic acid of the bortezomib of 10%-15% and 85%-90%;
(D) polylactic acid of the bortezomib of 15%-25% and 75%-85%;
(E) polylactic acid of the bortezomib of 25%-40% and 60%-75%;
(F) copolymer of the glycolic of the bortezomib of 1%-10% and 90%-99% and hydroxyacetic acid;
(G) copolymer of the glycolic of the bortezomib of 10%-20% and 80%-90% and hydroxyacetic acid;
(H) copolymer of the glycolic of the bortezomib of 20%-30% and 70%-80% and hydroxyacetic acid;
(I) copolymer of the glycolic of the bortezomib of 30%-40% and 60%-70% and hydroxyacetic acid;
(J) polifeprosan of the bortezomib of 5%-15% and 85%-95%; Or
(K) polifeprosan of the bortezomib of 15%-35% and 65%-85%.
3. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) mannitol of the polylactic acid of the bortezomib of 1%-5% and 85%-98% and 0.5%-15%;
(B) sorbitol of the polylactic acid of the bortezomib of 5%-10% and 90%-95% and 0.5%-10%;
(C) sodium chloride of the polylactic acid of the bortezomib of 10%-15% and 85%-90% and 0.5%-10%;
(D) mannitol of the polylactic acid of the bortezomib of 15%-25% and 75%-85% and 0.25%-5%;
(E) sorbitol of the polylactic acid 0.1%-8% of the bortezomib of 25%-40% and 60%-75%;
(F) mannitol of the copolymer of the glycolic of the bortezomib of 1%-10% and 90%-99% and hydroxyacetic acid and 0.5%-15%;
(G) sorbitol of the copolymer of the glycolic of the bortezomib of 10%-20% and 80%-90% and hydroxyacetic acid and 0.5%-10%;
(H) sodium chloride of the copolymer of the glycolic of the bortezomib of 20%-30% and 70%-80% and hydroxyacetic acid and 0.5%-10%;
(I) mannitol of the copolymer of the glycolic of the bortezomib of 30%-40% and 60%-70% and hydroxyacetic acid and 0.25%-5%;
(J) mannitol of the polifeprosan of the bortezomib of 5%-15% and 85%-95% and 1%-5%; Or
(K) mannitol of the polifeprosan of the bortezomib of 15%-35% and 65%-85% and 0.25%-7.5%.
4. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) 1% bortezomib and and 99% polylactic acid;
(B) 5% bortezomib and and 95% polylactic acid;
(C) 10% bortezomib and 90% polylactic acid;
(D) 15% bortezomib and 85% polylactic acid;
(E) 20% bortezomib and 80% polylactic acid;
(F) 5% bortezomib and 95% glycolic and the copolymer of hydroxyacetic acid;
(G) 10% bortezomib and 90% glycolic and the copolymer of hydroxyacetic acid;
(H) 20% bortezomib and 80% glycolic and the copolymer of hydroxyacetic acid;
(I) 30% bortezomib and 70% glycolic and the copolymer of hydroxyacetic acid;
(J) 5% bortezomib and 95% polifeprosan; Or
(K) 15% bortezomib and 85% polifeprosan.
5. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) 1% bortezomib and and 95% polylactic acid and 4% mannitol;
(B) 5% bortezomib and and 93% polylactic acid and 2% mannitol;
(C) 10% bortezomib and 85% polylactic acid and 5% mannitol;
(D) 15% bortezomib and 82% polylactic acid and 3% sodium chloride;
(E) 20% bortezomib and 78% polylactic acid and 2% sodium chloride;
(F) 5% bortezomib and 92% glycolic and the copolymer of hydroxyacetic acid and 2% sodium chloride;
(G) 10% bortezomib and 85% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(H) 20% bortezomib and 75% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(I) 30% bortezomib and 75% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(J) 5% bortezomib and 92.5% polifeprosan and 2.5% mannitol; Or
(K) 15% bortezomib and 75% polifeprosan and 10% mannitol.
6. according to the described anti-cancer sustained-released implantation agent of claim 1-5, the molecular weight peak value that it is characterized in that polylactic acid is 5000-15000,10000-20000,20000-35000 or 30000-50000.
7. according to the described anti-cancer sustained-released implantation agent of claim 1-5, the molecular weight peak value that it is characterized in that the copolymer of glycolic and hydroxyacetic acid is 5000-15000,15000-35000,35000-45000 or 45000-80000; The percentage by weight of polyglycolic acid and hydroxyacetic acid is 10: 90,20: 80, and 30: 70,40: 60,50: 50 or 60: 40.
8. according to the described anti-cancer sustained-released implantation agent of claim 1-5, it is characterized in that the percentage by weight to carboxy phenyl propane and decanedioic acid is 10: 90 in the polifeprosan (to carboxy phenyl propane-decanedioic acid copolymer), 20: 80,30: 70,40: 60,50: 50 or 60: 40.
9. the described sustained-release implant of claim 1-5 is characterized in that this sustained-release implant is slow releasing injection and solid sustained-release implant.
10. the sustained-release implant according to claim 1 is characterized in that described sustained-release implant is used to prepare the treatment cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma, tumor of head and neck and originates from the pharmaceutical preparation of cancer, sarcoma or the carcinosarcoma of gallbladder, oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, eyes former or secondary.
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| CNA2007102027598A CN101204365A (en) | 2007-11-29 | 2007-11-29 | Implant agent treating for solid tumor |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797219A (en) * | 2010-03-26 | 2010-08-11 | 中国人民解放军第四军医大学 | Solid sustained- release implant for curing esophageal carcinoma and preparation method thereof |
| EP2812338A4 (en) * | 2012-01-24 | 2015-09-23 | Millennium Pharm Inc | Method of treatment of nasopharyngeal caner |
| WO2018108164A1 (en) * | 2016-12-16 | 2018-06-21 | 宁波宁融生物医药有限公司 | Bortezomib pharmaceutical composition and applications thereof |
| WO2019148181A1 (en) * | 2018-01-29 | 2019-08-01 | Cognos Therapeutics, Inc. | Intratumoral delivery of bortezomib |
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2007
- 2007-11-29 CN CNA2007102027598A patent/CN101204365A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797219A (en) * | 2010-03-26 | 2010-08-11 | 中国人民解放军第四军医大学 | Solid sustained- release implant for curing esophageal carcinoma and preparation method thereof |
| EP2812338A4 (en) * | 2012-01-24 | 2015-09-23 | Millennium Pharm Inc | Method of treatment of nasopharyngeal caner |
| WO2018108164A1 (en) * | 2016-12-16 | 2018-06-21 | 宁波宁融生物医药有限公司 | Bortezomib pharmaceutical composition and applications thereof |
| CN108201622A (en) * | 2016-12-16 | 2018-06-26 | 宁波宁融生物医药有限公司 | A kind of bortezomib pharmaceutical composition and its application |
| CN110381975A (en) * | 2016-12-16 | 2019-10-25 | 宁波宁融生物医药有限公司 | A kind of bortezomib pharmaceutical composition and its application |
| WO2019148181A1 (en) * | 2018-01-29 | 2019-08-01 | Cognos Therapeutics, Inc. | Intratumoral delivery of bortezomib |
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