CN101219105A - Emtricitabine sustained-release implantation agent for treating solid tumors - Google Patents
Emtricitabine sustained-release implantation agent for treating solid tumors Download PDFInfo
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Abstract
The invention relates to an emtricitabine sustained release agent for treating solid tumors, which is characterized in that the sustained release agent contains emtricitabine and sustained-release excipient of effective anticancer amount and certain sustained release regulator. The solid tumors comprise lung cancer, esophageal cancer, carcinoma ventriculi, liver cancer, mammary cancer, oophoroma, prostatic carcinoma, carcinoma of urinary bladder and colorectal cancer. The sustained-release excipient is mainly one of or the combination of copolymer of glycollic acid and glycolic acid, Polifeprosan, poly (L-lactide-co-ethyl phosphate), poly (L-lactide-co-propyl phosphate), and the carmustine is slowly released into local tumor during the degradation and absorption process, therefore the invention not only obviously reduces toxic reaction of the whole body, but also maintains effective drug concentration at the local tumor. The sustained release agent is arranged or injected in the local tumor, which not only reduces the carmustine toxic reaction to the whole body, but also increases the drug concentration at the local tumor selectively, thereby improving treatment effect of chemotherapeutics, radiotherapeutics and other non-operative treatment.
Description
(1) technical field
The present invention relates to a kind of emtricitabine sustained-release implantation agent for the treatment of entity tumor,, belong to technical field of pharmaceuticals for sustained-release implant or slow releasing injection.
(2) background technology
Cancer morbidity rises year by year and is rejuvenation trend, has data to show that in less than the time in 20 years, China's cancer morbidity has risen 69%, and mortality rate has increased by 29.4%.According to World Health Organization's recent statistics, will increase by 50 percent to the year two thousand twenty whole world cancer morbidity, number of the infected increases to 15,000,000.Estimate that the year two thousand twenty China will have 4,000,000 people to die from cancer therefore every year, inquire into the focus that a kind of effective treatment method for cancer or medicine have become present research.
(3) summary of the invention
Based on above examination to prior art, the present invention has carried out studying extensively and profoundly to emtricitabine (Emtricitabine), sensitivity to its mechanism of action, route of administration and different entities tumor compares, the result shows, this chemical compound is used for that separately entity tumors such as the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer and rectal cancer are had comparatively significantly action effect, but general toxicity is more obvious.Discover that further the emtricitabine local sustained release 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.Obtained the anti-tumor effect that conventional method is difficult to realize.Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.
The present invention is directed to the deficiencies in the prior art, a kind of sustained-release implant is provided, be used for the treatment of entity tumor, not only effect is obvious, and its general toxicity obviously alleviates.
Outside first, specific slow-release auxiliary material has tangible influence to the release behavior of this medicine.
The present invention treats the sustained-release implant of entity tumor, it is characterized in that this sustained-release implant contains the emtricitabine of effective anticancer, slow-release auxiliary material and a certain amount of slow release regulator, and wherein the weight ratio of each constituent is:
(1) emtricitabine 0.1%-45%
(2) slow-release auxiliary material 55%-99%
(3) slow release regulator 0-15%
The percentage by weight of emtricitabine of the present invention in sustained-release implant serves as preferred with 0.1 to 45%, with 5%-30% for most preferably.Emtricitabine can be various salt, serves as preferred with phosphate and phosphate (emtricitabine).
Decanedioic acid (SA) copolymer), a kind of or its combination among poly-(L-lactide-co-etherophosphoric acid) (p (LAEG-EOP)), poly-(L-lactide-co-phosphoric acid propyl ester) (p (DAPG-EOP)) slow-release auxiliary material of the present invention mainly is selected from the copolymer (PLGA), polifeprosan of polylactic acid (PLA), glycolic and hydroxyacetic acid (to carboxy phenyl propane (p-CPP):.
Wherein the molecular weight peak value of polylactic acid (PLA) is 8000-15000,10000-20000,20000-35000 or 30000-50000; Serve as preferred wherein with 5000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.
The molecular weight peak value of the copolymer of glycolic and hydroxyacetic acid (PLGA) is 8000-15000,15000-35000,35000-45000 or 45000-80000; Serve as preferred wherein with 5000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.The percentage by weight of glycolic and hydroxyacetic acid is 90: 10,80: 20, and 75: 25,70: 30,60: 40,50: 50 or 40: 60; Wherein with 80: 20,75: 25,70: 30,60: 40, be preferred at 50: 50, with 60: 40 and 50: 50 for most preferably.
Polifeprosan (to carboxy phenyl propane (p-CPP): the percentage by weight to carboxy phenyl propane (p-CPP) and decanedioic acid (SA) decanedioic acid (SA) copolymer) is 10: 90,20: 80, and 30: 70,40: 60,50: 50 or 60: 40; Wherein with 80: 20,70: 30,60: 40, be preferred at 50: 50, with 60: 40 and 50: 50 for most preferably.
The molecular weight peak value of poly-(L-lactide-co-etherophosphoric acid) is 5000-15000,10000-20000,20000-35000 or 30000-50000, serve as preferred wherein with 5000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.
The slow release regulator is selected from a kind of or its combination in xylitol, oligosaccharide, chitin, potassium salt, sodium salt, mannitol, sorbitol, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
Slow-release auxiliary material also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned slow-release auxiliary material is applicable to the compositions that contains or do not contain additive.
The consumption of slow releasing agent depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But its principle is at the repair ability that can reduce tumor cell, when increasing the chemotherapy action effect and the toxic reaction of not obvious increase medicine.Effective dose is 10-1000 milligram/patient, is ideal with 100-700 milligram/patient, with 150-500 milligram/patient for the most desirable.
The present invention can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be made into various dosage forms, as, but be not limited to injection, muddy suspension, ointment, capsule, slow releasing agent, sustained-release implant and slow releasing injection etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and apperance; Can be through various administrations, as in tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Whether route of administration depends on multiple factor, as position, tumor place, perform the operation or transfer, gross tumor volume size, tumor classification, patient age, health, bearing status and requirement etc.For obtain active drug concentration in position, tumor place, arterial perfusion optionally, intra-bladder instillation (intracavitary), (intraspinal) administration in abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and the canalis spinalis, but also place in the internal organs, as in the enteric cavity, in the intravesical, uterine cavity, in intravaginal, gastric and the esophagus etc.In various approach, 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 preferred for tumor week or tumor chamber, can plant slow-releasing pump, slow releasing capsule, slow releasing agent as selecting for use, slow releasing agent choosing group sustained-release implant and slow releasing injection.
Available arbitrary method preparation.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and anti-cancer sustained-released implantation agent also can be packed in the liposome.The effective ingredient of compositions can be packaged in the whole slow-release auxiliary material equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.Each component and the weight percentage in compositions thereof are preferred one of following in the sustained-release implant:
(A) polylactic acid of the emtricitabine of 1%-5% and 95%-99%;
(B) polylactic acid of the emtricitabine of 5%-10% and 90%-95%;
(C) polylactic acid of the emtricitabine of 10%-15% and 85%-90%;
(D) polylactic acid of the emtricitabine of 15%-25% and 75%-85%;
(E) polylactic acid of the emtricitabine of 25%-40% and 60%-75%;
(F) copolymer of the glycolic of the emtricitabine of 1%-10% and 90%-99% and hydroxyacetic acid;
(G) copolymer of the glycolic of the emtricitabine of 10%-20% and 80%-90% and hydroxyacetic acid;
(H) copolymer of the glycolic of the emtricitabine of 20%-30% and 70%-80% and hydroxyacetic acid;
(I) copolymer of the glycolic of the emtricitabine of 30%-40% and 60%-70% and hydroxyacetic acid;
(J) polifeprosan of the emtricitabine of 5%-15% and 85%-95%;
(K) polifeprosan of the emtricitabine of 15%-35% and 65%-85%;
(L) 5% emtricitabine and 95% poly-(L-lactide-co-etherophosphoric acid);
(M) 10% emtricitabine and 90% poly-(L-lactide-co-etherophosphoric acid);
(N) 20% emtricitabine and 80% poly-(L-lactide-co-etherophosphoric acid);
(O) 30% emtricitabine and 70% poly-(L-lactide-co-etherophosphoric acid);
(P) 5% emtricitabine and 95% poly-(L-lactide-co-phosphoric acid propyl ester);
(Q) 10% emtricitabine and 90% poly-(L lactide-co-phosphoric acid propyl ester);
(R) 20% emtricitabine and 80% poly-(L-lactide-co-phosphoric acid propyl ester);
(S) 30% emtricitabine and 70% poly-(L-lactide-co-phosphoric acid propyl ester).
Each component and the weight percentage in compositions thereof are one of further preferred following in the sustained-release implant:
(A) mannitol of the polylactic acid of the emtricitabine of 1%-5% and 85%-98% and 0.5%-15%;
(B) sorbitol of the polylactic acid of the emtricitabine of 5%-10% and 90%-95% and 0.5%-10%;
(C) sodium chloride of the polylactic acid of the emtricitabine of 10%-15% and 85%-90% and 0.5%-10%;
(D) mannitol of the polylactic acid of the emtricitabine of 15%-25% and 75%-85% and 0.25%-5%;
(E) sorbitol of the polylactic acid 0.1%-8% of the emtricitabine of 25%-40% and 60%-75%;
(F) mannitol of the copolymer of the glycolic of the emtricitabine of 1%-10% and 90%-99% and hydroxyacetic acid and 0.5%-15%;
(G) sorbitol of the copolymer of the glycolic of the emtricitabine of 10%-20% and 80%-90% and hydroxyacetic acid and 0.5%-10%;
(H) sodium chloride of the copolymer of the glycolic of the emtricitabine of 20%-30% and 70%-80% and hydroxyacetic acid and 0.5%-10%;
(I) mannitol of the copolymer of the glycolic of the emtricitabine of 30%-40% and 60%-70% and hydroxyacetic acid and 0.25%-5%;
(J) mannitol of the polifeprosan of the emtricitabine of 5%-15% and 85%-95% and 1%-5%;
(K) mannitol of the polifeprosan of the emtricitabine of 15%-35% and 65%-85% and 0.25%-7.5%;
(L) 5% emtricitabine and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(M) 10% emtricitabine and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(N) 20% emtricitabine and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(O) 30% emtricitabine and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(P) 5% emtricitabine and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(Q) 10% emtricitabine and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(R) 20% emtricitabine and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(S) 30% emtricitabine and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol.
Sustained-release implant is used for the treatment of entity tumor, comprise the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma, lymphoma, tumor of head and neck and come from gallbladder, oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, eyes, former or cancer, sarcoma or the carcinosarcoma of secondary.Therefore, application of the present invention is the above-mentioned various pharmaceutical preparatioies that are used to make the above-mentioned tumor of treatment, serve as preferred wherein with injection, muddy suspension, ointment, capsule, implant, slow releasing agent and sustained-release implant, with sustained-release implant, controlled release implant or slowbreak implant for most preferably.
Also can add other medicinal ingredient in this anti-cancer sustained-released implantation agent, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Because anti-cancer sustained-released implantation agent of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.When share with above-mentioned non-operative treatment, anti-cancer sustained-released implantation agent of the present invention can be used simultaneously with non-operative treatment, also can in implementing a few days ago, non-operative treatment use, its purpose is to strengthen as far as possible the sensitivity of tumor, thereby provide a kind of more effective new method for effecting a radical cure former of various human bodies and animal and shifting entity tumor, have very high clinical value and remarkable economical and social benefit.
When used the part, said composition can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.The outer entity tumor of cranium had the obvious treatment effect.
Anti-cancer composition of the present invention can be implemented by many schemes, and its purpose is just in order to further specify, and is not in addition any restriction of enforcement of the present invention.
Test one, emtricitabine are to the inhibitory action of growth of tumour cell.
Be the inhibitory action of checking emtricitabine to other growth of tumour cell, this test is added to emtricitabine (15ug/ml) in 24 hours the various tumor cells of In vitro culture (table 1), continue to cultivate after 48 hours the counting cells sum and calculates its suppression ratio to growth of tumour cell (%).
The suppression ratio of growth of tumour cell (%)=((cellular control unit number-test group cell number)/cellular control unit number) * 100%
Table 1
The result of test one shows that compare with matched group, emtricitabine all has obvious inhibitory action (P＜0.05) to the examination growth of tumor.This is unexpected finds to constitute major technique feature of the present invention, for the treatment of entity tumor provides new selection.
The sustained-release implant that contains emtricitabine can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing of implanting.
The preparation method of sustained-release implant of the present invention is as follows:
1, the slow-release auxiliary material of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2, adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and slow-release auxiliary material is decided because of specific requirement.
3, remove organic solvent.Vacuum drying or cold drying all can.
4, dried solid composite is made different shape as required.
5, ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
(4) specific embodiment
Embodiment one,
The slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 8000-15000) of (80mg) of will weighing is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 20 milligrams of emtricitabines, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 20% emtricitabine.The drug release time of this sustained-release implant in external normal saline is 20-26 days, is 22-25 days at the subcutaneous drug release time of mice.
Embodiment two
Make sustained-release implant by embodiment one described method, but contained anticancer effective component is one of following:
(A) 1% emtricitabine and and 99% polylactic acid;
(B) 5% emtricitabine and and 95% polylactic acid;
(C) 10% emtricitabine and 90% polylactic acid;
(D) 15% emtricitabine and 85% polylactic acid;
(E) 20% emtricitabine and 80% polylactic acid.
Embodiment three
(molecular weight is the PLGA of 15000-25000 to the slow-release auxiliary material of (85mg) of will weighing, 50: 50) put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion), add the 15mg emtricitabine, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 15% emtricitabine.The drug release time of this sustained-release implant in external normal saline is 25-29 days, is 26-28 days at the subcutaneous drug release time of mice.
Embodiment four
Make sustained-release implant by embodiment three described methods, contained anticancer effective component that different is is one of following:
(1) copolymer of the glycolic of the emtricitabine of 1%-10% and 90%-99% and hydroxyacetic acid;
(2) copolymer of the glycolic of the emtricitabine of 10%-20% and 80%-90% and hydroxyacetic acid;
(3) copolymer of the glycolic of the emtricitabine of 20%-30% and 70%-80% and hydroxyacetic acid;
(4) copolymer of the glycolic of the emtricitabine of 30%-40% and 60%-70% and hydroxyacetic acid;
The copolymer of (5) 5% emtricitabine and 95% glycolic and hydroxyacetic acid;
The copolymer of (6) 10% emtricitabine and 90% glycolic and hydroxyacetic acid;
The copolymer of (7) 20% emtricitabine and 80% glycolic and hydroxyacetic acid;
The copolymer of (8) 30% emtricitabine and 70% glycolic and hydroxyacetic acid.
Embodiment five
(molecular weight is the PLGA of 25000-30000 to the slow-release auxiliary material of (85mg) of will weighing, 75: 25) put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion), add 10mg emtricitabine and 5mg mannitol, shake up the dry organic solvent of removing of final vacuum again with abundant dissolving.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 10% emtricitabine.The drug release time of this sustained-release implant in external normal saline is 25-30 days, is 24-28 days at the subcutaneous drug release time of mice.
Embodiment six
Make sustained-release implant by embodiment five described methods, contained anticancer effective component that different is is one of following:
(1) mannitol of the copolymer of the glycolic of the emtricitabine of 1%-10% and 90%-99% and hydroxyacetic acid and 0.5%-15%;
(2) sorbitol of the copolymer of the glycolic of the emtricitabine of 10%-20% and 80%-90% and hydroxyacetic acid and 0.5%-10%;
(3) sodium chloride of the copolymer of the glycolic of the emtricitabine of 20%-30% and 70%-80% and hydroxyacetic acid and 0.5%-10%;
(4) mannitol of the copolymer of the glycolic of the emtricitabine of 30%-40% and 60%-70% and hydroxyacetic acid and 0.25%-5%;
The copolymer of (5) 5% emtricitabine and 92% glycolic and hydroxyacetic acid and 2% sodium chloride;
The copolymer of (6) 10% emtricitabine and 85% glycolic and hydroxyacetic acid and 5% mannitol;
The copolymer of (7) 20% emtricitabine and 75% glycolic and hydroxyacetic acid and 5% mannitol;
The copolymer of (8) 30% emtricitabine and 75% glycolic and hydroxyacetic acid and 5% mannitol.
Embodiment seven
85mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 50: 50) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 15mg emtricitabine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain percentage by weight 15% emtricitabine sustained-release implant.The drug release time of this sustained-release implant in external normal saline is 14-20 days, is 12-20 days at the subcutaneous drug release time of mice.
Embodiment eight
Make sustained-release implant by embodiment seven described methods, that contained anticancer effective component is is one of following but different is:
(1) polifeprosan of the emtricitabine of 1%-15% and 85%-95%;
(2) polifeprosan of the emtricitabine of 15%-35% and 65%-85%;
(3) 5% emtricitabine and 95% polifeprosan;
(4) 10% emtricitabine and 90% polifeprosan;
(5) 15% emtricitabine and the polifeprosan of 85%-95%;
(6) 20% emtricitabine and 80% polifeprosan.
Embodiment nine
80mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 30: 70) and 5mg sodium chloride are put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 15mg emtricitabine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain percentage by weight 15% emtricitabine sustained-release implant.The drug release time of this sustained-release implant in external normal saline is 14-20 days, is 14-19 days at the subcutaneous drug release time of mice.
Embodiment ten
Make sustained-release implant by embodiment ten described methods, that contained anticancer effective component is is one of following but different is:
(1) mannitol of the polifeprosan of the emtricitabine of 5%-15% and 85%-95% and 1%-5%; Or
(2) mannitol of the polifeprosan of the emtricitabine of 15%-35% and 65%-85% and 0.25%-7.5%.
Embodiment 11
85mg slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 15000-30000) and 10mg mannitol are put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 5 milligrams of emtricitabines, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains sustained-release implant and contains 5% emtricitabine.The drug release time of this sustained-release implant in external normal saline is 20-26 days, is 22-28 days at the subcutaneous drug release time of mice.
Embodiment 12
Make sustained-release implant by embodiment 11 described methods, used slow-release auxiliary material is selected from one of following or its combination:
(A) 1% emtricitabine and and 95% polylactic acid and 4% mannitol;
(B) 5% emtricitabine and and 93% polylactic acid and 2% mannitol;
(C) 10% emtricitabine and 85% polylactic acid and 5% mannitol;
(D) 15% emtricitabine and 82% polylactic acid and 3% sodium chloride;
(E) 20% emtricitabine and 78% polylactic acid and 2% sodium chloride.
Embodiment 13
Make sustained-release implant by embodiment 1 to 11 described method, used slow-release auxiliary material is selected from one of following or its combination:
A) molecular weight is the polylactic acid (PLA) of 10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 15000-35000,35000-45000 or 45000-80000 and the copolymer of hydroxyacetic acid (PLGA);
C) polifeprosan is (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) copolymer), be 20: 80,30: 70,40: 60,50: 50 or 60: 40 to the percentage by weight of carboxy phenyl propane (p-CPP) and decanedioic acid (SA).
On the basis of above-mentioned slow release, the present invention finds that further body is implanted into emtricitabine other entity tumors such as hepatocarcinoma, pulmonary carcinoma, breast carcinoma, cancer of pancreas, colon cancer, rectal cancer, ovarian cancer, skin carcinoma, lymphoma and carcinoma of prostate are also had good therapeutical effect.Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.Following in vivo test is used for explanation but not limitation of the present invention.
Embodiment 14
With 70,80,90 and 95mg molecular weight peak value be that the p (LAEG-EOP) of 10000-25000 puts into first, second, third, four containers of fourth respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in four containers, add 30mg, 20mg, 10mg and 5mg emtricitabine respectively, shake up the sustained-release implant that the preparation of after drying method contains 30%, 20%, 10% and 5% emtricitabine again.The drug release time of this slow releasing agent in external normal saline is 28-32 days, is about 26-34 days at the subcutaneous drug release time of mice.
Embodiment 15
The method step that is processed into sustained-release implant is identical with embodiment 14, but the molecular weight peak value of different is p (LAEG-EOP) is 25000-45000, and contained anticancer effective component and percentage by weight thereof are:
(1) 1%-5% emtricitabine;
(2) 5%-10% emtricitabine;
(3) 10%-20% emtricitabine;
(4) 20%-40% emtricitabine;
The sodium chloride of (5) 5% emtricitabine and 92% p (LAEG-EOP) and 2%;
The mannitol of (6) 10% emtricitabine and 85% p (LAEG-EOP) and 5%;
The mannitol of (7) 20% emtricitabine and 75% p (LAEG-EOP) and 5%;
The mannitol of (8) 30% emtricitabine and 75% p (LAEG-EOP) and 5%.
Embodiment 16
With 70,80,90 and 95mg molecular weight peak value be that the p (DAPG-EOP) of 10000-25000 puts into first, second, third, four containers of fourth respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in four containers, add 30mg, 20mg, 10mg and 5mg emtricitabine respectively, shake up the sustained-release implant that the preparation of after drying method contains 30%, 20%, 10% and 5% emtricitabine again.The drug release time of this slow releasing agent in external normal saline is 26-32 days, is about 28-36 days at the subcutaneous drug release time of mice.
Embodiment 17
The method step that is processed into sustained-release implant is identical with embodiment 16, but the molecular weight peak value of different is p (DAPG-EOP) is 25000-45000, and contained anticancer effective component and percentage by weight thereof are:
(1) 1%-5% emtricitabine;
(2) 5%-10% emtricitabine;
(3) 10%-20% emtricitabine;
(4) 20%-40% emtricitabine;
The sodium chloride of (5) 5% emtricitabine and 92% p (DAPG-EOP) and 2%;
The mannitol of (6) 10% emtricitabine and 85% p (DAPG-EOP) and 5%;
The mannitol of (7) 20% emtricitabine and 75% p (DAPG-EOP) and 5%;
The mannitol of (8) 30% emtricitabine and 75% p (DAPG-EOP) and 5%.
Embodiment 18, tumor are implanted into the inhibitory action of emtricitabine to entity tumor
Method and step: tumor cell inoculation is subcutaneous in the right side of mice axillary fossa, and (inoculation back the 8th day) is divided into 7 groups at random with animal, 5 every group when diameter of tumor grows to the 0.8cm left and right sides.Be normal saline group, emtricitabine lumbar injection group (hereinafter to be referred as emtricitabine abdominal cavity group), emtricitabine local injection group (being called for short the emtricitabine partial groups), high molecular polymer group (being called for short high poly-group), emtricitabine sustained-release implant group with (5% group, 10% group of the made sustained-release implant of embodiment four, with 20% group, be called for short implant 5%, implant 10%, implant 20%).With 70% alcohol disinfecting tumor surface skin, selection is apart from tumor lower edge 1cm place, cut off the long otch of 1mm, with puncture needle with in the emtricitabine implant implantation tumour tissue, not pastille high molecular polymer, emtricitabine implant 5%, emtricitabine implant 10%, emtricitabine implant 20%.Sew up the incision and prevent that implant from spilling.Put to death animal in 15 days with vernier caliper measurement tumor size after the implant embedding in per 3 days, the back of weighing is complete peels off tumor and claims tumor heavy.Calculate tumor control rate %, DAS.ver1.0 pharmacology software is done statistical procedures.
Tumor control rate=(the average tumor of the average tumor weight/normal saline of 1-administration group group is heavy) * 100%
Embodiment 19, tumor are implanted into the tumor-inhibiting action of emtricitabine spit of fland sustained-release implant to mice lung cancer
Check the tumor-inhibiting action of emtricitabine sustained-release implant according to embodiment 18 described methods and step to mice lung cancer.Used implant adjuvant is PLGA (molecular weight is 15000-30000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50), is derived from embodiment four.The emtricitabine 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.Emtricitabine implant tumor control rate is respectively 34%, 62%, 78%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Repeated experiments: tumor control rate is respectively 42%, 50%, 70%, compares with the local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Emtricitabine lumbar injection group and emtricitabine local injection group and normal saline group comparison of tumor suppression ratio are 12% and 10%, and repeated experiments: tumor control rate is 18% and 13%.The tumour inhibiting rate of emtricitabine implant obviously surpasses emtricitabine lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 20 tumors are implanted into the tumor-inhibiting action of emtricitabine sustained-release implant to mouse breast cancer
Check the tumor-inhibiting action of emtricitabine sustained-release implant to mouse breast cancer according to embodiment 18 described methods and step, used implant is from embodiment one.Experimental result shows that the tumor control rate of 1%, 10% and 25% emtricitabine implant is respectively 40%, 52%, 66%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 42%, 60%, 70%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Emtricitabine lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 10% and 14%, and repeated experiments: tumor control rate is 8% and 12%.The tumour inhibiting rate of emtricitabine implant obviously surpasses emtricitabine lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 21, tumor are implanted into the tumor-inhibiting action of emtricitabine sustained-release implant to the mouse ovarian cancer
Check the tumor-inhibiting action of emtricitabine sustained-release implant according to embodiment 18 described methods and step to the mouse ovarian cancer, used implant is 5%, 10% and 20% polifeprosan (percentage by weight to carboxy phenyl propane (p-CPP) and decanedioic acid (SA) is 50: 50), from embodiment eight.The emtricitabine implant of experimental result proof various dose is implanted in the mouse ovarian cancer and can obviously be suppressed tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Emtricitabine implant tumor control rate is respectively 40%, 54%, 79%, compares with emtricitabine local injection group, and low dose group P value equals 0.001, and middle and high dosage group P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 42%, 56%, 68%, compares with emtricitabine local injection group, and low dose group P value is less than 0.05, and middle and high dosage group P value is all less than 0.001.Difference has the height statistical significance.Emtricitabine lumbar injection group and emtricitabine local injection group and normal saline group comparison of tumor suppression ratio are 12% and 22%, and repeated experiments: tumor control rate is 10% and 16%.The tumour inhibiting rate of emtricitabine implant obviously surpasses emtricitabine lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 22 tumors are implanted into the tumor-inhibiting action of emtricitabine sustained-release implant to the mice esophageal carcinoma
Check the tumor-inhibiting action of emtricitabine sustained-release implant to the mice esophageal carcinoma according to embodiment 18 described methods and step, used implant is selected from embodiment six.The emtricitabine 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.Emtricitabine implant tumor control rate is respectively 40%, 56%, 72%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Repeated experiments finds that tumor control rate is respectively 40%, 62%, 74%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Emtricitabine lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 10% and 8%, and repeated experiments shows that tumor control rate is 12% and 10%.The tumour inhibiting rate of emtricitabine implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 23, tumor are implanted into the tumor-inhibiting action of emtricitabine sustained-release implant to mouse pancreas cancer
Check the tumor-inhibiting action of emtricitabine sustained-release implant to mouse pancreas cancer according to embodiment 18 described methods and step, used implant adjuvant is PLGA (molecular weight is 20000-35000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50).The content of emtricitabine in sustained-release implant is 2.5%, 7.5% and 12.5%.The emtricitabine 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.Emtricitabine implant tumor control rate is respectively 36%, 52%, 80%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 38%, 54%, 70%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Emtricitabine lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 21% and 14%.Repeated experiments finds that tumor control rate is 10% and 14%.The tumour inhibiting rate of emtricitabine implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 24, tumor are implanted into the tumor-inhibiting action of emtricitabine sustained-release implant to the mice rectal cancer
Check the tumor-inhibiting action of emtricitabine sustained-release implant to the mice rectal cancer according to embodiment 18 described methods and step, used implant adjuvant is PLGA (molecular weight is 20000-35000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50).The content of emtricitabine in sustained-release implant is the emtricitabine implant of 7.5%, 15% and 25%. experimental results proof various dose, can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Emtricitabine implant tumor control rate is respectively 40%, 72%, 84%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 50%, 60%, 78%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Emtricitabine lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 21% and 18%.Repeated experiments finds that tumor control rate is 12% and 10%.The tumour inhibiting rate of emtricitabine implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 25, tumor are implanted into the tumor-inhibiting action of emtricitabine sustained-release implant to the mice carcinoma of prostate
Check the tumor-inhibiting action of emtricitabine sustained-release implant to the mice carcinoma of prostate according to embodiment 18 described methods and step, used implant adjuvant is p (LAEG-EOP) (molecular weight is 10000-25000).The content of emtricitabine in sustained-release implant is 5%, 10% and 20% (from embodiment 14).The emtricitabine implant of experimental result proof various dose is implanted in the nude mice model human prostata cancer entity tumor, can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Emtricitabine implant tumor control rate is respectively 38%, 52%, 68%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 42%, 58%, 72%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Emtricitabine lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 21% and 14%.Repeated experiments finds that tumor control rate is 12% and 14%.The tumour inhibiting rate of emtricitabine implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
Embodiment 26, tumor are implanted into the tumor-inhibiting action of emtricitabine sustained-release implant to rat liver cancer
Check the tumor-inhibiting action of emtricitabine sustained-release implant to rat liver cancer according to embodiment 18 described methods and step, used implant adjuvant is p (DAPG-EOP) (molecular weight is 10000-25000).The content of emtricitabine in sustained-release implant is 5%, 10% and 20% (from embodiment 16). the content of emtricitabine in sustained-release implant is the emtricitabine implant of 7.5%, 15% and 25%. experimental results proof various dose, can obviously suppress tumor growth, tumor control rate and drug dose are obvious dose-effect relationship.Emtricitabine implant tumor control rate is respectively 30%, 54%, 68%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Repeated experiments shows that tumor control rate is respectively 32%, 46%, 66%, compares with emtricitabine local injection group, and the P value is all less than 0.001.Difference has the height statistical significance.Emtricitabine lumbar injection group and local injection group and normal saline group comparison of tumor suppression ratio are 16% and 8%.Repeated experiments finds that tumor control rate is 8% and 10%.The tumour inhibiting rate of emtricitabine implant obviously surpasses lumbar injection group and local injection group, twice experimental result good reproducibility.
In addition, tumor is implanted into the emtricitabine sustained-release implant other entity tumors such as gastric cancer, bladder cancer, carcinoma of testis, carcinoma of endometrium, lymphoma, the cerebral tumor, cervical cancer, renal carcinoma is also had good therapeutical effect, and its effect obviously surpasses emtricitabine lumbar injection group and local injection group.This is unexpected finds to constitute another major technique feature of the present invention, for the treatment of entity tumor provides another new selection.
Claims (10)
1. an emtricitabine sustained-release implantation agent for the treatment of entity tumor is characterized in that this slow releasing agent contains the emtricitabine of effective anticancer, slow-release auxiliary material and a certain amount of slow release regulator, and wherein the weight ratio of each constituent is:
(1) emtricitabine 0.1%-50%
(2) slow-release auxiliary material 50%-99%
(3) slow release regulator 0-15%
Below all be weight percentage.
2. the slow releasing agent according to claim 1 is characterized in that slow-release auxiliary material is selected from a kind of or its combination in the copolymer of polylactic acid, polyglycolic acid and hydroxyacetic acid, polifeprosan, poly-(L-lactide-co-etherophosphoric acid), poly-(the L lactide-co-phosphoric acid propyl ester).
3. the slow releasing agent according to claim 1 is characterized in that the slow release regulator is selected from a kind of or its combination in xylitol, oligosaccharide, chitin, potassium salt, sodium salt, mannitol, sorbitol, the chrondroitin.
4. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) 1% emtricitabine and and 99% polylactic acid;
(B) 5% emtricitabine and and 95% polylactic acid;
(C) 10% emtricitabine and 90% polylactic acid;
(D) 15% emtricitabine and 85% polylactic acid;
(E) 20% emtricitabine and 80% polylactic acid;
(F) 5% emtricitabine and 95% glycolic and the copolymer of hydroxyacetic acid;
(G) 10% emtricitabine and 90% glycolic and the copolymer of hydroxyacetic acid;
(H) 20% emtricitabine and 80% glycolic and the copolymer of hydroxyacetic acid;
(I) 30% emtricitabine and 70% glycolic and the copolymer of hydroxyacetic acid;
(J) 5% emtricitabine and 95% polifeprosan;
(K) 15% emtricitabine and 85% polifeprosan;
(L) 5% emtricitabine and 95% poly-(L-lactide-co-etherophosphoric acid);
(M) 10% emtricitabine and 90% poly-(L-lactide-co-etherophosphoric acid);
(N) 20% emtricitabine and 80% poly-(L-lactide-co-etherophosphoric acid);
(O) 30% emtricitabine and 70% poly-(L-lactide-co-etherophosphoric acid);
(P) 5% emtricitabine and 95% poly-(L-lactide-co-phosphoric acid propyl ester);
(Q) 10% emtricitabine and 90% poly-(L-lactide-co-phosphoric acid propyl ester);
(R) 20% emtricitabine and 80% poly-(L-lactide-co-phosphoric acid propyl ester);
(S) 30% emtricitabine and 70% poly-(L-lactide-co-phosphoric acid propyl ester).
5. the sustained-release implant according to claim 1 is characterized in that in the anticancer effective component of this sustained-release implant that each component and the weight percentage in implant thereof are one of following:
(A) 1% emtricitabine and and 95% polylactic acid and 4% mannitol;
(B) 5% emtricitabine and and 93% polylactic acid and 2% mannitol;
(C) 10% emtricitabine and 85% polylactic acid and 5% mannitol;
(D) 15% emtricitabine and 82% polylactic acid and 3% sodium chloride;
(E) 20% emtricitabine and 78% polylactic acid and 2% sodium chloride;
(F) 5% emtricitabine and 92% glycolic and the copolymer of hydroxyacetic acid and 2% sodium chloride;
(G) 10% emtricitabine and 85% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(H) 20% emtricitabine and 75% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(I) 30% emtricitabine and 75% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(J) 5% emtricitabine and 92.5% polifeprosan and 2.5% mannitol;
(K) 15% emtricitabine and 75% polifeprosan and 10% mannitol;
(L) 5% emtricitabine and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(M) 10% emtricitabine and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(N) 20% emtricitabine and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(O) 30% emtricitabine and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(P) 5% emtricitabine and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(Q) 10% emtricitabine and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(R) 20% emtricitabine and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(S) 30% emtricitabine and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol.
6. according to the described anticancer sustained-release agent of claim 1-5, the molecular weight peak value that it is characterized in that polylactic acid is 5000-15000,10000-20000,20000-35000 or 30000-50000.
7. according to the described anticancer sustained-release agent of claim 1-5, the molecular weight peak value that it is characterized in that the copolymer of glycolic and hydroxyacetic acid is 5000-15000,15000-35000,35000-45000 or 45000-80000; The percentage by weight of glycolic and hydroxyacetic acid is 80: 20,75: 25, and 70: 30,60: 40,50: 50 or 40: 60.
8. according to the described anticancer sustained-release agent of claim 1-5, it is characterized in that the percentage by weight to carboxy phenyl propane and decanedioic acid is 20: 80 in the polifeprosan (to carboxy phenyl propane-decanedioic acid copolymer), 30: 70,40: 60,50: 50 or 60: 40.
9. the described slow releasing agent of claim 1-5 is characterized in that this slow releasing agent is in the tumor or the slow releasing injection and the solid sustained-release implant of all injections of tumor or placement.
10. the slow releasing agent according to claim 1 is characterized in that described slow releasing agent is used to prepare the treatment cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma, lymphoma, tumor of head and neck and originates from the pharmaceutical preparation of cancer, sarcoma or the carcinosarcoma of gallbladder, oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, eyes former or secondary.
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| CN101797219A (en) * | 2010-03-26 | 2010-08-11 | 中国人民解放军第四军医大学 | Solid sustained- release implant for curing esophageal carcinoma and preparation method thereof |
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| CN101797219A (en) * | 2010-03-26 | 2010-08-11 | 中国人民解放军第四军医大学 | Solid sustained- release implant for curing esophageal carcinoma and preparation method thereof |
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