CN101219102A - Lapatinib sustained-release implantation agent for treating solid tumors - Google Patents
Lapatinib sustained-release implantation agent for treating solid tumors Download PDFInfo
- Publication number
- CN101219102A CN101219102A CNA200710202970XA CN200710202970A CN101219102A CN 101219102 A CN101219102 A CN 101219102A CN A200710202970X A CNA200710202970X A CN A200710202970XA CN 200710202970 A CN200710202970 A CN 200710202970A CN 101219102 A CN101219102 A CN 101219102A
- Authority
- CN
- China
- Prior art keywords
- lapatinib
- sustained
- acid
- release
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention relates to a solid tumors-curing Lapatinib sustained-release implant, which is characterized in that the sustained-release implant contains effective anti-tumor dose of Lapatinib, sustained-release auxiliary material and a certain amount of sustained-release regulator. Solid tumors consist of lung cancer, esophageal cancer, gastric cancer, liver cancer, breast cancer, ovarian cancer, prostatic cancer, bladder cancer and colorectal cancer. The sustained-release auxiliary materials are mainly one or mixture of copolymer of glycolic acid and hydroxyacetic acid, polifeprosan, poly (L-lactide-co-ethyl phosphate) and poly (L-lactide-co-propyl phosphate). When the sustained-release auxiliary materials are degrading and absorbed, Lapatinib is slowly released into tumor part, thus while reducing toxic reaction of the whole body, the sustained-release auxiliary materials can sustain concentration of effective drug at the tumor part. Placing the anti-tumor sustained-release implant at the tumor part can not only reduce toxic reaction of the whole body of Lapatinib, but also improve drug concentration at the tumor part and enhance treatment effects of nonspecific treatments, such as chemotherapeutics, radiotherapy, etc.
Description
(1) technical field
The present invention relates to a kind of Lapatinib sustained-release implantation agent for the treatment of entity tumor, belong to technical field of pharmaceuticals.
(2) background technology
Though the research about cancer has obtained bigger progress, its mortality rate still occupies the prostatitis of the various common causes of the death.Up-to-date data show that China had 3,000,000 people to die from cancer in 2006.Cancer morbidity rises year by year and is rejuvenation trend, has data to show that in less than the time in 20 years, China's cancer morbidity has risen 69%, and mortality rate has increased by 29.4%.According to World Health Organization's recent statistics, will increase by 50 percent to the year two thousand twenty whole world cancer morbidity, number of the infected increases to 15,000,000.Estimate that the year two thousand twenty China will have 4,000,000 people to die from cancer therefore every year, inquire into the focus that a kind of effective treatment method for cancer or medicine have become present research.
Phosphoric acid Lapatinib (fludarabine phosphate, Fuda China) be used for B cellularity chronic lymphocytic leukemia (CLL) patient's treatment, these patients accepted the alkylating agent scheme treatment of a standard at least, but during treating or after the treatment, progress is not improved or still continued to the state of an illness.Adult's recommended dose is a phosphoric acid Lapatinib 25mg/m2 every day body surface area, and logotype 5 days per 28 days was 1 vein course of treatment.Yet this effect that will be used for the treatment of other tumor separately is unclear.Though unite some tumors may be had certain effect by tool, limited its clinical practice by the caused whole body toxic and side effects of conventional route administration with other anticarcinogen.
(3) summary of the invention
Based on above examination to prior art, the present invention compares other tumor, found that Lapatinib has comparatively significantly action effect to entity tumors such as the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer and rectal cancer.Discover that further the Lapatinib local sustained release also has good therapeutical effect to the outer entity tumor of other craniums such as thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate.Yet conventional method is difficult to bring into play its anti-tumor effect.Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.
The present invention is directed to the deficiencies in the prior art, a kind of sustained-release implant is provided, be used for the treatment of entity tumor, not only effect is obvious, and its general toxicity obviously alleviates.
The present invention treats the sustained-release implant of entity tumor, it is characterized in that this sustained-release implant contains the Lapatinib 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) Lapatinib 0.1%-50%
(2) slow-release auxiliary material 50%-99%
(3) slow release regulator 0-15%
The percentage by weight of Lapatinib of the present invention in sustained-release implant serves as preferred with 0.1 to 50%, with 5%-30% for most preferably.Lapatinib can be various salt, serves as preferred with phosphate (Lapatinib).
Decanedioic acid (SA) copolymer), a kind of or its combination among poly-(L-lactide-co-etherophosphoric acid) (p (LAEG-EOP)), poly-(L-lactide-co-phosphoric acid propyl ester) (p (DAPG-EOP)) slow-release auxiliary material of the present invention mainly is selected from the copolymer (PLGA), polifeprosan of polylactic acid (PLA), glycolic and hydroxyacetic acid (to carboxy phenyl propane (p-CPP):.
Wherein the molecular weight peak value of polylactic acid (PLA) is 5000-15000,10000-20000,20000-35000 or 30000-50000; Serve as preferred wherein with 5000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.
The molecular weight peak value of the copolymer of glycolic and hydroxyacetic acid (PLGA) is 5000-15000,15000-35000,35000-45000 or 45000-80000; Serve as preferred wherein with 5000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.The percentage by weight of glycolic and hydroxyacetic acid is 90: 10,80: 20, and 70: 30,60: 40,50: 50 or 40: 60; Wherein with 80: 20,70: 30,60: 40, be preferred at 50: 50, with 60: 40 and 50: 50 for most preferably.
Polifeprosan (to carboxy phenyl propane (p-CPP): the percentage by weight to carboxy phenyl propane (p-CPP) and decanedioic acid (SA) decanedioic acid (SA) copolymer) is 10: 90,20: 80, and 30: 70,40: 60,50: 50 or 60: 40; Wherein with 80: 20,70: 30,60: 40, be preferred at 50: 50, with 60: 40 and 50: 50 for most preferably.
The molecular weight peak value of poly-(L-lactide-co-etherophosphoric acid) is 10000-15000,15000-25000,25000-35000 or 35000-60000, serve as preferred wherein with 10000-15000,15000-35000,35000-45000, with 15000-35000 for most preferably.
In " slow-release auxiliary material complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor), slow-release auxiliary material is had a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some slow-release auxiliary material.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker.Above slow-release auxiliary material has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of composition for treating solid tumor of the present invention can be any or multiple material in the above-mentioned slow-release auxiliary material, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The slow release regulator is selected from a kind of or its combination in xylitol, oligosaccharide, chitin, potassium salt, sodium salt, mannitol, sorbitol, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
For regulating other characteristic of drug releasing rate or change anti-cancer sustained-released implantation agent of the present invention, can change the monomer component of polymer or the composition and the proportioning of molecular weight, interpolation or adjusting slow-release auxiliary material, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt and sodium salt etc.
Characteristics of the present invention are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other slow-release auxiliary material.The slow-release auxiliary material of adding is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Slow-release auxiliary material also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned slow-release auxiliary material is applicable to the compositions that contains or do not contain additive.
The consumption of sustained-release implant depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But its principle is at the repair ability that can reduce tumor cell, when increasing the chemotherapy action effect and the toxic reaction of not obvious increase medicine.Effective dose is 10-15000 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, implant, slow releasing agent and implantation slow release agent etc., wherein implant is mainly sustained-release implant, controlled release implant or slowbreak implant; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and apperance; Can be through various administrations, as in tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Whether route of administration depends on multiple factor, as position, tumor place, perform the operation or transfer, gross tumor volume size, tumor classification, patient age, health, bearing status and requirement etc.For obtain active drug concentration in position, tumor place, arterial perfusion optionally, intra-bladder instillation (intracavitary), (intraspinal) administration in abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and the canalis spinalis, but also place in the internal organs, as in the enteric cavity, in the intravesical, uterine cavity, in intravaginal, gastric and the esophagus etc.In various approach, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, to place the form that slowly discharges serve as preferably for tumor week or tumor chamber, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant and sustained-release implant as selecting for use.
Available arbitrary method preparation.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and anti-cancer sustained-released implantation agent also can be packed in the liposome.The effective ingredient of compositions can be packaged in the whole slow-release auxiliary material equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.Each component and the weight percentage in compositions thereof are preferred one of following in the sustained-release implant:
(A) polylactic acid of the Lapatinib of 1%-5% and 95%-99%;
(B) polylactic acid of the Lapatinib of 5%-10% and 90%-95%;
(C) polylactic acid of the Lapatinib of 10%-15% and 85%-90%;
(D) polylactic acid of the Lapatinib of 15%-25% and 75%-85%;
(E) polylactic acid of the Lapatinib of 25%-40% and 60%-75%;
(F) copolymer of the glycolic of the Lapatinib of 1%-10% and 90%-99% and hydroxyacetic acid;
(G) copolymer of the glycolic of the Lapatinib of 10%-20% and 80%-90% and hydroxyacetic acid;
(H) copolymer of the glycolic of the Lapatinib of 20%-30% and 70%-80% and hydroxyacetic acid;
(I) copolymer of the glycolic of the Lapatinib of 30%-40% and 60%-70% and hydroxyacetic acid;
(J) polifeprosan of the Lapatinib of 5%-15% and 85%-95%;
(K) polifeprosan of the Lapatinib of 15%-35% and 65%-85%;
(L) 5% Lapatinib and 95% poly-(L-lactide-co-etherophosphoric acid);
(M) 10% Lapatinib and 90% poly-(L-lactide-co-etherophosphoric acid);
(N) 20% Lapatinib and 80% poly-(L-lactide-co-etherophosphoric acid);
(O) 30% Lapatinib and 70% poly-(L-lactide-co-etherophosphoric acid);
(P) 5% Lapatinib and 95% poly-(L-lactide-co-phosphoric acid propyl ester);
(Q) 10% Lapatinib and 90% poly-(L-lactide-co-phosphoric acid propyl ester);
(R) 20% Lapatinib and 80% poly-(L-lactide-co-phosphoric acid propyl ester);
(S) 30% Lapatinib 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 Lapatinib of 1%-5% and 85%-98% and 0.5%-15%;
(B) sorbitol of the polylactic acid of the Lapatinib of 5%-10% and 90%-95% and 0.5%-10%;
(C) sodium chloride of the polylactic acid of the Lapatinib of 10%-15% and 85%-90% and 0.5%-10%;
(D) mannitol of the polylactic acid of the Lapatinib of 15%-25% and 75%-85% and 0.25%-5%;
(E) sorbitol of the polylactic acid 0.1%-8% of the Lapatinib of 25%-40% and 60%-75%;
(F) mannitol of the copolymer of the glycolic of the Lapatinib of 1%-10% and 90%-99% and hydroxyacetic acid and 0.5%-15%;
(G) sorbitol of the copolymer of the glycolic of the Lapatinib of 10%-20% and 80%-90% and hydroxyacetic acid and 0.5%-10%;
(H) sodium chloride of the copolymer of the glycolic of the Lapatinib of 20%-30% and 70%-80% and hydroxyacetic acid and 0.5%-10%;
(I) mannitol of the copolymer of the glycolic of the Lapatinib of 30%-40% and 60%-70% and hydroxyacetic acid and 0.25%-5%;
(J) mannitol of the polifeprosan of the Lapatinib of 5%-15% and 85%-95% and 1%-5%;
(K) mannitol of the polifeprosan of the Lapatinib of 15%-35% and 65%-85% and 0.25%-7.5%;
(L) 5% Lapatinib and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(M) 10% Lapatinib and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(N) 20% Lapatinib and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(O) 30% Lapatinib and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(P) 5% Lapatinib and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(Q) 10% Lapatinib and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(R) 20% Lapatinib and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(S) 30% Lapatinib 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, Lapatinib are to the inhibitory action of growth of tumour cell.
Be the inhibitory action of checking Lapatinib to other growth of tumour cell, this test is added to Lapatinib (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, Lapatinib all has obvious inhibitory action (P＜0.05) to the examination growth of tumor, and is wherein right.This is unexpected finds to constitute major technique feature of the present invention, for the treatment of entity tumor provides new selection.
The sustained-release implant that contains Lapatinib can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing of implanting.
The preparation method of sustained-release implant of the present invention is as follows:
1, the slow-release auxiliary material of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2, adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and slow-release auxiliary material is decided because of specific requirement.
3, remove organic solvent.Vacuum drying or cold drying all can.
4, dried solid composite is made different shape as required.
5, ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
(4) specific embodiment
Embodiment one,
The slow-release auxiliary material (molecular weight is the polylactic acid (PLA) of 10000-20000) of (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 Lapatinibs, 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% Lapatinib.The drug release time of this sustained-release implant in external normal saline is 12-16 days, is 10-15 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% Lapatinib and and 99% polylactic acid;
(B) 5% Lapatinib and and 95% polylactic acid;
(C) 10% Lapatinib and 90% polylactic acid;
(D) 15% Lapatinib and 85% polylactic acid;
(E) 20% Lapatinib 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 Lapatinib, 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% Lapatinib.The drug release time of this sustained-release implant in external normal saline is 12-16 days, is 13-18 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 Lapatinib of 1%-10% and 90%-99% and hydroxyacetic acid;
(2) copolymer of the glycolic of the Lapatinib of 10%-20% and 80%-90% and hydroxyacetic acid;
(3) copolymer of the glycolic of the Lapatinib of 20%-30% and 70%-80% and hydroxyacetic acid;
(4) copolymer of the glycolic of the Lapatinib of 30%-40% and 60%-70% and hydroxyacetic acid;
The copolymer of (5) 5% Lapatinib and 95% glycolic and hydroxyacetic acid;
The copolymer of (6) 10% Lapatinib and 90% glycolic and hydroxyacetic acid;
The copolymer of (7) 20% Lapatinib and 80% glycolic and hydroxyacetic acid;
The copolymer of (8) 30% Lapatinib 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 Lapatinib 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% Lapatinib.The drug release time of this sustained-release implant in external normal saline is 20-24 days, is 20-22 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 Lapatinib of 1%-10% and 90%-99% and hydroxyacetic acid and 0.5%-15%;
(2) sorbitol of the copolymer of the glycolic of the Lapatinib of 10%-20% and 80%-90% and hydroxyacetic acid and 0.5%-10%;
(3) sodium chloride of the copolymer of the glycolic of the Lapatinib of 20%-30% and 70%-80% and hydroxyacetic acid and 0.5%-10%;
(4) mannitol of the copolymer of the glycolic of the Lapatinib of 30%-40% and 60%-70% and hydroxyacetic acid and 0.25%-5%;
The copolymer of (5) 5% Lapatinib and 92% glycolic and hydroxyacetic acid and 2% sodium chloride;
The copolymer of (6) 10% Lapatinib and 85% glycolic and hydroxyacetic acid and 5% mannitol;
The copolymer of (7) 20% Lapatinib and 75% glycolic and hydroxyacetic acid and 5% mannitol;
The copolymer of (8) 30% Lapatinib 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 Lapatinib, 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% Lapatinib sustained-release implantation agent.The drug release time of this sustained-release implant in external normal saline is 8-12 days, is 8-14 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 Lapatinib of 1%-15% and 85%-95%;
(2) polifeprosan of the Lapatinib of 15%-35% and 65%-85%;
(3) 5% Lapatinib and 95% polifeprosan;
(4) 10% Lapatinib and 90% polifeprosan;
(5) 15% Lapatinib and the polifeprosan of 85%-95%;
(6) 20% Lapatinib 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 Lapatinib, 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% Lapatinib sustained-release implantation agent.The drug release time of this sustained-release implant in external normal saline is 12-14 days, is 14-18 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 Lapatinib of 5%-15% and 85%-95% and 1%-5%; Or
(2) mannitol of the polifeprosan of the Lapatinib 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 Lapatinibs, 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% Lapatinib.The drug release time of this sustained-release implant in external normal saline is 18-24 days, is 20-28 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% Lapatinib and and 95% polylactic acid and 4% mannitol;
(B) 5% Lapatinib and and 93% polylactic acid and 2% mannitol;
(C) 10% Lapatinib and 85% polylactic acid and 5% mannitol;
(D) 15% Lapatinib and 82% polylactic acid and 3% sodium chloride;
(E) 20% Lapatinib and 78% polylactic acid and 2% sodium chloride.
Embodiment 13
Make sustained-release implant by embodiment 1 to 11 described method, used slow-release auxiliary material is selected from one of following or its combination:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,15000-35000,35000-45000 or 45000-80000 and the copolymer of hydroxyacetic acid (PLGA);
C) polifeprosan is (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) copolymer), be 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to the percentage by weight of carboxy phenyl propane (p-CPP) and decanedioic acid (SA);
On the basis of above-mentioned slow release, the present invention finds that further body is implanted into Lapatinib other entity tumors such as the cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer, rectal cancer, ovarian cancer, skin carcinoma, lymphoma, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate are also had good therapeutical effect.Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.Following in vivo test is used for explanation but not limitation of the present invention.
Embodiment 14
With 70,80,90 and 95mg molecular weight peak value be that the p (LAEG-EOP) of 10000-25000 puts into first, second, third, four containers of fourth respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in four containers, add 30mg, 20mg, 10mg and 5mg Lapatinib respectively, shake up the sustained-release implant that the preparation of after drying method contains 30%, 20%, 10% and 5% Lapatinib again.The drug release time of this slow releasing agent in external normal saline is 26-32 days, is about 25-34 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% Lapatinib;
(2) 5%-10% Lapatinib;
(3) 10%-20% Lapatinib;
(4) 20%-40% Lapatinib;
The sodium chloride of (5) 5% Lapatinib and 92% p (LAEG-EOP) and 2%;
The mannitol of (6) 10% Lapatinib and 85% p (LAEG-EOP) and 5%;
The mannitol of (7) 20% Lapatinib and 75% p (LAEG-EOP) and 5%;
The mannitol of (8) 30% Lapatinib 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 Lapatinib respectively, shake up the sustained-release implant that the preparation of after drying method contains 30%, 20%, 10% and 5% Lapatinib again.The drug release time of this slow releasing agent in external normal saline is 16-22 days, is about 22-28 days at the subcutaneous drug release time of mice.
Embodiment 17
The method step that is processed into sustained-release implant is identical with embodiment 16, but the molecular weight peak value of different is p (DAPG-EOP) is 25000-45000, and contained anticancer effective component and percentage by weight thereof are:
(1) 1%-5% Lapatinib;
(2) 5%-10% Lapatinib;
(3) 10%-20% Lapatinib;
(4) 20%-40% Lapatinib;
The sodium chloride of (5) 5% Lapatinib and 92% p (DAPG-EOP) and 2%;
The mannitol of (6) 10% Lapatinib and 85% p (DAPG-EOP) and 5%;
The mannitol of (7) 20% Lapatinib and 75% p (DAPG-EOP) and 5%;
The mannitol of (8) 30% Lapatinib and 75% p (DAPG-EOP) and 5%.
Embodiment 18, tumor are implanted into the inhibitory action of Lapatinib 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 5 groups at random with animal, 5 every group when diameter of tumor grows to the 0.8-1.5cm left and right sides.Be normal saline group (matched group), Lapatinib sustained-release implantation agent group, with the made sustained-release implant (5%, 10%, 20% of embodiment four, be called for short 5% group, 10% group and 20% group) and Lapatinib lumbar injection group (i.p. group), chamber injection group dosage is with 5% sustained-release implant group.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 Lapatinib implant implantation tumour tissue, not pastille high molecular polymer, Lapatinib implant 5%, Lapatinib implant 10%, Lapatinib 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 Lapatinib spit of fland sustained-release implant to mice lung cancer
Check the tumor-inhibiting action of Lapatinib sustained-release implantation agent according to embodiment 18 described methods and step to mice lung cancer.Used implant adjuvant is PLGA (molecular weight is 15000-30000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50), is derived from embodiment four.This experimental result sees Table 2.
Table 2
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 10 | ＞0.05 |
| 3 | 5% group | 38 | ＜0.05 |
| 4 | 10% group | 48 | ＜0.01 |
| 5 | 20% group | 66 | ＜0.01 |
The result shows that the Lapatinib implant obviously strengthens than the lumbar injection effect, and the Lapatinib implant of various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.
Embodiment 20 tumors are implanted into the tumor-inhibiting action of Lapatinib sustained-release implantation agent to mouse breast cancer
Check the tumor-inhibiting action of Lapatinib sustained-release implantation agent to mouse breast cancer according to embodiment 18 described methods and step, used implant is from embodiment two.Experimental result sees Table 3
Table 3
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 16 | ＞0.05 |
| 3 | 1% group | 40 | ＜0.05 |
| 4 | 10% group | 48 | ＜0.01 |
| 5 | 20% group | 76 | ＜0.01 |
The tumor control rate that shows 1%, 10% and 20% Lapatinib implant is respectively 40%, 48%, 76%, compares with Lapatinib local injection group, and the P value is all less than 0.001.The tumour inhibiting rate that the Lapatinib implant is described obviously surpasses Lapatinib lumbar injection group group, twice experimental result good reproducibility.
Embodiment 21, tumor are implanted into the tumor-inhibiting action of Lapatinib sustained-release implantation agent to the mouse ovarian cancer
Check the tumor-inhibiting action of Lapatinib sustained-release implantation agent according to embodiment 18 described methods and step to the mouse ovarian cancer, used implant is 5%, 10% and 20% polifeprosan (percentage by weight to carboxy phenyl propane (p-CPP) and decanedioic acid (SA) is 50: 50), from embodiment eight.Experimental result sees Table 4.
Table 4
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 14 | ＞0.05 |
| 3 | 5% group | 40 | ＜0.05 |
| 4 | 10% group | 54 | ＜0.01 |
| 5 | 20% group | 78 | ＜0.01 |
The Lapatinib implant of 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.Lapatinib implant tumor control rate is respectively 40%, 54%, 78%, compares with Lapatinib 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.
Embodiment 22 tumors are implanted into the tumor-inhibiting action of Lapatinib sustained-release implantation agent to the mice esophageal carcinoma
Check the tumor-inhibiting action of Lapatinib sustained-release implantation agent to the mice esophageal carcinoma according to embodiment 18 described methods and step, used implant is selected from embodiment six.Experimental result sees Table 5.
Table 5
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 15 | ＞0.05 |
| 3 | 5% group | 48 | ＜0.05 |
| 4 | 10% group | 58 | ＜0.01 |
| 5 | 20% group | 78 | ＜0.01 |
The Lapatinib implant of 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.Lapatinib implant tumor control rate is respectively 48%, 58%, 78%, compares with Lapatinib local injection group, and the P value is all less than 0.001.
Embodiment 23, tumor are implanted into the tumor-inhibiting action of Lapatinib sustained-release implantation agent to mouse pancreas cancer
Check the tumor-inhibiting action of Lapatinib sustained-release implantation agent to mouse pancreas cancer according to embodiment 18 described methods and step, used implant adjuvant is PLGA (molecular weight is 20000-35000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50).The content of Lapatinib in sustained-release implant is 5%, 10% and 30%, from embodiment six. experimental result sees Table 6.
Table 6
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 16 | ＞0.05 |
| 3 | 5% group | 36 | ＜0.05 |
| 4 | 10% group | 68 | ＜0.01 |
| 5 | 30% group | 86 | ＜0.01 |
The result proves in Lapatinib implant implantation nude mice model human pancreas cancer (JF305) entity tumor of various dose that can obviously suppress tumor growth, tumor control rate and drug dose are obvious dose-effect relationship.Compare with Lapatinib local injection group, the P value is all less than 0.001.
Embodiment 24, tumor are implanted into the tumor-inhibiting action of Lapatinib sustained-release implantation agent to the mice rectal cancer
Check the tumor-inhibiting action of Lapatinib sustained-release implantation agent to the mice rectal cancer according to embodiment 18 described methods and step, used implant adjuvant is PLGA (molecular weight is 20000-35000, and the blending ratio of glycolic and hydroxyacetic acid is 50: 50).The content of Lapatinib in sustained-release implant is 7.5%, 15% and 25%.Experimental result sees Table 7.
Table 7
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 14 | ＞0.05 |
| 3 | 7.5% group | 40 | ＜0.05 |
| 4 | 15% group | 74 | ＜0.01 |
| 5 | 25% group | 86 | ＜0.01 |
The Lapatinib implant of various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Lapatinib implant tumor control rate is respectively 40%, 74%, 86%, compares with Lapatinib local injection group, and the P value is all less than 0.001.
Embodiment 25, tumor are implanted into the tumor-inhibiting action of Lapatinib sustained-release implantation agent to the mice carcinoma of prostate
Check the tumor-inhibiting action of Lapatinib sustained-release implantation agent to the mice carcinoma of prostate according to embodiment 18 described methods and step, used implant adjuvant is p (LAEG-EOP) (molecular weight is 10000-25000).The content of Lapatinib in sustained-release implant is 5%, 10% and 20% (from embodiment 14). experimental result sees Table 8.
Table 8
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 12 | ＞0.05 |
| 3 | 5% group | 38 | ＜0.05 |
| 4 | 10% group | 46 | ＜0.01 |
| 5 | 20% group | 68 | ＜0.01 |
The result shows that the Lapatinib implant of 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.Lapatinib implant tumor control rate is respectively 38%, 46%, 68%, compares with Lapatinib local injection group, and the P value is all less than 0.001.
Embodiment 26, tumor are implanted into the tumor-inhibiting action of Lapatinib sustained-release implantation agent to rat liver cancer
Check the tumor-inhibiting action of Lapatinib sustained-release implantation agent to rat liver cancer according to embodiment 18 described methods and step, used implant adjuvant is p (DAPG-EOP) (molecular weight is 10000-25000).The content of Lapatinib in sustained-release implant is 5%, 10% and 20% (from embodiment 16). the content of Lapatinib in sustained-release implant is that 7.5%, 15% and 25%. experimental results see Table 9.
Table 9
| Group | Treatment | Tumor control rate (%) | The P value |
| 1 | Matched group | ||
| 2 | I.p. organize | 14 | ＞0.05 |
| 3 | 5% group | 36 | ＜0.05 |
| 4 | 10% group | 54 | ＜0.01 |
| 5 | 20% group | 74 | ＜0.01 |
The Lapatinib implant of proof various dose can obviously suppress tumor growth, and tumor control rate and drug dose are obvious dose-effect relationship.Lapatinib implant tumor control rate is respectively 36%, 54%, 74%, compares with Lapatinib local injection group, and the P value is all less than 0.001.
In addition, tumor is implanted into Lapatinib sustained-release implantation agent other entity tumors such as gastric cancer, bladder cancer, carcinoma of testis, colon cancer, carcinoma of endometrium, lymphoma, the cerebral tumor, cervical cancer, renal carcinoma is also had good therapeutical effect, and its effect obviously surpasses Lapatinib lumbar injection group and local injection group.This is unexpected finds to constitute another major technique feature of the present invention, for the treatment of entity tumor provides another new selection.
Claims (10)
1. a Lapatinib sustained-release implantation agent for the treatment of entity tumor is characterized in that this sustained-release implant contains the Lapatinib of effective anticancer, slow-release auxiliary material and a certain amount of slow release regulator, wherein,
The percentage by weight of Lapatinib in sustained-release implant is 0.1%-50%;
Slow-release auxiliary material 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-(L-lactide-co-phosphoric acid propyl ester);
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, and its percentage by weight in sustained-release implant is 0-15%.
2. according to the described anti-cancer sustained-released implantation agent of claim, the molecular weight peak value that it is characterized in that polylactic acid in the slow-release auxiliary material is 5000-15000,10000-20000,20000-35000 or 30000-50000.
3. according to the described anti-cancer sustained-released implantation agent of claim 1, it is characterized in that the molecular weight peak value of the copolymer of glycolic and hydroxyacetic acid in the slow-release auxiliary material is 5000-15000,15000-35000,35000-45000 or 45000-80000.
4. according to the described anti-cancer sustained-released implantation agent of claim 1, it is characterized in that the percentage by weight of glycolic and hydroxyacetic acid is 90: 10 in the copolymer of glycolic and hydroxyacetic acid in the slow-release auxiliary material, 80: 20,70: 30,60: 40,50: 50 or 40: 60.
5. according to the described anti-cancer sustained-released implantation agent of claim 1, it is characterized in that in the slow-release auxiliary material that the percentage by weight to carboxy phenyl propane and decanedioic acid is 10: 90 in the polifeprosan, 20: 80,30: 70,40: 60,50: 50 or 60: 40.
6. according to the described anti-cancer sustained-released implantation agent of claim, it is characterized in that the molecular weight peak value of poly-(L-lactide-co-etherophosphoric acid) in the slow-release auxiliary material is 10000-15000,15000-25000,25000-35000 or 35000-60000.
7. according to the described anti-cancer sustained-released implantation agent of claim 1, it is characterized in that the molecular weight peak value of the copolymer of poly-(L-lactide-co-phosphoric acid propyl ester) in the slow-release auxiliary material is 8000-20000,20000-30000,30000-40000 or 40000-80000.
8. 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% Lapatinib and and 99% polylactic acid;
(B) 5% Lapatinib and and 95% polylactic acid;
(C) 10% Lapatinib and 90% polylactic acid;
(D) 15% Lapatinib and 85% polylactic acid;
(E) 20% Lapatinib and 80% polylactic acid;
(F) 5% Lapatinib and 95% glycolic and the copolymer of hydroxyacetic acid;
(G) 10% Lapatinib and 90% glycolic and the copolymer of hydroxyacetic acid;
(H) 20% Lapatinib and 80% glycolic and the copolymer of hydroxyacetic acid;
(I) 30% Lapatinib and 70% glycolic and the copolymer of hydroxyacetic acid;
(J) 5% Lapatinib and 95% polifeprosan;
(K) 15% Lapatinib and 85% polifeprosan;
(L) 5% Lapatinib and 95% poly-(L-lactide-co-etherophosphoric acid);
(M) 10% Lapatinib and 90% poly-(L-lactide-co-etherophosphoric acid);
(N) 20% Lapatinib and 80% poly-(L-lactide-co-etherophosphoric acid);
(O) 30% Lapatinib and 70% poly-(L-lactide-co-etherophosphoric acid);
(P) 5% Lapatinib and 95% poly-(L-lactide-co-phosphoric acid propyl ester);
(Q) 10% Lapatinib and 90% poly-(L-lactide-co-phosphoric acid propyl ester);
(R) 20% Lapatinib and 80% poly-(L-lactide-co-phosphoric acid propyl ester);
(S) 30% Lapatinib and 70% poly-(L-lactide-co-phosphoric acid propyl ester).
9. 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% Lapatinib and and 95% polylactic acid and 4% mannitol;
(B) 5% Lapatinib and and 93% polylactic acid and 2% mannitol;
(C) 10% Lapatinib and 85% polylactic acid and 5% mannitol;
(D) 15% Lapatinib and 82% polylactic acid and 3% sodium chloride;
(E) 20% Lapatinib and 78% polylactic acid and 2% sodium chloride;
(F) 5% Lapatinib and 92% glycolic and the copolymer of hydroxyacetic acid and 2% sodium chloride;
(G) 10% Lapatinib and 85% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(H) 20% Lapatinib and 75% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(I) 30% Lapatinib and 75% glycolic and the copolymer of hydroxyacetic acid and 5% mannitol;
(J) 5% Lapatinib and 92.5% polifeprosan and 2.5% mannitol;
(K) 15% Lapatinib and 75% polifeprosan and 10% mannitol;
(L) 5% Lapatinib and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(M) 10% Lapatinib and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(N) 20% Lapatinib and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(O) 30% Lapatinib and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(P) 5% Lapatinib and 92% poly-(L-lactide-co-etherophosphoric acid) and 2% sodium chloride;
(Q) 10% Lapatinib and 85% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(R) 20% Lapatinib and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol;
(S) 30% Lapatinib and 75% poly-(L-lactide-co-etherophosphoric acid) and 5% mannitol.
10. the sustained-release implant according to claim 1 is characterized in that described sustained-release implant is used for the preparation treatment cerebral tumor, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma, lymphoma, tumor of head and neck and originate from gallbladder, the oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, former or the cancer of secondary of eyes, the pharmaceutical preparation of sarcoma or carcinosarcoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710202970XA CN101219102A (en) | 2007-12-11 | 2007-12-11 | Lapatinib sustained-release implantation agent for treating solid tumors |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710202970XA CN101219102A (en) | 2007-12-11 | 2007-12-11 | Lapatinib sustained-release implantation agent for treating solid tumors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101219102A true CN101219102A (en) | 2008-07-16 |
Family
ID=39629379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200710202970XA Pending CN101219102A (en) | 2007-12-11 | 2007-12-11 | Lapatinib sustained-release implantation agent for treating solid tumors |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101219102A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102626393A (en) * | 2011-10-17 | 2012-08-08 | 复旦大学 | Albumin nanometer particle preparation for soluble injection and preparation method of albumin nanometer particle preparation |
| CN103897043A (en) * | 2012-12-28 | 2014-07-02 | 天津药物研究院 | Preparation and application of transmembrane polypeptide connected lapatinib |
| CN115887473A (en) * | 2021-08-20 | 2023-04-04 | 上海医药工业研究院 | Application of verbascoside compound or derivative thereof in preparation of bladder cancer resistant medicines |
| CN116139081A (en) * | 2023-03-14 | 2023-05-23 | 浙江省肿瘤医院 | Oral lapatinib suspension and preparation method thereof |
-
2007
- 2007-12-11 CN CNA200710202970XA patent/CN101219102A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102626393A (en) * | 2011-10-17 | 2012-08-08 | 复旦大学 | Albumin nanometer particle preparation for soluble injection and preparation method of albumin nanometer particle preparation |
| CN102626393B (en) * | 2011-10-17 | 2015-10-28 | 复旦大学 | A kind of solubility injection albumin nano granular preparation and preparation method thereof |
| CN103897043A (en) * | 2012-12-28 | 2014-07-02 | 天津药物研究院 | Preparation and application of transmembrane polypeptide connected lapatinib |
| CN115887473A (en) * | 2021-08-20 | 2023-04-04 | 上海医药工业研究院 | Application of verbascoside compound or derivative thereof in preparation of bladder cancer resistant medicines |
| CN116139081A (en) * | 2023-03-14 | 2023-05-23 | 浙江省肿瘤医院 | Oral lapatinib suspension and preparation method thereof |
| CN116139081B (en) * | 2023-03-14 | 2023-12-22 | 浙江省肿瘤医院 | Oral lapatinib suspension and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101185633A (en) | Neratinib sustained-release implant for treating solid tumor | |
| CN101219102A (en) | Lapatinib sustained-release implantation agent for treating solid tumors | |
| CN101181230A (en) | Estramustine sustained-release implantation agent for curing entity tumour | |
| CN101204365A (en) | Implant agent treating for solid tumor | |
| CN100563644C (en) | A kind of carmustine sustained-release implantation agent for the treatment of entity tumor | |
| CN101219101A (en) | Fludarabine sustained-release implantation agent for treating solid tumors | |
| CN101185627B (en) | Nilotinib sustained-release implant for treating solid tumor | |
| CN101224185A (en) | Bosutinib sustained release implant for treating solid tumors | |
| CN101204367A (en) | Axitinib sustained-release implplant treating for solid tumor | |
| CN101185629A (en) | Decitabine sustained-release preparation for treating solid tumor | |
| CN101181232B (en) | Marseilledinun sustained-release implantation agent for curing entity tumour | |
| CN100563645C (en) | A kind of Beisalutin sustained-release implantation agent for the treatment of entity tumor | |
| CN101204369A (en) | Sorafenib sustained-release implant treating for solid tumor | |
| CN101181229A (en) | Busulfan sustained-release implantation agent for curing entity tumour | |
| CN101181235B (en) | Tantudinun sustained-release implantation agent for curing entity tumour | |
| CN101181234B (en) | Literdinun sustained-release implantation agent for curing entity tumour | |
| CN101185632A (en) | Lonafarnib sustained-release implant for treating solid tumor | |
| CN100531712C (en) | Dasatini sustained-release implants for treating entity tumor | |
| CN100531711C (en) | Erlotinib sustained-release implants for treating entity tumor | |
| CN101176715A (en) | Gefitinib sustained-release implantation agent for curing entity tumour | |
| CN101176710A (en) | Mitoxantrone sustained-release implantation agent for curing entity tumour | |
| CN101185625B (en) | Rubitecan sustained-release implant for treating solid tumor | |
| CN101219105A (en) | Emtricitabine sustained-release implantation agent for treating solid tumors | |
| CN101181231B (en) | Sustained-release implantation agent of urotrotiken | |
| CN101176716A (en) | Sunitinib sustained-release implantation agent for curing entity tumour |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080716 |