CN101176713B - Carmustine sustained-release implantation agent for curing entity tumour - Google Patents
Carmustine sustained-release implantation agent for curing entity tumour Download PDFInfo
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- CN101176713B CN101176713B CN2007102028919A CN200710202891A CN101176713B CN 101176713 B CN101176713 B CN 101176713B CN 2007102028919 A CN2007102028919 A CN 2007102028919A CN 200710202891 A CN200710202891 A CN 200710202891A CN 101176713 B CN101176713 B CN 101176713B
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Abstract
The invention relates to a slow-release implant agent of carmustine, which is characterized by effective amounts of carmustine, slow-release excipients and releasing regulatory agents in the slow-release implant agent. The excipients comprise macromolecules which are biologically compatible and degradable, mainly PLA and PLGA. The releasing regulatory agents are selected from one or more items from mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, chondroitin, gelatin and albumin. The slow-release implant agent slowly releases carmustine on the local tumor in the process of degradation and absorption, so the argent can evidently reduce the systemic toxicity and simultaneously apply to the effective drug concentration control on the local tumor. Therefore, the argent can be applied separately or combined with the non-surgical treatments such as chemotherapy drug and radiotherapy, which can be also widely used for tumor treatment of different phases, not only selectively improving the drug concentration on local tumor but also reinforcing the therapeutic effect of non-surgical treatments such as chemotherapy drug and radiotherapy.
Description
(1) technical field
The present invention relates to a kind of carmustine 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.In China 1,600,000 people's cancer strickens are arranged approximately every year, nearly 1,300,000 people die from cancer, account for 1/5th of total death toll.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.Therefore, inquire into the focus that a kind of effective treatment method for cancer or medicine have become present research.
For many years, carmustine is used as the choice drug as the treatment cerebroma always.The effect that is used for the treatment of other tumor separately is unclear.Though unite some tumor tool is had certain effect, limited its clinical practice by the caused whole body toxic and side effects of conventional route administration with other anticarcinogen.
For improving its general toxicity and to the therapeutic effect of kinds of tumors, the local slow free list reveals great superiority, sees Chinese patent (ZL200410035923.7; ZL200410035926.0; ZL200410035924.1; ZL200410035927.5; ZL200510042434.9; ZL200510042433.4; ZL2005100424800).Yet existing slow releasing agent is a slow-released carrier with polyester such as PLA and PLGA (polyesters) family macromolecule, and its release cycle is shorter, relatively poor for the tumor cell effect that enters rest period, therefore relatively poor to the effect of remaining tumor cell, easily prominent releasing, thereby toxic reaction is heavier.
(3) summary of the invention
Based on examination to prior art, the present invention has carried out a large amount of comparisons to existing adjuvant and the slow release regulator that may influence drug release, found that carmustine is in polyester (polyesters) family macromolecule, particularly under the condition of polyester such as PLA and PLGA and the existence of slow release regulator, have more stable release behavior, entity tumors such as cervical cancer, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer and rectal cancer are had comparatively significantly action effect.Discover that further the carmustine 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
No matter be inside and outside drug release behavior or general toxicity or therapeutic effect, the interpolation of the slow release regulator of given dose all shows beyond thought effect.
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 multiple entity tumor.
The present invention treats the sustained-release implant of entity tumor, comprises anticancer effective component and slow-release auxiliary material, and wherein anticancer effective component is carmustine (Carmustine).
This sustained-release implant is made up of one of following composition, all percentage by weight not:
(1) carmustine 1%-40%
(2) slow-release auxiliary material 45%-98.9%
(3) release regulator 0.1%-15%
Total amount is 100%.
Wherein, carmustine can be its various salt, serves as preferred with its hydrochlorate;
The percentage by weight of carmustine in sustained-release implant is 1%-40%, is preferred with 2%-20%, with 5%-15% for choosing is arranged most.
Slow-release auxiliary material is selected from the copolymer of polylactic acid or lactic acid and glycolic,
Wherein, the molecular weight peak value of polylactic acid is 500-5000,5000-10000,10000-25000,25000-35000 or 30000-50000, with 5000-10000,10000-25000,25000-35000 or 30000-50000 serves as preferred, with 10000-25000,25000-35000 or 30000-50000 choosing is arranged most;
Poly-lactonaphthol and co-glycolic acid the molecular weight peak value be 500-5000,5000-10000,10000-25000,25000-35000 or 30000-50000, with 5000-10000,10000-25000,25000-35000 or 30000-50000 serves as preferred, with 10000-25000,25000-35000 or 30000-50000 choosing is arranged most; Wherein, the percentage by weight of poly-lactonaphthol and polyglycolic acid is 90: 10,70-80: 20-30,60-40: 40-60,75: 25,25: 75 or 50: 50, with 90: 10 serve as preferably, with 75: 25 and 50: 50 for choosing is arranged most.
Release regulator is selected from a kind of or its combination in mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin; With mannitol, sorbitol, chitin, sodium salt, chrondroitin serves as preferred, with mannitol, sorbitol for most preferably; The percentage by weight of release regulator in sustained-release implant is 0.1%-15%, is preferred with 0.5%-10%, with 1%-8% for choosing is arranged most.
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 0.01-300 milligram/patient, is ideal with 1-100 milligram/patient, with 2-50 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, microsphere, nanosphere, 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 sustained-release implant 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 sustained-release implant thereof are preferred one of following in the sustained-release implant:
(1) sodium chloride of the PLGA of the carmustine of 1%-5%, 90%-98%, 1%-5%, mannitol or sorbitol;
(2) sodium chloride of the PLGA of the carmustine of 5%-10%, 80%-93%, 2%-10%, mannitol or sorbitol;
(3) sodium chloride of the PLGA of the carmustine of 10%-15%, 75%-89%, 1%-10%, mannitol or sorbitol;
(4) sodium chloride of the PLGA of the carmustine of 15%-20%, 84%-85%, 1%-5%, mannitol or sorbitol;
(5) sodium chloride of the PLGA of the carmustine of 20%-35%, 60%-79%, 1%-5%, mannitol or sorbitol are poly-;
(6) sodium chloride of the PLA of the carmustine of 1%-5%, 90%-98%, 1%-5%, mannitol or sorbitol;
(7) sodium chloride of the PLA of the carmustine of 5%-10%, 80%-93%, 2%-10%, mannitol or sorbitol;
(8) sodium chloride of the PLA of the carmustine of 10%-15%, 75%-89%, 1%-10%, mannitol or sorbitol;
(9) sodium chloride of the PLA of the carmustine of 15%-20%, 84%-85%, 1%-5%, mannitol or sorbitol;
(10) carmustine of 20%-35% and and sodium chloride, mannitol or the sorbitol of PLA, the 1%-5% of 60%-79% poly-.
Wherein, the molecular weight peak value of polylactic acid (PLA) is 500-5000,5000-10000,10000-25000,25000-35000 or 30000-50000;
The molecular weight peak value of the copolymer of polylactic acid and polyglycolic acid (PLGA) is 1000-10000,10000-25000,25000-40000 or 40000-60000;
The percentage by weight of poly-lactonaphthol and polyglycolic acid is 90: 10,70-80: 20-30,60-40: 40-60,75: 25,25: 75 or 50: 50;
Above-mentioned sustained-release implant is granular, microsphere, nanosphere, lamellar, sphere, bulk, needle-like, bar-shaped or apperance.
In the sustained-release implant each component and the weight percentage in sustained-release implant thereof with one of following for most preferably:
(1) 1% carmustine, 95% PLGA, 4% chitin, mannitol or sorbitol;
(2) 5% carmustine, 90% PLGA, 5% sodium chloride, mannitol or chrondroitin;
(3) 10% carmustine, 80% PLGA, 10% chitin, mannitol or sorbitol;
(4) 15% carmustine, 80% PLGA, 5% sodium chloride, mannitol or chrondroitin;
(5) 20% carmustine, 75% PLGA, 5% sodium chloride, mannitol or sorbitol are poly-;
(6) 2% carmustine, 90% PLA, 8% chitin, mannitol or sorbitol;
(7) 7.5% carmustine, 85% PLA, 7.5% sodium chloride, mannitol or chrondroitin;
(8) 10% carmustine, 75% PLA, 5% chitin, mannitol or sorbitol;
(9) 12.5% carmustine, 70% PLA, 12.5% sodium chloride, mannitol or chrondroitin;
(10) 25% carmustine, 70% PLA, 5% sodium chloride, mannitol or sorbitol are poly-.
Wherein, the molecular weight peak value of polylactic acid (PLA) is 10000-25000,25000-35000 or 30000-50000; The molecular weight peak value of the copolymer of lactic acid and glycolic (PLGA) is 10000-25000,25000-40000 or 40000-60000; The percentage by weight of lactonaphthol and glycolic is 75: 25,25: 75 or 50: 50.
Each component and the weight percentage in sustained-release implant thereof also comprise one of following in the most preferred sustained-release implant:
(1) 5% carmustine, 90% PLGA, 5% mannitol or sorbitol;
(2) 10% carmustine, 80% PLGA, 10% mannitol;
(3) 10% carmustine, 80% PLGA, 10% sorbitol;
(4) 15% carmustine, 80% PLGA, 5% sodium chloride or mannitol;
(5) 20% carmustine, 75% PLGA, 5% mannitol;
(6) 5% carmustine, 90% PLA, 5% mannitol or sorbitol;
(7) 7.5% carmustine, 85% PLA, 7.5% mannitol;
(8) 10% carmustine, 75% PLA, 5% chitin, mannitol or sorbitol;
(9) 12.5% carmustine, 70% PLA, 12.5% mannitol or chrondroitin;
(10) 15% carmustine, 75% PLA, 5% mannitol or sorbitol are poly-.
Wherein, the molecular weight peak value of polylactic acid is 15000-30000; The molecular weight peak value of the copolymer of lactic acid and glycolic is 15000-30000; The percentage by weight of lactonaphthol and glycolic is 50: 50.
Sustained-release implant is used for the treatment of entity tumor, comprises the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, osteosarcoma, 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 comes from former or cancer, sarcoma or the carcinosarcoma of secondary of gallbladder, oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, eyes.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.
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, this sustained-release implant 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 sustained-released implantation agent 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.
Studies show that carmustine is had the obvious suppression effect to multiple solid tumor cell growth.To the suppression ratio of growth of tumour cell such as 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, skin carcinoma and carcinoma of testis at 60%-96%.
Further research table carmustine all has obvious inhibitory action (P＜0.05) to the growth of the metastatic tumor of osteosarcoma and above-mentioned tumor.This is unexpected finds to constitute major technique feature of the present invention, for the treatment of the entity tumor of metastasis provides new selection.
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 slow release regulator of weighing shakes up again.The usage ratio of anticancer active ingredient and slow-release auxiliary material is decided because of specific requirement;
3, 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;
4, remove organic solvent.Vacuum drying or cold drying all can.
5, dried solid sustained-release implant is made different shape as required.
6, ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
The the 2nd and 3 goes on foot and can carry out simultaneously or with different orders, depends primarily on stability of drug.
(4) specific embodiment
Embodiment one,
(molecular weight is 15000-25000 PLGA with the slow-release auxiliary material of weighing, 50: 50) put into different containers respectively with slow release regulator (mannitol), add the carmustine that adds Different Weight behind the certain amount of organic solvent dissolving mixing (being as the criterion) more then, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid sustained-release implant is shaped immediately, obtains following sustained-release implant:
(A) 1% carmustine contains 1mg carmustine, 99mgPLGA
(a) 1% carmustine contains 1mg carmustine, 95mgPLGA, 4mg mannitol;
(B) 5% carmustine, contain 5mg carmustine, 95mgPLGA;
(b) 5% carmustine, contain 5mg carmustine, 91mgPLGA, 4mg mannitol;
(C) 10% carmustine, contain 10mg carmustine, 90mgPLGA;
(c) 10% carmustine, contain 10mg carmustine, 80mgPLGA, 10mg mannitol;
(D) 15% carmustine, contain 15mg carmustine, 85mgPLGA;
(d) 15% carmustine, contain 15mg carmustine, 80mgPLGA, 5mg mannitol;
(E) 20% carmustine, contain 20mg carmustine, 80mgPLGA;
(e) 20% carmustine, contain 20mg carmustine, 75mgPLGA, 5mg mannitol.
Embodiment two
10 sustained-release implants among the embodiment one are put into the drug accumulation burst size (%) that digestion instrument is measured its different time respectively, found that (A) in the sustained-release implant, (B), (C), (D) and (E) five carmustine sustained-release implantation agents that do not contain slow release regulator (mannitol) prominent to release phenomenon obvious, it is prominent releases phenomenon and mostly occurs at 26-30 days, account for the 40-60% of total content of dispersion, and (a), (b), (c), (d) and (e) the prominent phenomenon of releasing of carmustine sustained-release implantation agent that etc. contains slow release regulator (mannitol) is obviously not obvious, and drug slow discharged for 35 weeks.
Embodiment three
(molecular weight is the PLGA of 20000-30000 with the slow-release auxiliary material of weighing, 75: 25) put into different containers respectively with slow release regulator (mannitol), add the carmustine that adds Different Weight behind the certain amount of organic solvent dissolving mixing (being as the criterion) more then, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid sustained-release implant is shaped immediately, obtains following sustained-release implant:
(A) 1% carmustine contains 1mg carmustine, 99mgPLGA
(a) 1% carmustine contains 1mg carmustine, 95mgPLGA and 4mg sorbitol;
(B) 5% carmustine, contain 5mg carmustine, 95mgPLGA;
(b) 5% carmustine, contain 5mg carmustine, 91mgPLGA and 4mg sorbitol;
(C) 10% carmustine, contain 10mg carmustine, 90mgPLGA;
(c) 10% carmustine, contain 10mg carmustine, 80mgPLGA and 10% sorbitol;
(D) 15% carmustine, contain 15mg carmustine, 85mgPLGA;
(d) 15% carmustine, contain 15mg carmustine, 80mgPLGA, 5mg sorbitol;
(E) 20% carmustine, contain 20mg carmustine, 80mgPLGA;
(e) 20% carmustine, contain 20mg carmustine, 75mgPLGA, 5mg sorbitol.
Embodiment four
10 sustained-release implants among the embodiment three are put into the drug accumulation burst size (%) that digestion instrument is measured its different time respectively, found that (A) in the sustained-release implant, (B), (C), (D) and (E) five carmustine sustained-release implantation agents that do not contain slow release regulator (sorbitol) prominent to release phenomenon obvious, it is prominent releases phenomenon and mostly occurs at 26-32 days, account for the 40-50% of total content of dispersion, and (a), (b), (c), (d) and (e) the prominent phenomenon of releasing of carmustine sustained-release implantation agent that etc. contains slow release regulator (mannitol) is obviously not obvious, and drug slow discharges 28-36 days.
Embodiment five
The slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 15000-25000) of weighing is put into different containers respectively with slow release regulator (sodium chloride), add the carmustine that adds Different Weight behind the certain amount of organic solvent dissolving mixing (being as the criterion) more then, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid sustained-release implant is shaped immediately, obtains following sustained-release implant:
(A) 2% carmustine contains 2mg carmustine, 98mg PLA;
(a) 2% carmustine contains 2mg carmustine, 90mg PLA, 8mg sodium chloride;
(B) 7.5% carmustine, contain 7.5mg carmustine, 92.5mg PLA;
(b) 7.5% carmustine, contain 7.5mg carmustine, 85mg PLA, 7.5mg sodium chloride;
(C) 10% carmustine, contain 10mg carmustine, 90mg PLA;
(c) 10% carmustine, contain 10mg carmustine, 85mg PLA, 5mg sodium chloride;
(D) 12.5% carmustine, contain 12.5mg carmustine, 87.5mg PLA;
(d) 12.5% carmustine, contain 12.5mg carmustine, 75mg PLA, 12.5mg sodium chloride;
(E) 25% carmustine, contain 25mg carmustine, 75mg PLA;
(e) 25% carmustine, contain 25mg carmustine, 70mg PLA, 5mg sodium chloride.
Embodiment six
10 sustained-release implants among the embodiment five are put into the drug accumulation burst size (%) that digestion instrument is measured its different time respectively, found that (A) in the sustained-release implant, (B), (C), (D) and (E) five carmustine sustained-release implantation agents that do not contain slow release regulator (sodium chloride) prominent to release phenomenon obvious, it is prominent releases phenomenon and mostly occurs at 24-32 days, account for the 40-50% of total content of dispersion, and (a), (b), (c), (d) and (e) the prominent phenomenon of releasing of carmustine sustained-release implantation agent that etc. contains slow release regulator (mannitol) is obviously not obvious, and drug slow discharges 28-36 days.
Embodiment seven
(molecular weight is 25000-40000PLGA with the slow-release auxiliary material of weighing, 75: 25) put into different containers respectively with slow release regulator (mannitol), add the carmustine that adds Different Weight behind the certain amount of organic solvent dissolving mixing (being as the criterion) more then, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid sustained-release implant is shaped immediately, obtains following sustained-release implant:
(1) 5% carmustine, 90% PLGA, 5% mannitol or sorbitol;
(2) PLGA of the carmustine of 5%-10%, 80%-93%, 2%-10% mannitol or sorbitol;
(3) PLGA of the carmustine of 10%-15%, 75%-89%, 1%-10% mannitol or sorbitol;
(4) PLGA of the carmustine of 15%-20%, 84%-85%, 1%-5% mannitol or sorbitol;
(5) 20%% carmustine, 75% PLGA, 5% mannitol or sorbitol are poly-.
Embodiment eight
Make sustained-release implant by embodiment one, three, five described methods, contained anticancer effective component that different is is one of following:
(1) sodium chloride of the PLGA of the carmustine of 1%-5%, 90%-98%, 1%-5%, mannitol or sorbitol;
(2) sodium chloride of the PLGA of the carmustine of 5%-10%, 80%-93%, 2%-10%, mannitol or sorbitol;
(3) sodium chloride of the PLGA of the carmustine of 10%-15%, 75%-89%, 1%-10%, mannitol or sorbitol;
(4) sodium chloride of the PLGA of the carmustine of 15%-20%, 84%-85%, 1%-5%, mannitol or sorbitol;
(5) sodium chloride of the PLGA of the carmustine of 20%-35%, 60%-79%, 1%-5%, mannitol or sorbitol are poly-;
(6) sodium chloride of the PLA of the carmustine of 1%-5%, 90%-98%, 1%-5%, mannitol or sorbitol;
(7) sodium chloride of the PLA of the carmustine of 5%-10%, 80%-93%, 2%-10%, mannitol or sorbitol;
(8) sodium chloride of the PLA of the carmustine of 10%-15%, 75%-89%, 1%-10%, mannitol or sorbitol;
(9) sodium chloride of the PLA of the carmustine of 15%-20%, 84%-85%, 1%-5%, mannitol or sorbitol;
(10) carmustine of 20%-35% and and sodium chloride, mannitol or the sorbitol of PLA, the 1%-5% of 60%-79% poly-.
Wherein, the molecular weight peak value of polylactic acid (PLA) is 500-5000,5000-10000,10000-25000,25000-35000 or 30000-50000;
The molecular weight peak value of the copolymer of polylactic acid and polyglycolic acid (PLGA) is 1000-10000,10000-25000,25000-40000 or 40000-60000;
The percentage by weight of poly-lactonaphthol and polyglycolic acid is 90: 10,70-80: 20-30,60-40: 40-60,75: 25,25: 75 or 50: 50.
Embodiment nine
(molecular weight is 15000-25000 PLGA with the slow-release auxiliary material of weighing, 50: 50) put into different containers respectively with slow release regulator (mannitol), add the carmustine that adds Different Weight behind the certain amount of organic solvent dissolving mixing (being as the criterion) more then, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid sustained-release implant is shaped immediately, obtains following sustained-release implant:
(1) 5% carmustine, 90% PLGA, 5% mannitol;
(2) 10% carmustine, 83% PLGA, 7% mannitol;
(3) 15% carmustine, 75% PLGA, 10% mannitol;
(4) 20% carmustine, 77.5% PLGA, 2.5% mannitol;
(5) 25%% carmustine, 70% PLGA, 5% mannitol.
The drug release time of above sustained-release implant in external normal saline is 25-35 days, is 25-40 days at the subcutaneous drug release time of mice.All there be not prominent releasing.
Embodiment ten
After the subcutaneous implantation of implant mice among the embodiment one, take out to be placed in the room temperature normal saline with different time and soak, survey the burst size of different time medicine (carmustine), and calculate accumulative total and discharge percent (%).Be shown in Table 1.
Table 1
| Embodiment one | 1 day | 3 days | 5 days | 7 days | 14 days | 21 days | 28 days | 35 days | 42 days | 56 days |
| (A) | 1.0 | 2.2 | 4 | 4.8 | 12 | 50 | 68 | 82 | 98 | 100 |
| (a) | 2 | 8 | 14 | 22 | 40 | 50 | 60 | 72 | 84 | 92 |
| (B) | 2 | 4 | 4.6 | 7 | 8 | 48 | 72 | 78 | 86 | 98 |
| (b) | 2.4 | 12 | 18 | 24 | 48 | 54 | 62 | 76 | 88 | 96 |
| (C) | 2.1 | 3.3 | 4.2 | 6 | 10 | 62 | 80 | 88 | 96 | 98 |
| (c) | 2.2 | 7.9 | 16 | 24 | 42.8 | 56 | 64 | 78 | 84 | 94 |
| (D) | 1.2 | 3.1 | 5.2 | 6.8 | 10 | 58 | 78 | 89 | 96 | 100 |
| (d) | 3 | 7.2 | 18 | 24 | 41 | 52 | 68 | 80 | 90 | 98 |
| (E) | 1.1 | 3.0 | 5.0 | 7 | 8.2 | 58 | 76 | 86 | 94 | 98 |
| (e) | 2.2 | 11 | 18 | 26 | 39 | 52 | 68 | 82 | 86 | 92 |
Table 1 discharges data and shows, does not contain the carmustine sustained-release implantation agent (A), (B), (C), (D) of regulator and (E) discharges lessly in two weeks, is no more than 18%, concentrates release above 50% between week at 2-3; And contain the carmustine sustained-release implantation agent (a) and (b), (c), (d) of regulator and (e) discharging slowly steadily, do not have prominent releases phenomenon in 3-6 week average deenergized period.This unexpected formation another major technique feature of the present invention of finding is for the better control drug release time provides new guidance.
On this basis, the present invention finds that further body is implanted into carmustine other entity tumors such as bone 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 had better 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.
Tumor is implanted into the inhibitory action of carmustine implant to entity tumor
Method and step: tumor cell inoculation is subcutaneous in the right side of mice axillary fossa, and (inoculation back the 14th day) is divided into 11 groups at random with animal, 10 every group when diameter of tumor grows to the 0.8cm left and right sides.Be the normal saline group, do not contain regulator carmustine implant group (hereinafter to be referred as the carmustine group), contain the carmustine local injection group (be called for short carmustine regulator) of regulator.With 70% alcohol disinfecting tumor surface skin, select to cut off the long otch of 1mm apart from tumor lower edge 1cm place, with puncture needle with in the implant implantation tumour tissue.Sew up the incision and prevent that implant from spilling.Put to death animal in 20 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 11 tumors are implanted into the tumor-inhibiting action of carmustine spit of fland sustained-release implant to Mice Bearing Lewis Lung Cancer
The carmustine sustained-release implantation agent that makes with step check embodiment one is to the tumor-inhibiting action of Mice Bearing Lewis Lung Cancer according to the method described above.The carmustine 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.Carmustine group (A), (B), (C), (D) and tumor control rate (E) are respectively 23%, 49%, 60%, 70% and 76%; And the carmustine sustained-release implantation agent (a) and (b), (c), (d) and the tumor control rate (e) that contain regulator are respectively 40%, 59%, 75%, 86% and 92%.The P value is all less than 0.001.Repeated experiments P value is all less than 0.001, and difference has the height statistical significance.The tumour inhibiting rate that contains the carmustine sustained-release implantation agent of regulator obviously surpasses the carmustine sustained-release implantation agent group that does not contain regulator, twice experimental result good reproducibility.It should be noted that especially, carmustine group (A), (B), (C), (D) and (E) in, the average weight of animal contain the carmustine sustained-release implantation agent (a) and (b), (c), (d) of regulator and (e) group obviously alleviate, wherein (C), (D) and (E) in have 20%, 40% and 50% animal dead in advance respectively, and death focused mostly between 20-30 days.Therefore illustrate that prominent the releasing of medicine may be the main cause that causes toxic reaction.And containing the carmustine sustained-release implantation agent (a) and (b) of regulator, (c), (d) and (e) group, no animal dead.This is unexpected finds to constitute another major technique feature of the present invention, provides another new selection and guidance for what use carmustine sustained-release implantation agent treatment entity tumor.
Embodiment 12 tumors are implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to mouse breast cancer
The carmustine sustained-release implantation agent that makes with step check embodiment three is to the tumor-inhibiting action of mouse breast cancer according to the method described above.The carmustine implant of experimental result proof various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.The carmustine sustained-release implantation agent (a) and (b), (c), (d) and the tumor control rate (e) that contain regulator are respectively 44%, 58%, 74%, 80% and 84%.The P value is all less than 0.001.Repeated experiments P value is all less than 0.001, and difference has the height statistical significance.
Embodiment 13 tumors are implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to rat liver cancer
The carmustine sustained-release implantation agent that makes according to embodiment 11 and 12 described methods and step check embodiment nine is to the tumor-inhibiting action of rat liver cancer.The carmustine 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.5%, the tumor control rate of 10%, 15%, 20% and 25% carmustine implant is respectively 43%, 56%, 68%, 74% and 80%.Compare with matched group, the P value is equal to or less than 0.001.
Embodiment 14 tumors are implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to the mice esophageal carcinoma
The carmustine sustained-release implantation agent that makes according to embodiment 11 and 12 described methods and step check embodiment nine is to the tumor-inhibiting action of mice esophageal carcinoma.The carmustine 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.5%, the tumor control rate of 10%, 15%, 20% and 25% carmustine implant is respectively 40%, 54%, 68%, 74% and 80%.Compare with matched group, the P value is all less than 0.001.
Embodiment 15 tumors are implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to mouse pancreas cancer
The carmustine sustained-release implantation agent that makes according to embodiment 11 and 12 described methods and step check embodiment nine is to the tumor-inhibiting action of mouse pancreas cancer.The carmustine 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.5%, the tumor control rate of 10%, 15%, 20% and 25% carmustine implant is respectively 32%, 40%, 57%, 68% and 78%, compares with matched group, and the P value is all less than 0.001.
Embodiment 16 carmustine sustained-release implantation agents are to the tumor-inhibiting action of the subcutaneous plantation ovarian cancer of mice
The carmustine sustained-release implantation agent that makes according to embodiment 11 and 12 described methods and step check embodiment nine is to the mice tumor-inhibiting action of plantation ovarian cancer down.The carmustine 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.5%, the tumor control rate of 10%, 15%, 20% and 25% carmustine implant is respectively 40%, 56%, 66%, 74% and 82%.Compare with matched group, the P value is equal to or less than 0.001.
Embodiment 17 tumors are implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to mouse cervical cancer
The carmustine sustained-release implantation agent that makes according to embodiment 11 and 12 described methods and step check embodiment nine is to the tumor-inhibiting action of mouse cervical cancer.The carmustine 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.5%, the tumor control rate of 10%, 15%, 20% and 25% carmustine implant is respectively 43%, 52%, 72%, 78% and 88%.Compare with matched group, the P value is all less than 0.001.
Embodiment 18 tumors are implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to the mice carcinoma of prostate
The carmustine sustained-release implantation agent that makes according to embodiment 11 and 12 described methods and step check embodiment nine is to the tumor-inhibiting action of mice carcinoma of prostate.The carmustine 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.5%, the tumor control rate of 10%, 15%, 20% and 25% carmustine implant is respectively 28%, 44%, 57%, 64% and 78%, compares with matched group, and the P value is all less than 0.001.
Embodiment 19 tumors are implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to Mouse Gastric Cancer
The carmustine sustained-release implantation agent that makes according to embodiment 11 and 12 described methods and step check embodiment nine is to the tumor-inhibiting action of Mouse Gastric Cancer.The carmustine 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.5%, the tumor control rate of 10%, 15%, 20% and 25% carmustine implant is respectively 44%, 50%, 76%, 78% and 86%.Compare with matched group, the P value is all less than 0.001.
Embodiment 20 tumors are implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to mouse junction cancer
The carmustine sustained-release implantation agent that makes according to embodiment 11 and 12 described methods and step check embodiment nine is to the tumor-inhibiting action of mouse junction cancer.The carmustine 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.5%, the tumor control rate of 10%, 15%, 20% and 25% carmustine implant is respectively 30%, 35%, 46%, 56% and 68%, compares with matched group, and the P value is all less than 0.001.
In addition, tumor is implanted into the carmustine sustained-release implantation agent that contains the slow release regulator other entity tumors such as bladder cancer, carcinoma of testis, colon cancer, carcinoma of endometrium, osteosarcoma, nasopharyngeal carcinoma, renal carcinoma is also had good therapeutical effect, and its effect obviously surpasses equivalent not carmustine sustained-release implantation agent and the carmustine lumbar injection group and the local injection group of slow release regulator.This is unexpected finds to constitute another major technique feature of the present invention, for the treatment of entity tumor provides another new selection.
The foregoing description is to be used for illustrating and also unrestricted the present invention that concrete performance is based on claim.
Claims (1)
1. carmustine sustained-release implantation agent for the treatment of entity tumor is characterized in that this sustained-release implant is made up of one of following composition, all is weight percentage:
(1) anticancer effective component is 1% carmustine, and slow-release auxiliary material is that 95% molecular weight is the PLGA of 15000-25000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 4% mannitol;
(2) anticancer effective component is 5% carmustine, and slow-release auxiliary material is that 91% molecular weight is the PLGA of 15000-25000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 4% mannitol;
(3) anticancer effective component is 10% carmustine, and slow-release auxiliary material is that 80% molecular weight is the PLGA of 15000-25000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 10% mannitol;
(4) anticancer effective component is 15% carmustine, and slow-release auxiliary material is that 80% molecular weight is the PLGA of 15000-25000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 5% mannitol;
(5) anticancer effective component is 20% carmustine, and slow-release auxiliary material is that 75% molecular weight is the PLGA of 15000-25000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 5% mannitol;
(6) anticancer effective component is 1% carmustine, and slow-release auxiliary material is that 95% molecular weight is the PLGA of 20000-30000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 75:25, and the slow release regulator is 4% sorbitol;
(7) anticancer effective component is 5% carmustine, and slow-release auxiliary material is that 91% molecular weight is the PLGA of 20000-30000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 75:25, and the slow release regulator is 4% sorbitol;
(8) anticancer effective component is 10% carmustine, and slow-release auxiliary material is that 80% molecular weight is the PLGA of 20000-30000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 75:25, and the slow release regulator is 10% sorbitol;
(9) anticancer effective component is 15% carmustine, and slow-release auxiliary material is that 80% molecular weight is the PLGA of 20000-30000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 75:25, and the slow release regulator is 5% sorbitol;
(10) anticancer effective component is 20% carmustine, and slow-release auxiliary material is that 75% molecular weight is the PLGA of 20000-30000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 75:25, and the slow release regulator is 5% sorbitol;
(11) anticancer effective component is 2% carmustine, and slow-release auxiliary material is that 90% molecular weight is the PLA of 15000-25000, and the slow release regulator is 8% sodium chloride;
(12) anticancer effective component is 7.5% carmustine, and slow-release auxiliary material is that 85% molecular weight is the PLA of 15000-25000, and the slow release regulator is 7.5% sodium chloride;
(13) anticancer effective component is 10% carmustine, and slow-release auxiliary material is that 85% molecular weight is the PLA of 15000-25000, and the slow release regulator is 5% sodium chloride;
(14) anticancer effective component is 12.5% carmustine, and slow-release auxiliary material is that 75% molecular weight is the PLA of 15000-25000, and the slow release regulator is 12.5% sodium chloride;
(15) anticancer effective component is 25% carmustine, and slow-release auxiliary material is that 70% molecular weight is the PLA of 15000-25000, and the slow release regulator is 5% sodium chloride;
(16) anticancer effective component is 5% carmustine, and slow-release auxiliary material is that 90% molecular weight is the PLGA of 15000-25000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 5% mannitol;
(17) anticancer effective component is 10% carmustine, and slow-release auxiliary material is that 83% molecular weight is the PLGA of 15000-25000, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 7% mannitol;
(18) anticancer effective component is 15% carmustine, and slow-release auxiliary material is that 75% molecular weight is 15000-25000 PLGA, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 10% mannitol; Or
(19) anticancer effective component is 20% carmustine, and slow-release auxiliary material is that 77.5% molecular weight is 15000-25000 PLGA, and the percentage by weight of wherein poly-lactonaphthol and polyglycolic acid is 50:50, and the slow release regulator is 2.5% mannitol.
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