CN1698592A - Medicament composition for treating extracranial noumenal tumour - Google Patents
Medicament composition for treating extracranial noumenal tumour Download PDFInfo
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- CN1698592A CN1698592A CN 200510043480 CN200510043480A CN1698592A CN 1698592 A CN1698592 A CN 1698592A CN 200510043480 CN200510043480 CN 200510043480 CN 200510043480 A CN200510043480 A CN 200510043480A CN 1698592 A CN1698592 A CN 1698592A
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- carmustine
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Disclosed is a medicament composition for treating extracranial noumenal tumor, wherein the medicinal composition contains effective dose of anticancer Carmuine and other medicinal subsidiary materials, the medicinal subsidiary materials mainly comprise bio-compactable and degradable macromolecular polymers, which can slowly release the Carmustine onto tumor partially during the degradation and absorption process, thus the whole body toxicity reaction is reduced appreciably , and the effective medicinal concentration can be sustained to the tumor partially. when locally dispensed on the tumor, the composition can lower down the whole body toxicity reaction of Carmustine, selectively increase the tumor local medicinal concentration.
Description
(1) technical field
The present invention relates to a kind of pharmaceutical composition for the treatment of the outer entity tumor of cranium, 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, BCNU is used as the choice drug of the treatment cerebral tumor always, and more show with the experience of the BCNU local sustained release treatment cerebral tumor, topical remedy's slow release has guaranteed stable lastingly and drug level in local application's scope, reduced systemic drug concentration, alleviate toxic and side effects, brought hope for the glioma chemotherapy.Why use BCNU, particularly local sustained release BCNU treats the cerebral tumor, its rationale is: (1) is owing to be subjected to the restriction of blood brain barrier, many chemotherapeutics can not enter in the brain when conventional intravenous chemotherapy or drug level is difficult to reach or keeps long-time valid density, by contrast, it is less that BCNU is subjected to the restriction of blood brain barrier; (2) 90% patient is in operation inherent local (in the 2cm) recurrence in back 1 year; (3) BCNU has high relatively selectivity as the medicine of the most frequently used treatment cerebral tumor to the cerebral tumor.
(3) summary of the invention
Based on above examination to prior art, the present invention compares the cerebral tumor and the outer tumor of some cranium, found that carmustine has comparatively significantly action effect to the outer entity tumor of craniums such as hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer and rectal cancer.Discover that further the BCNU 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 pharmaceutical composition for the treatment of the outer entity tumor of cranium is provided.
The present invention treats the pharmaceutical composition of the outer entity tumor of cranium, comprises anticancer effective component and pharmaceutic adjuvant, and wherein anticancer effective component is a carmustine, claims carmustine, BCNU or carmustine again.
Pharmaceutic adjuvant 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), certain herbaceous plants with big flowers diacid (sebacic acid), polifeprosan (to the copolymer of carboxy phenyl propane and certain herbaceous plants with big flowers diacid) 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 certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid 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).
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 10,000-50000 is preferred, with 10,000-20000 is for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is 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 10,000-50000 is preferred; With 10,000-20000 is 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 certain herbaceous plants with big flowers diacid 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 the certain herbaceous plants with big flowers diacid, molecular weight is that 30000 to 80000 PLGA mixes with the certain herbaceous plants with big flowers diacid.
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 anticancer pharmaceutical composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, 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 pharmaceutic adjuvant of pharmaceutical composition of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid 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, certain herbaceous plants with big flowers diacid 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 the copolymerization of certain herbaceous plants with big flowers diacid 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.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant 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 pharmaceutic adjuvant.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant 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 pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
Certain herbaceous plants with big flowers diacid (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, pharmaceutic adjuvant 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 5000-15000,10000-20000,25000-35000 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 weight ratio 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 weight ratio to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA) certain herbaceous plants with big flowers diacid (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 pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds 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.
Pharmaceutic adjuvant 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 pharmaceutic adjuvant 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 composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, 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 pharmaceutical composition 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 1-30 milligram/patient, with 2-20 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 graininess, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous; 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 have a detailed description in U.S. Pat 5651986, 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 anticancer pharmaceutical composition also can be packed in the liposome.The effective ingredient of compositions can be packaged in the whole pharmaceutic adjuvant 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.
It is one of preferred following that the present invention treats the pharmaceutical composition of the outer entity tumor of cranium, all is weight percentage:
(A) copolymer of the polyglycolic acid of the carmustine of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the carmustine of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the carmustine of 5-15% and 85-95%;
(D) polylactic acid of the carmustine of 15-35% and 65-85%;
(E) polifeprosan of the carmustine of 5-15% and 85-95%;
(F) polifeprosan of the carmustine of 15-35% and 65-85%;
(G) polifeprosan of the copolymer of the polyglycolic acid of the carmustine of 5-35% and 1-95% and hydroxyacetic acid and 1-95%;
(H) polifeprosan of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95%;
(I) copolymer of the polyglycolic acid of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95% and hydroxyacetic acid;
(J) polifeprosan of the copolymer of the polyglycolic acid of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95% and hydroxyacetic acid and 1-95%.
Pharmaceutical composition of the present invention is used for the treatment of the outer entity tumor of cranium, comprise 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.
The present invention treats in the pharmaceutical composition of the outer entity tumor of cranium also can add other medicinal ingredient, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Because anticancer pharmaceutical composition 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, anticancer pharmaceutical composition 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.
The present invention treats that Main Ingredients and Appearance is a holder with the bio-capacitivity material in the pharmaceutical composition of the outer entity tumor of cranium, 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.
The present invention treats in the pharmaceutical composition of the outer entity tumor of cranium and 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, carmustine are to the inhibitory action of the outer growth of tumour cell of cranium.
Be the inhibitory action of checking carmustine to the outer growth of tumour cell of cranium, this test is added to carmustine (10ug/ml) in the outer tumor cell of 24 hours various craniums of In vitro culture (table 1), continues to cultivate after 48 hours the counting cells sum and calculates its suppression ratio to growth of tumour cell (%).
The suppression ratio of growth of tumour cell (%)=((cellular control unit number-test group cell number)/cellular control unit number) * 100%
Table 1
| Tumor cell | Suppression ratio (%) |
| Liver cancer lung cancer cancer of the esophagus cancer of the stomach breast cancer cancer of pancreas thyroid cancer nasopharyngeal carcinoma oophoroma carcinoma of endometrium cervix cancer kidney prostate cancer carcinoma of urinary bladder colon cancer carcinoma of the rectum cutaneum carcinoma carcinoma of testis | ??92 ??90 ??82 ??88 ??84 ??94 ??92 ??88 ??68 ??80 ??80 ??68 ??70 ??82 ??82 ??80 ??86 ??84 |
The result of test one shows that compare with matched group, carmustine all has obvious inhibitory action (P＜0.05) to the examination growth of tumor, and is wherein right.This unexpected formation major technique feature of the present invention of finding is for the outer entity tumor treatment of cranium provides new selection.
The pharmaceutical composition that the present invention treats the outer entity tumor of cranium can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing of implanting.
The preparation of pharmaceutical compositions method that the present invention treats the outer entity tumor of cranium is as follows:
(1) pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
(2) adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.
(3) remove organic solvent.Vacuum drying or cold drying all can.
(4) dried solid composite is made different shape as required.
(5) ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
(4) specific embodiment
Embodiment one:
With the pharmaceutic adjuvant molecular weight of 90mg is that 10000 polylactic acid (PLA) is put into container, adds 100 milliliters of dichloromethane dissolvings of organic solvent mixing, adds the 10mg carmustine, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the outer entity tumor of treatment cranium of percentage by weight 10% carmustine, as Anticarcinogenic internal implant agent.
Embodiment two: as described in embodiment one, component that different is is one of following, all is weight percentage:
(A) copolymer of the polyglycolic acid of the carmustine of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the carmustine of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the carmustine of 5-15% and 85-95%;
(D) polylactic acid of the carmustine of 15-35% and 65-85%;
(E) polifeprosan of the carmustine of 5-15% and 85-95%;
(F) polifeprosan of the carmustine of 15-35% and 65-85%.
Embodiment three:
With the pharmaceutic adjuvant molecular weight of the 85mg that weighs is that 15000 polylactic acid (PLA) is put into container, adds 100 milliliters of dichloromethane dissolvings of organic solvent mixing, adds the 15mg carmustine, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the outer entity tumor of treatment cranium of percentage by weight 15% carmustine, as Anticarcinogenic internal implant agent.
Embodiment four: as described in embodiment three, component that different is is one of following, all is weight percentage:
(A) copolymer of the polyglycolic acid of the carmustine of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the carmustine of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the carmustine of 5-15% and 85-95%;
(D) polylactic acid of the carmustine of 15-35% and 65-85%;
(E) polifeprosan of the carmustine of 5-15% and 85-95%;
(F) polifeprosan of the carmustine of 15-35% and 65-85%.
Embodiment five:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that 15000 ethylene vinyl acetate copolymer (EVAc) is put into container, adds 100 milliliters of dichloromethane dissolvings of organic solvent mixing, adds the 20mg carmustine, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the outer entity tumor of treatment cranium of percentage by weight 20% carmustine, as Anticarcinogenic internal implant agent.
Embodiment six: as described in embodiment five, component that different is is one of following, all is weight percentage:
(A) copolymer of the polyglycolic acid of the carmustine of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the carmustine of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the carmustine of 5-15% and 85-95%;
(D) polylactic acid of the carmustine of 15-35% and 65-85%;
(E) polifeprosan of the carmustine of 5-15% and 85-95%;
(F) polifeprosan of the carmustine of 15-35% and 65-85%.
Embodiment seven:
85mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 15mg carmustine, 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 containing the pharmaceutical composition of the outer entity tumor of treatment cranium of percentage by weight 15% carmustine, as Anticarcinogenic internal implant agent.It is 15-25 days that this body is implanted into the drug release time of agent in external normal saline, is 25-40 days at the subcutaneous drug release time of mice.
Embodiment eight: as described in embodiment seven, component that different is is one of following, all is weight percentage:
(A) copolymer of the polyglycolic acid of the carmustine of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the carmustine of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the carmustine of 5-15% and 85-95%;
(D) polylactic acid of the carmustine of 15-35% and 65-85%;
(E) polifeprosan of the carmustine of 5-15% and 85-95%;
(F) polifeprosan of the carmustine of 15-35% and 65-85%.
Embodiment nine:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that 10000 ethylene vinyl acetate copolymer (EVAc) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 20mg carmustine, 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 containing the pharmaceutical composition of the outer entity tumor of treatment cranium of percentage by weight 20% carmustine, as Anticarcinogenic internal implant agent.
Embodiment ten:
With the pharmaceutic adjuvant 40mg molecular weight of weighing is that 20000 polylactic acid and 40mg molecular weight are that 20000 polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add the 20mg carmustine, 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 containing the pharmaceutical composition of the outer entity tumor of treatment cranium of percentage by weight 20% carmustine, as Anticarcinogenic internal implant agent.
Embodiment 11: as described in embodiment ten, component that different is is one of following, all is weight percentage:
(A) copolymer of the polyglycolic acid of the carmustine of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the carmustine of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the carmustine of 5-15% and 85-95%;
(D) polylactic acid of the carmustine of 15-35% and 65-85%;
(E) polifeprosan of the carmustine of 5-15% and 85-95%;
(F) polifeprosan of the carmustine of 15-35% and 65-85%;
(G) polifeprosan of the copolymer of the polyglycolic acid of the carmustine of 5-35% and 1-95% and hydroxyacetic acid and 1-95%;
(H) polifeprosan of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95%;
(I) copolymer of the polyglycolic acid of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95% and hydroxyacetic acid;
(J) polifeprosan of the copolymer of the polyglycolic acid of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95% and hydroxyacetic acid and 1-95%.
Embodiment 12:
As embodiment one pharmaceutical composition to the outer entity tumor of embodiment 11 described treatment craniums, used pharmaceutic adjuvant is selected from one of following or its combination that different is:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 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) ethylene vinyl acetate copolymer (EVAc);
D) polifeprosan is (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (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 certain herbaceous plants with big flowers diacid (SA);
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 13: different embodiment medicine extracorporeal releasing characteristics relatively
Implant among the embodiment 11 is placed in the room temperature normal saline soaks, survey the burst size of different time medicine (carmustine), and calculate accumulative total and discharge percent (%).Be shown in Table 2.
Table 2
| Embodiment 12 | 1 day | 3 days | 5 days | 7 days | 14 days |
| (A) (B) (C) (D) (E) (F) (G) (H) (I) (J) | ??19 ??20 ??21 ??21 ??21 ??23 ??12 ??13 ??12 ??11 | ??40 ??39 ??41 ??42 ??41 ??39 ??31 ??32 ??30 ??31 | ??59 ??61 ??61 ??61 ??61 ??60 ??52 ??48 ??50 ??49 | ??78 ??78 ??72 ??81 ??71 ??79 ??68 ??72 ??73 ??70 | ??92 ??88 ??89 ??89 ??86 ??92 ??80 ??81 ??80 ??78 |
Embodiment 14: release characteristics relatively in the different embodiment medicine bodies
It is subcutaneous that Anticarcinogenic internal implant agent among the embodiment 11 is put in white mice, regularly takes out and measure medicament contg, according to the residual drug amount, and calculates accumulative total and discharge percent (%).Be shown in Table 3.
Table 3
| Embodiment 12 | 1 day | 3 days | 5 days | 7 days | 14 days | 21 days | 28 days |
| (A) (B) (C) (D) (E) (F) (G) | ?10 ?12 ?11 ?14 ?12 ?12 ?6 | ?27 ?21 ?22 ?20 ?23 ?23 ?15 | ?33 ?33 ?33 ?29 ?26 ?26 ?20 | ?50 ?52 ?51 ?48 ?49 ?48 ?36 | ?72 ?72 ?73 ?72 ?69 ?68 ?62 | ?92 ?92 ?91 ?89 ?88 ?90 ?78 | ?95 ?96 ?95 ?94 ?89 ?89 ?85 |
| ??(H) ??(I) ??(J) | ??9 ??8 ??9 | ??17 ??15 ??16 | ??21 ??19 ??18 | ??31 ??33 ??36 | ??60 ??58 ??56 | ??74 ??76 ??74 | ??84 ??86 ??82 |
By table 2 and 3 as can be seen, the inside and outside discharges but notable difference, and release in vitro is fast than being released in the body, and release in vitro 50% needs 5 day time, and inside and outside release 50% needs 10-14 days time.Discharged about 11-23% the 14th day release 78-92 in external first day; Discharged about 6-12% the 14th day release 56-73, the 28th day release 82-96% in the body in first day.It should be noted that the release time that has obviously prolonged medicine when polifeprosan and PLGA or PLA share especially, this is unexpected finds to constitute another major technique feature of the present invention, for the better control drug release time provides new guidance.
On this basis, the present invention finds that further body is implanted into BCNU the outer entity tumor of other craniums such as hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer, rectal cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate is also had good therapeutical effect.Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.
Tumor is implanted into the inhibitory action experiment of BCNU to the outer entity tumor of cranium
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, carmustine lumbar injection group (hereinafter to be referred as carmustine abdominal cavity group), carmustine local injection group (being called for short the carmustine partial groups), high molecular polymer group (being called for short high poly-group), 7.5% group of carmustine sustained-release implantation agent, 15% group of carmustine sustained-release implantation agent, 30% group of carmustine sustained-release implantation agent (being called for short implant 7.5%, implant 15%, implant 30%).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 carmustine implant implantation tumour tissue, not pastille high molecular polymer, carmustine implant 7.5%, carmustine implant 15%, carmustine implant 30%.
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.
Embodiment 15: tumor is implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to Mice Bearing Lewis Lung Cancer
According to the method described above with the tumor-inhibiting action of step check carmustine sustained-release implantation agent to Mice Bearing Lewis Lung Cancer.Used adjuvant is PLGA (molecular weight is 10000-15000, and the blending ratio of polyglycolic acid and hydroxyacetic acid is 50: 50).Experimental result sees Table 4
Table 4, tumor are implanted into the growth inhibited effect of carmustine implant mice lung cancer (Lewis)
Group dosage number of animals route of administration body weight (x ± s, g) the heavy suppression ratio p of tumor value
(mg/kg) (x ± s.g) (%) before and after (only) number of times
Normal saline group 10 ip * 1 19.61 ± 1.15 21.775 ± 1.1 5.4089 ± 0.921-
Carmustine abdominal cavity group 21.768 10 ip * 1 19.84 ± 2.0 21.057 ± 1.6 3.669 ± 0.728 32.14＜0.001
Carmustine partial groups 21.768 10 ip * 10 19.64 ± 1.8 22.387 ± 2.1 4.309 ± 0.549 20.47=0.005
High poly-group 0 10 tumors are implanted into 19.52 ± 1.5 23.634 ± 0.95 5.389 ± 0.644 0.36＞0.1
7.5% group of 117.18 10 tumor of implant is implanted into 19.42 ± 1.2 22.089 ± 1.5 4.738 ± 0.834 12.37＞0.1
15% group of 234.37 10 tumor of implant is implanted into 19.89 ± 1.1 19.043 ± 1.7 1.353 ± 0.764 74.9＜0.001
30% group of 468.75 10 tumor of implant is implanted into 19.11 ± 1.7 16.803 ± 17 0.458 ± 0.266 91 5＜0.001
The carmustine implant (117.18mg.Kg-1,234.37mg.Kg-1,468.75mg.Kg-1) of this experimental result proof various dose is implanted in the mouse model breast carcinoma entity tumor, can obviously suppress tumor growth, tumor control rate and drug dose are obvious dose-effect relationship, experimental result: carmustine implant tumor control rate is respectively 12.37%, 74.9%, 91.5%, compares with carmustine local injection group; The P value is all less than 0.001.Repeated experiments: tumor control rate is respectively 10.46%, 71.77%, 90.73%, compares with carmustine local injection group; The P value is all less than 0.001.Difference has the height statistical significance.Carmustine lumbar injection group and carmustine local injection group and normal saline group comparison of tumor suppression ratio are 12.71% and 5.085%, and repeated experiments: tumor control rate is 11.11% and 11.568%.The tumour inhibiting rate of carmustine implant obviously surpasses carmustine lumbar injection group and carmustine local injection group, twice experimental result good reproducibility.
Embodiment 16: tumor is implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to mouse breast cancer
Check the tumor-inhibiting action of carmustine sustained-release implantation agent to mouse breast cancer according to embodiment 15 described methods and step, used implant adjuvant is polifeprosan (percentage by weight to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA) is 50: 50).Experimental result shows that carmustine implant tumor control rate is respectively 12.37%, 74.9%, 91.5%, compares with carmustine local injection group; The P value is all less than 0.001.Use repeated experiments: tumor control rate is respectively 10.46%, 71.77%, 90.73%, compares with carmustine local injection group; The P value is all less than 0.001.Difference has the height statistical significance.Carmustine lumbar injection group and carmustine local injection group and normal saline group comparison of tumor suppression ratio are 12.71% and 5.085%, and repeated experiments: tumor control rate is 11.11% and 11.568%.The tumour inhibiting rate of carmustine implant obviously surpasses carmustine lumbar injection group and carmustine local injection group, twice experimental result good reproducibility.
Embodiment 17: tumor is implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to rat liver cancer
Check the tumor-inhibiting action of carmustine sustained-release implantation agent to rat liver cancer according to embodiment 15 described methods and step, used implant adjuvant is polifeprosan (percentage by weight to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA) is 50: 50).The carmustine implant (117.18mg.Kg-1,234.37mg.Kg-1,468.75mg.Kg-1) of experimental result proof various dose is implanted in rat liver cancer (H22) entity tumor, can obviously suppress tumor growth, tumor control rate and drug dose are obvious dose-effect relationship, experimental result: carmustine implant tumor control rate is respectively 51.35%, 69.93%, 88.14%, compares with carmustine local injection group; Low dose group P value equals 0.001, and middle and high dosage group P value is all less than 0.001.Repeated experiments: tumor control rate is respectively 35.297%, 70.617%, 85.93%, compares with carmustine local injection group; Low dose group P value is less than 0.05.Middle and high dosage group P value is all less than 0.001.Difference has the height statistical significance.Carmustine lumbar injection group and carmustine local injection group and normal saline group comparison of tumor suppression ratio are 29.286% and 24.564%, and repeated experiments: tumor control rate is 26.36% and 19.899%.The tumour inhibiting rate of carmustine implant obviously surpasses carmustine lumbar injection group and carmustine local injection group, twice experimental result good reproducibility.
Embodiment 18: tumor is implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to the mice esophageal carcinoma
Check the tumor-inhibiting action of carmustine sustained-release implantation agent to the mice esophageal carcinoma according to embodiment 15 described methods and step, used implant adjuvant is PLGA (molecular weight is 20000-35000, and the blending ratio of polyglycolic acid and hydroxyacetic acid is 50: 50).The carmustine implant (117.18mg.Kg-1,234.37mg.Kg-1,468.75mg.Kg-1) of experimental result proof various dose is implanted in nude mice model human esophagus cancer (9706) entity tumor, can obviously suppress tumor growth, tumor control rate and drug dose are obvious dose-effect relationship, experimental result: carmustine implant tumor control rate is respectively 24.15%, 63.08%, 78.761%, compares with carmustine local injection group; The P value is all less than 0.001.Repeated experiments: tumor control rate is respectively 59.767%, 81.23%, 83.815%, compares with carmustine local injection group; The P value is all less than 0.001.Difference has the height statistical significance.Carmustine lumbar injection group and carmustine local injection group and normal saline group comparison of tumor suppression ratio are 12.71% and 5.085%, and repeated experiments: tumor control rate is 11.11% and 11.568%.The tumour inhibiting rate of carmustine implant obviously surpasses carmustine lumbar injection group and carmustine local injection group, twice experimental result good reproducibility.
Embodiment 19: tumor is implanted into the tumor-inhibiting action of carmustine sustained-release implantation agent to mouse pancreas cancer
Check the tumor-inhibiting action of carmustine sustained-release implantation agent 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 polyglycolic acid and hydroxyacetic acid is 50: 50).Carmustine implant (the 117.18mg.Kg of experimental result proof various dose
-1, 234.37mg.Kg
-1, 468.75mg.Kg
-1) 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, experimental result: carmustine implant tumor control rate is respectively 29.34%, 56.71%, 86.212%, compares with carmustine local injection group; The P value is all less than 0.001.Repeated experiments: tumor control rate is respectively 57.845%, 74.16%, 81.9%, compares with carmustine local injection group; The P value is all less than 0.001.Difference has the height statistical significance.Carmustine lumbar injection group and carmustine local injection group and normal saline group comparison of tumor suppression ratio are 20.34% and 6.71%.Repeated experiments: tumor control rate is 11.51% and 8.995%.The tumour inhibiting rate of carmustine implant obviously surpasses carmustine lumbar injection group and carmustine local injection group, twice experimental result good reproducibility.
In addition, tumor is implanted into carmustine sustained-release implantation agent the outer entity tumor of other craniums such as gastric cancer, bladder cancer, carcinoma of testis, colon cancer, rectal cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate is also had good therapeutical effect, and its effect obviously surpasses carmustine lumbar injection group and carmustine local injection group.This unexpected formation major technique feature of the present invention of finding is for the outer entity tumor treatment medicine of cranium provides another new selection.
Claims (10)
1. a pharmaceutical composition for the treatment of the outer entity tumor of cranium is characterized in that this pharmaceutical composition contains the carmustine and the pharmaceutic adjuvant of effective anticancer.
2. the pharmaceutical composition of the outer entity tumor of treatment cranium according to claim 1 is characterized in that this pharmaceutical composition is injection, suspensoid or implant.
3. as the pharmaceutical composition of the outer entity tumor of the treatment cranium as described in the claim 2, it is characterized in that described implant is sustained-release implant, controlled release implant or slowbreak implant.
4. the pharmaceutical composition of the outer entity tumor of treatment cranium according to claim 1 is characterized in that pharmaceutic adjuvant is selected from the mixture of macromolecule polymer, macromolecule polymer or copolymer, water-soluble low-molecular chemical compound.
5. the pharmaceutical composition of the outer entity tumor of treatment cranium according to claim 1 is characterized in that used pharmaceutic adjuvant is selected from a kind of or its combination in the copolymer of polylactic acid, polyglycolic acid and hydroxyacetic acid, polifeprosan, ethylene vinyl acetate copolymer, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
6. the pharmaceutical composition of the outer entity tumor of treatment cranium according to claim 1 is characterized in that this components of pharmaceutical composition is one of following, percentage by weight:
(A) copolymer of the polyglycolic acid of the carmustine of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the carmustine of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the carmustine of 5-15% and 85-95%;
(D) polylactic acid of the carmustine of 15-35% and 65-85%;
(E) polifeprosan of the carmustine of 5-15% and 85-95%;
(F) polifeprosan of the carmustine of 15-35% and 65-85%;
(G) polifeprosan of the copolymer of the polyglycolic acid of the carmustine of 5-35% and 1-95% and hydroxyacetic acid and 1-95%;
(H) polifeprosan of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95%;
(I) copolymer of the polyglycolic acid of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95% and hydroxyacetic acid;
(J) polifeprosan of the copolymer of the polyglycolic acid of the polylactic acid of the carmustine of 5-35% and 1-95% and 1-95% and hydroxyacetic acid and 1-95%.
7. as the pharmaceutical composition of the outer entity tumor of the treatment cranium as described in claim 5 or 6, the molecular weight peak value that it is characterized in that polylactic acid is 5000-15000,10000-20000,25000-35000 or 30000-50000.
8. as the pharmaceutical composition of the outer entity tumor of the treatment cranium as described in claim 5 or 6, the molecular weight peak value that it is characterized in that the copolymer of polyglycolic acid and hydroxyacetic acid is 5000-15000,15000-35000,35000-45000 or 45000-80000; The weight ratio of polyglycolic acid and hydroxyacetic acid is 10: 90,20: 80, and 30: 70,40: 60,50: 50 or 60: 40.
9. as the pharmaceutical composition of the outer entity tumor of the treatment cranium as described in claim 5 or 6, it is characterized in that the weight ratio to carboxy phenyl propane and certain herbaceous plants with big flowers diacid is 10: 90 in the polifeprosan, 20: 80,30: 70,40: 60,50: 50 or 60: 40.
10. the pharmaceutical composition of the outer entity tumor of described any of claim 1～9 treatment cranium, be used to prepare the medicine of the outer entity tumor of treatment cranium, the outer entity tumor of described cranium comprises 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, the oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, former or the cancer of secondary of eyes, sarcoma or carcinosarcoma.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100434800A CN1330299C (en) | 2005-05-13 | 2005-05-13 | Medicament composition for treating extracranial noumenal tumour |
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| CNB2005100434800A CN1330299C (en) | 2005-05-13 | 2005-05-13 | Medicament composition for treating extracranial noumenal tumour |
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| CN1330299C CN1330299C (en) | 2007-08-08 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016095592A1 (en) * | 2014-12-15 | 2016-06-23 | 山东蓝金生物工程有限公司 | Bcnu sustained-release implant for treating solid tumor and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5854382A (en) * | 1997-08-18 | 1998-12-29 | Meadox Medicals, Inc. | Bioresorbable compositions for implantable prostheses |
| CN1524580A (en) * | 2003-02-26 | 2004-09-01 | 天津市第一中心医院 | Carmustine slow-release tablet and its preparation method |
| CN1687494A (en) * | 2005-04-05 | 2005-10-26 | 中国科学院长春应用化学研究所 | Method of preparing superfie fiber formulation for carmustine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016095592A1 (en) * | 2014-12-15 | 2016-06-23 | 山东蓝金生物工程有限公司 | Bcnu sustained-release implant for treating solid tumor and preparation method thereof |
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