CN101347409A - Sustained-release injection containing octadecyl dimethyl-4-piperidine phosphate - Google Patents
Sustained-release injection containing octadecyl dimethyl-4-piperidine phosphate Download PDFInfo
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- CN101347409A CN101347409A CNA2008103021998A CN200810302199A CN101347409A CN 101347409 A CN101347409 A CN 101347409A CN A2008103021998 A CNA2008103021998 A CN A2008103021998A CN 200810302199 A CN200810302199 A CN 200810302199A CN 101347409 A CN101347409 A CN 101347409A
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Abstract
A sustained release anti-cancer injection with edelfosine consists of the edelfosine with effective anti-cancer amount and an amphiphilic block copolymer hydrogel, wherein, part or the whole of the edelfosine is encapsulated in sustained release microsphere and exists singly in the form of the sustained release microsphere or microsphere and micro-powder in the sustained release injection. The amphiphilic block copolymer hydrogel is selected from PLGA-polyethylene glycol-PLGA, sustained release gel has temperature-sensitive gelation property; and the sustained release gel is flowable fluid in an environment below body temperature, and can automatically change into biodegradable and absorbable non-flowable water-insoluble gel in bodies of warm blooded animals, thus causing the drug to be slowly released in the local part of tumor; the sustained release microsphere is favorable to the stable and sustained release of the drug, the dual sustained release is beneficial to controlling tumor cells in dormancy stage, the drug in the form of the micro-powder in the sustained release gel is favorable to the relatively quick release, thus being beneficial to controlling cells with quicker proliferation. The sustained release anti-cancer injection with edelfosine can be used together with radiotherapeutic particles, chemotherapeutic drugs, etc.
Description
(1) technical field
The present invention relates to a kind of slow-releasing anticarcinogen injection, belong to technical field of pharmaceuticals.Particularly, this invention relates to a kind of octadecyl methyl glyceryl phosphocholine (edelfosine) can being stablized and is released to the partial sustained-release gel preparation of entity tumor, be mainly the slow dual gel injection of releasing that contains sustained-release micro-spheres, this sustained-release gel preparation at room temperature is an aqueous solution, can be changed into semisolid or solid gel in the warm-blooded animal body, sustained-release gel and sustained-release micro-spheres can slowly discharge the several months at tumor by local with edelfosine.
(2) background technology
Phosphoinositide 3 kinases (phosphoinositide 3-kinase, abbreviation PI3K) inhibitor has the obvious suppression effect to the growth of kinds of tumor cells, yet, the body angular vein is used the therapeutic effect of entity tumor and not obvious, and its root problem is that traditional chemotherapy can not realize active drug concentration and keeps enough action time at tumor locus.Simple increase dosage is subjected to the restriction of general reactions such as its haemolysis again.Because the effect of chemotherapy not only depends on the sensitivity of medicine, medicine is even more important at the action time and the drug level of tumor locus, and conventional chemotherapy not only can not be realized above target, and but the diffusion and the transfer that also can stimulate tumor are gone back in the not only chemical sproof generation of induced tumor cell of the unsuitable chemotherapy of low dosage.
Local chemotherapy can make medicine improve at the prolongation action time of tumor locus, drug level, thereby realizes the irrealizable target of conventional chemotherapy, and can reduce the chance that produces or stimulate tumor to spread and shift because of low-dosage chemotherapy induced tumor cell drug resistance.
Yet present biodegradable sustained-release preparation multi-purpose solid polymer such as polyglycolic acid, polylactic acid or its copolymer etc. are as slow-released carrier.Because the hydrophobic performance of this type of macromolecule carrier, these polymer need organic solvent in the slow releasing pharmaceutical preparation process, as dichloromethane, and chloroform, acetic acid or dimethyl formamide etc.For removing deleterious organic solvent, must be extensively dry.Therefore, in most of the cases, final slow releasing preparation mostly is solid shape (for example, microsphere, lamellar or bar-shaped), needs complicated implantation process, and easily causes tissue injury even tumor cell to plant or send out.In addition, organic solvent or high thermal process often cause many anticancer active ingredient degraded degeneration.
The solid implant can not effectively cover the irregular tumor chamber behind the tumor resection, therefore can not effectively remove postoperative residual tumor cell, can not effectively control postoperative recurrence.
Therefore, new easy operating, environmental protection, the effective and widely applicable slow releasing preparation of research and development just becomes present problem demanding prompt solution.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of slow releasing agent that contains cancer therapy drug is provided, particularly, is a kind of sustained-release implant that contains cancer therapy drug.
The sustained-release implant local chemotherapy can make medicine improve at the prolongation action time of tumor locus, drug level, thereby realize the irrealizable target of conventional chemotherapy, and can reduce the chance that produces or stimulate the tumor diffusion and shift because of low-dosage chemotherapy induced tumor cell drug resistance.
The present invention is directed to the deficiencies in the prior art, a kind of slow releasing injection that contains cancer therapy drug also is provided.Slow releasing injection can be sustained-release micro-spheres, also can be sustained-release gel injection.
This sustained-release gel preparation at room temperature is an aqueous solution, can be changed into semisolid or solid gel in the warm-blooded animal body; Thereby effectively remove postoperative residual tumor cell in the irregular tumor chamber that good fluidity can not only make slow releasing agent effectively cover behind the tumor resection, and postoperative hemostasis and the diffusion of prevention oncocyte are also had preventive effect preferably.Cancer therapy drug discharges from gel and microsphere, and dual control can not only prolong drug also can be kept higher drug level release time, and can increase the sensitivity of medicine, particularly to the rest period cell; This anticancer medicine slow-release preparation containing not only has good drug release feature, and environmental protection, zest are little, and it is convenient to use, and effect is obvious.
The present invention find when the formed amphipathic aqueous copolymers solution of hydrophobicity polyester and hydrophilic polyglycol with can form water for injection gel after a certain amount of cancer therapy drug mixes with slow-release function, this hydrogel is a transparent liquid under 5 ℃ of-25 ℃ of conditions, can be changed into immobilising semisolid or solid water gel about 30 ℃-37 ℃.But this gelling temperature is subjected to multiple factor affecting, wherein mainly is monomeric weight ratio in the molecular weight, polyester of weight ratio, the Polyethylene Glycol of hydrophobicity polyester and hydrophilic polyglycol in the molecular weight of hydrogel Chinese medicine kind, medicament contg, amphipathic copolymer, the amphipathic copolymer.
The present invention finds that also the hydrogel that contains cancer therapy drug can slowly discharge cancer therapy drug wherein, and the cycle of its release can be a few days to the several months, and cancer therapy drug is wrapped in the sustained-release micro-spheres, and pharmaceutical release time is further delayed.And hydrophobicity polyester and the weight ratio of hydrophilic polyglycol in the molecular weight of molecular weight, polyester and Polyethylene Glycol of used amphipathic copolymer and block configuration thereof, the amphipathic copolymer, the kind and the content of cancer therapy drug are mainly also depended in the release of medicine.
Find that through lot of experiments sustained-release gel injection of the present invention is grouped into by following one-tenth:
A: cancer therapy drug 0.01-40%
B: amphipathic copolymer 5%-40%
C: solvent 60%-90%
D: regulator 0-10%
More than be weight percentage
Wherein, cancer therapy drug is selected from 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine (1-O-Octadecyl-2-O-methyl-rac-glycerophosphocholine, ET-18-OCH3 edelfosine), is called for short octadecyl methyl glyceryl phosphocholine or edelfosine.
The percentage by weight of cancer therapy drug in slow releasing agent be from 0.01%-40%, is preferred with 0.1%-30%, with 1%-20% for the most preferred.
Cancer therapy drug exists with the form of sustained-release micro-spheres or microsphere and micropowder in the slow releasing agent injection, the cancer therapy drug that is effective anticancer partly or entirely is wrapped in the sustained-release micro-spheres, the part drug release that is wrapped in the microsphere is slow, help controlling the tumor cell that enters rest period, the medicine that exists with the micropowder form in sustained-release gel helps discharging very fast relatively, help controlling the cell faster that rises in value, the two is united and helps steadily slowly release of medicine, acts on each phase tumor cell.
The preparation of method for preparing microsphere has several different methods, as, but be not limited to multi-emulsion method, O/W method, O/O method, phase separation method, spray drying method, cold nebulization extraction method etc.
1, multi-emulsion method (W/O/W method): accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Under high-speed stirred or ultrasonic concussion, inject the two fun gi polysaccharides aqueous solution, homodisperse, form the colostric fluid of W/O, aqueous phase outside this solution is injected under high-speed stirred or under the ultrasonic concussion, emulsion factor minute (1～30min), form the W/O/W emulsion, in gentle agitation a few hours (1～10hr), the volatilization organic solvent, solidified microsphere.Centrifugal or the filtration collection with microsphere suspension liquid, and back for several times after 37 ℃ of vacuum dryings or lyophilization with the second distillation water washing, in 4 ℃ of refrigerators, preserve after the powder packing.
Wherein, surfactant can be, and singly is not limited to span 20; Organic solvent is selected from, as, but be not limited to a kind of or mixed liquor of dichloromethane, ethyl acetate, acetonitrile etc.; Outer water can be the saturated solution of medicine, also can add surfactants such as salts such as emulsifying agent, 1～10% sodium chloride, 0.001～2% tween such as 0.1～10%PVA and improve balling-up character.Also can add stabilizing agents such as cosolvent, gelatin solution and improve entrapment efficiency.
2, O/W method
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution.
Water (can be the saturated solution of medicine outside above-mentioned suspension or solution was injected under high-speed stirred or under the ultrasonic concussion, also can add surfactants such as salts such as emulsifying agent, sodium chloride, tween such as PVA and improve balling-up character) in, emulsion factor minute (1～30min), form the O/W emulsion, in gentle agitation a few hours (1～10hr), the volatilization organic solvent, solidified microsphere.Centrifugal or the filtration collection with microsphere suspension liquid, and back for several times after 37 ℃ of vacuum dryings or lyophilization with the second distillation water washing, in 4 ℃ of refrigerators, preserve after the powder packing.
3, the O/O method one:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution
Be injected into above-mentioned suspension or solution in the saturated dimethicone of dichloromethane under high-speed stirred or under the ultrasonic concussion, under the high-speed stirred or ultrasonic concussion number minute (after 1～30min), put in the petroleum ether of q.s, high-speed stirred number minute (1～30min), centrifugal or the filtration collection with microsphere suspension liquid behind the solidified microsphere, washing in 37 ℃ vacuum dryings or lyophilization after, powder packing after 4 ℃ refrigerators in is preserved after removing outer oil phase for several times.
4, the O/O method two:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution
Above-mentioned suspension or solution are injected under high-speed stirred or under the ultrasonic concussion in the inertia oil phases such as liquid paraffin, room temperature or heated and stirred or ultrasonic concussion a few hours (1～30hr), the volatilization organic solvent, behind the solidified microsphere, centrifugal or the filtration collection with microsphere suspension liquid, after washing is removed outer oil phase for several times, in 37? vacuum drying or lyophilization, after the powder packing 4? preserve in the refrigerator.
5, phase separation method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution
Organic solvents such as petroleum ether with q.s (1～10 times) under high-speed stirred or under the ultrasonic concussion slowly join in above-mentioned suspension or the solution, continue stirring or ultrasonic concussion tens of minutes (30～120min), the volatilization organic solvent, behind the solidified microsphere, centrifugal or the filtration collection with microsphere suspension liquid, washing in 37 ℃ vacuum dryings or lyophilization, powder packing after 4 ℃ refrigerators in is preserved after removing outer oil phase for several times.
6, spray drying method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution
Above-mentioned suspension or solution under agitation or under the ultrasonic concussion are carried out spray drying with pumping in the spray dryer.Spray condition: 50 ℃-70 ℃ of inlet temperatures, about 40 ℃ of outlet temperature.In 4 ℃ of refrigerators, preserve after collecting the packing of dried microsphere powder.
7, cold nebulization extraction method:
Accurately take by weighing slow-release auxiliary material (PLGA etc.) or add an amount of oil phase surfactant, be dissolved in and form polymer solution in the appropriate amount of organic.Can drug particles be prepared into fine powder (micron order) with methods such as pulverizing for insoluble drugs, perhaps medicine be dropped in the above-mentioned polymer solution, (1000～30000rpm) are prepared into uniform suspension with the ultra high shear machine.Can directly medicine be dropped in the above-mentioned polymer solution for soluble agents and to dissolve, stir or ultrasonic concussion forms homogeneous solution
With above-mentioned suspension or solution under agitation or ultrasonic concussion down with pumping in the spray dryer, method by spraying forms droplet, freezing in liquid nitrogen, obtain microsphere with the organic solvent of a low temperature organic cosolvent (for example ethanol) extracting dissolve polymer.In 4 ℃ of refrigerators, preserve after collecting the packing of dried microsphere powder.
The preferred a kind of mode of sustained-release gel injection is the sustained-release micro-spheres that sustained-release gel contains cancer therapy drug, the preferred another kind of mode of sustained-release gel injection is that sustained-release gel contains cancer therapy drug and the sustained-release micro-spheres that contains cancer therapy drug, the weight ratio of cancer therapy drug is arbitrarily in cancer therapy drug micropowder and the sustained-release micro-spheres, can be 19-1: 1-19, with 9-1: 1-9 serves as preferred, and 5-1: 1-5 is for most preferably.
The slow-release auxiliary material of microsphere also can be, but be not limited to, the copolymer of polylactic acid, lactic acid and glycolic, polifeprosan with and compositions, also can add release regulator in addition, be selected from a kind of or its combination in mannitol, sorbitol, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, chrondroitin, gelatin and the albumin.
The molecular weight peak value of polylactic acid is 500-5000,5000-10000,10000-25000,25000-35000 or 30000-50000; The molecular weight peak value of lactic acid and ethanol copolymer is 1000-10000,10000-25000,25000-40000 or 40000-60000; The percentage by weight of poly-lactonaphthol and polyglycolic acid is 90: 10,70-80: 20-30,60-40: 40-60,75: 25,25: 75 or 50: 50; The weight ratio of CPP in the polifeprosan: SA is 50-10: 90-50.
The preparation of sustained-release gel injection has several different methods, and slow releasing injection of the present invention can prepare with following method and step:
(1) prepares amphipathic aqueous copolymers solution (B+C) with solvent earlier, add a certain amount of cancer therapy drug (A) then, become anticancer sustained-release gel injection behind the dissolving mixing.-10 ℃ or following storing for future use.Injection in redissolution, the body before using; This kind method is fit to be easy to the medicine of hydrolysis degeneration.Can finish at workshop with mixing of cancer therapy drug, also its independent packing transportation can be stored, before clinical practice, finish.Finish at workshop and to help medical personnel operation.Made anticancer sustained-release gel injection is at-10 ℃ or the following 1-2 that stores.If before clinical practice, carry out mixing of cancer therapy drug and syringeability hydrogel, be preferably in injection and finished and be stored in the best freezing state of low temperature in preceding 1 to 3 day, heat up before using redissolve after use.
The content of amphipathic copolymer in the injectivity hydrogel can be 5% to 40%, but serves as preferred with 10% to 30%, and 15% to 28% for most preferably.
(2) prepare amphipathic aqueous copolymers solution and cancer therapy drug respectively, packing stores separately, injection is preceding to be stored in low temperature or freezing state then with making anticancer sustained-release gel injection behind amphipathic aqueous copolymers solution and the abundant mixing of cancer therapy drug, uses after intensification is redissolved before using;
(3) the preparation cancer therapy drug is made medicaments injection earlier, is mixed into anticancer sustained-release gel injection with a certain amount of amphipathic copolymer then.-10 ℃ or following storing for future use.Injection in the body after redissolving before using; This kind method is applicable to poorly water-soluble but the medicine of good stability.Can finish at workshop with mixing of amphipathic copolymer, also its independent packing transportation can be stored, before clinical practice, finish.If before clinical practice, mix, be preferably in to inject and finished and be stored in the best freezing state of low temperature in preceding 1 to 3 day, use after intensification is redissolved before using.
The content of amphipathic copolymer in the injectivity hydrogel can be 5% to 40%, but serves as preferred with 10% to 30%, and 15% to 28% for most preferably.
(4) prepare cancer therapy drug aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind cancer therapy drug aqueous solution and the abundant mixing of amphipathic copolymer, be stored in low temperature or freezing state then before injection, use the redissolution back of heating up before using;
(5) a certain amount of amphipathic copolymer is mixed with a certain amount of cancer therapy drug, add solvent then and make slow-releasing anticarcinogen injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Gel process can be finished at workshop, also amphipathic copolymer and cancer therapy drug can separately or can be mixed back packing, transportation, store, and adds solvent before clinical practice.If before clinical practice, add solvent, be preferably in and fully mix before the injection and be stored in the best freezing state of low temperature, heat up before using and redissolve the back and use.
Production technology and clinical practice requirement are depended in the packing of cancer therapy drug and sustained-release gel and application.Cancer therapy drug and sustained-release gel can separately or be organized (mixing) and close packing.Assembly packaging is stored in the unified packing box after referring to produce separately also packing, and hybrid packed finger cancer therapy drug is dispersed in the sustained-release gel.Pack alone or in combination with hybrid packed difference and be, mix with sustained-release gel before cancer therapy drug is injected in vivo when packing alone or in combination, hybrid packed then is cancer therapy drug to be dispersed in the sustained-release gel in process of production, direct injection after at room temperature heating up with preceding need.
Or
(6) a certain amount of amphipathic copolymer is mixed with a certain amount of cancer therapy drug, separately or mix back packing, transportation, store, before clinical practice, add solvent and fully mix and be stored in low temperature, heat up before using and redissolve the back and use to freezing state.
The regulator that can add 0-15% in the above method.
Said method just is used for explanation but not limitation the present invention.Wherein method " (1) " is preferred.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation.Yet the composition of the kind of medicine and content and amphipathic copolymer and monomeric weight ratio are the gelling temperature of decision slow releasing injection and the key factor of drug release behavior, must just can obtain through a large amount of tests and creative work.The viscosity of sustained-release gel is 10cp-3000cp (5 ℃-30 ℃ time), preferred 100cp-2000cp (5 ℃-30 ℃ time), most preferably 100cp-1000cp (5 ℃-30 ℃ time).
Be suitable for amphipathic copolymer of the present invention and form by polyester and Polyethylene Glycol, wherein,
Polyester and Polyethylene Glycol block are configured as: polyester-polyethylene glycol-ester or polyethylene glycol-ester-Polyethylene Glycol are first-selection with polyester-polyethylene glycol-ester; Polyester can be, but be not limited to, the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), any one or multiple copolymer in the end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH).The mean molecule quantity of above-mentioned polyester can be 500-30000, wherein is preferred with 800-20000, and 1000-10000 is for most preferably.
Polyester and polyethyleneglycol block copolymer can be, but be not limited to, polylactic acid-polyglycol-polylactic acid (PLA-PEG-PLA), Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide (PLGA-PEG-PLGA), polyethylene glycol-lactic acid-Polyethylene Glycol (PEG-PLA-PEG), Polyethylene Glycol-Vicryl Rapide-Polyethylene Glycol (PEG-PLGA-PEG), serve as preferred wherein with PLGA-PEG-PLGA and PEG-PLGA-PEG, with PLGA-PEG-PLGA for most preferably
Being suitable in the above-mentioned polyester of the present invention, serves as preferred with PLA and PLGA, with PLGA for most preferably; When select for use polylactic acid/ethanol copolymer (D, in the time of L-PLGA), the weight ratio of lactic acid and hydroxyacetic acid plays important regulating action to control drug release, the weight ratio of the two can be 15-1: 1; Wherein with 9-1: 1 serves as preferred, and with 5-1: 1 for most preferably.In other words, the blend ratio of lactic acid (LA) and glycolic (GA) can be 95/5 to 60/40 (weight), is preferably 75/25 to 40/60 (weight), with 75/25 to 50/50 (weight) for most preferably.The method of blend is arbitrarily.The molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be, but is not limited to, 300-30, and 000, but with 500-20,000 is preferred, with 1000-10,000 for most preferably
The mean molecule quantity of amphipathic copolymer can be 500-28000, wherein is preferred with 600-16000, and 1000-8000 is for most preferably; In the amphipathic copolymer, the weight ratio of polyester and Polyethylene Glycol can be 9-6: 1-4, with 9-7: 1-3 serves as preferred, with 9-7: 1-2 for most preferably, in other words, the percentage by weight of Polyethylene Glycol can be 5%-40% in the amphipathic copolymer, with 7% to 30% serves as preferred, and with 10% to 25% for most preferably, the percentage by weight of polyester can be 60%-95%, with 70% to 93% serves as preferred, with 75% to 90% for most preferably;
The gelling temperature of amphipathic copolymer promptly becomes the not temperature of flow-gel, can be 30 ℃-37 ℃, serves as preferred with 31 ℃-36.5 ℃, with 32 ℃-36 ℃ for most preferably.
The mean molecule quantity of Polyethylene Glycol can be 200-20000, wherein is preferred with 300-10000, and 500-3000 is for most preferably.
But the solvent in the sustained-release gel system for sterilization after the liquid of injection in the body, as, but be not limited to, distilled water, water for injection, physiology is towards liquid, cell culture fluid, the buffer of body fluid, tissue fluid or the preparation of various salt, as, but be not limited to phosphate buffer.The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, but must operate in strict accordance with related standards.The percentage by weight of solvent in slow releasing injection is 60%-90%, is preferred with 70%-90%, with 75%-85% for most preferably.
The present invention finds that also when adding materials such as mannitol, sorbitol in the sustained-release gel, variation to a certain degree can take place for gelling temperature and drug releasing rate, and the material of this type of scalable drug releasing rate or gelling temperature is called regulator.The regulator that can add in the sustained-release gel can be, but be not limited to a kind of or its combination in various sugar or salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, the albumin glue.Regulator can be other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.Its weight ratio in sustained-release gel can be 0.01%-15.0%, because of specifically needing to decide.
The route of administration of slow releasing injection depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, arterial thrombosis, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
The tumor of above-mentioned internal organs can be different histological type, and why the tumor of the lymph node of lymph node divides outstanding golden lymphoma and non_hodgkin lymphoma, and pulmonary carcinoma comprises small cell lung cancer and nonsmall-cell lung cancer etc., and the cerebral tumor comprises glioma etc.Yet common tumor comprises entity tumors such as the retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis of the cerebral tumor, cerebral glioma, renal carcinoma, hepatocarcinoma, carcinoma of gallbladder, cancer of biliary duct, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, hemangioma, osteosarcoma, lymphoma, pulmonary carcinoma, thymic carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, eyes.Except that above-mentioned primary tumo(u)r, its metastatic tumor of locating at brain, central nervous system, spinal cord, spinal column, kidney, adrenal gland, liver, incidence, oral cavity, thyroid, skin, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum etc. also makes indication of the present invention.
Slow releasing injection can be used for the tumor resection postoperative, can effectively control remaining oncocyte, thereby the may command postoperative recurrence; Can be used for the patient that a variety of causes can not excision; Can be used for controlling metastatic lesion, as lymph node etc.; Be used for end-stage patients; The control late complication; With the associating of its cancer therapy drug or method, as local injection associating, and the associating of radiotherapy or immunization therapy of cancer therapy drug and the chemotherapeutics of other administration.
The clinical practice dosage of cancer therapy drug depends on patient's concrete condition, comprises age, body weight, sex, tumor type, tumor locus, tumor size and number, treatment experience.Can be from 0.001 to 1000mg/kg body weight, be preferred with 0.1-500mg/kg, 0.5-300mg/kg is for most preferably.But for the sustained-release gel injection made from the crude drug of clinical whole body administration, its medication total amount can be more than the several times of its intravenous administration maximum tolerated dose.
Also can add other medicinal ingredient in the made slow releasing injection of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
(4) specific embodiment
Embodiment 1.
With 4,2,1 and 0.5g amphipathic nature block polymer (PLGA-PEG-PLGA) put into first, second, third, four containers of fourth respectively, then respectively to first, second, third and four containers of fourth in add 6,8,9 and 9.5 milliliters of waters of injection, make 40%, 20%, 10% and 5% hydrogel.
The molecular weight of Polyethylene Glycol is 800-1200 in the amphipathic nature block polymer, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6: 1.
The preparation of microsphere prepares with multi-emulsion method or O/W method, adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000, and the weight ratio of copolymer and edelfosine is 9: 1.
Embodiment 2.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 1, the result shows that the gelling temperature of 40% and 20% hydrogel is respectively 32 ℃ (40%) and 37.5 ℃ (20%), and does not measure under 12 ℃-38.5 ℃ of the gelling temperatures of 10% and 5% hydrogel
Embodiment 3.
With 4,2,1 and 0.5g amphipathic nature block polymer (PLGA-PEG-PLGA) put into first, second, third, four containers of fourth respectively, then respectively to first, second, third and four containers of fourth in add 6,8,9 and 9.5 milliliters of waters of injection, make 40%, 20%, 10% and 5% hydrogel.
The molecular weight of Polyethylene Glycol is 1200-1600 in the amphipathic nature block polymer, accounts for 15% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 5: 1.
The preparation of microsphere prepares with multi-emulsion method or O/W method, adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 20000-35,000, the weight ratio of copolymer and edelfosine is 6: 4.
Embodiment 4.
Measure the gelling temperature of four kinds of hydrogels among the embodiment 3, the result show 40% and 20% hydrogel gelling temperature be respectively 29 ℃ (40%) and 36 ℃ (20%), and do not measure under 10 ℃-39 ℃ of the gelling temperatures of 10% and 5% hydrogel.
Above result of the test shows, when gel solution concentration is lower than 5%-10%, and the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection
Embodiment 5.
(molecular weight of Polyethylene Glycol is 1500 among the amphipathic nature block polymer PLGA-PEG-PLGA, accounts for 15% of amphipathic nature block polymer weight with the 2.5g amphipathic nature block polymer; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4: 1) put into container, add 7.5 milliliters of normal saline then, make 25% copolymer aquagel.Then average mark install to 5 fill respectively 400,200,100,20 and the container of 2mg edelfosine in, make and contain 20%, 10%, 5%, 1% and the anticancer sustained-release gel injection of 0.1%edelfosine.Record its gelling temperature and be respectively 37,35,34,31 and 29 ℃.
Embodiment 6.
(molecular weight of Polyethylene Glycol is 1600 among the amphipathic nature block polymer PLGA-PEG-PLGA, accounts for 15% of amphipathic nature block polymer weight with the 2.5g amphipathic nature block polymer; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 5: 1) put into container, add 7.5 milliliters of normal saline then, make 25% copolymer aquagel.Then average mark install to 5 fill respectively 400,200,100,20 and the container of 2mg edelfosine in, make and contain 20%, 10%, 5%, 1% and the anticancer sustained-release gel injection of 0.1%edelfosine.Record its gelling temperature and be respectively 37.5,36,33,32 and 31 ℃.
Embodiment 7.
Measure (subcutaneous) release cycle in the mice body of variable concentrations edelfosine of embodiment 5 and 6, found that 20%, 10%, 5%, 1% and the 0.1%edelfosine body in average time (estimating) of discharging can measure the time in the blood be respectively 84,77,62,52 and 48 days; 20%, 10%, 5%, 1% and the body of 0.1%edelfosine in average time of discharging be respectively 84,76,66,56 and 46 days.
Embodiment 8.
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find that the concentration and the medicine of block copolymer aqueous solution are as follows in the gel injection weight percentage ranges in the preferred sustained-release gel injection:
The block copolymer aqueous solution of 10%-30% contains 0.005%-30%edelfosine; Or
The block copolymer aqueous solution of 10%-30% contains 0.05%-30%edelfosine.
The gelling temperature of above-mentioned anticancer sustained-release gel injection is 31 ℃-37 ℃, and medicine is distributed in the gel with the form of micropowder, and be 2-8 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1000-1600, accounts for the 15-25% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 6-9: 1.
Embodiment 9.
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find that the concentration and the medicine of block copolymer aqueous solution also comprise one of row in the gel injection weight percentage ranges in the preferred sustained-release gel injection:
The block copolymer aqueous solution of 20%-25% contains 0.5%-20%edelfosine; Or
The block copolymer aqueous solution of 20%-26% contains 0.5%-10%edelfosine.
Medicine in the above-mentioned anticancer sustained-release gel injection is a sustained-release micro-spheres, and gelling temperature is 31 ℃-38.5 ℃, and be 3-9 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1000-1600, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-9: 1;
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
Embodiment 10
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, preferred anticancer sustained-release gel injection also comprises and followingly contains concentration, becomes to be grouped into and percentage by weight:
(1) 1%edelfosine, formulated by 10mg edelfosine, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 5%edelfosine, formulated by 50mg edelfosine, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 10%edelfosine, formulated by 100mg edelfosine, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 2%edelfosine, formulated by 20mg edelfosine, 260mg amphipathic nature block polymer and 740ul normal saline;
(5) 15%edelfosine, formulated by 150mg edelfosine, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(6) 20%edelfosine, formulated by 200mg edelfosine, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
(7) 25%edelfosine, formulated by 250mg edelfosine, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(8) 30%edelfosine, formulated by 300mg edelfosine, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
Medicine in the above-mentioned anticancer sustained-release gel injection is drug powder and sustained-release micro-spheres, and gelling temperature is 32 ℃-37 ℃, and be 5-12 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1200-1600, accounts for 18% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 3-6: 1.
The therapeutic effect of anticancer sustained-release gel injection can further specify by following test and treatment embodiment:
Embodiment 11
Use more convenient according to the anticancer sustained-release gel injection that method " (1) " makes, 1-6 makes multiple anticancer sustained-release gel injection in conjunction with the embodiments, discharge in gelling temperature and the body after measured and find, it is one of following that preferred anticancer sustained-release gel injection also comprises:
(1) 0.05%edelfosine, formulated by 1mg edelfosine, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1%edelfosine, formulated by 10mg edelfosine, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2%edelfosine, formulated by 20mg edelfosine, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 4%edelfosine, formulated by 40mg edelfosine, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 10%edelfosine, formulated by 100mg edelfosine, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 20%edelfosine, formulated by 200mg edelfosine, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 0.5%edelfosine, formulated by 5mg edelfosine, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 1%edelfosine, formulated by 10m edelfosine, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 5%edelfosine, formulated by 50mg edelfosine, 230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline;
(10) 10%edelfosine, formulated by 100mg edelfosine, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection;
(11) 8%edelfosine, formulated by 80mg edelfosine, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 1%edelfosine, formulated by 10mg edelfosine, 200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline;
(13) 1.25%edelfosine, formulated by 12.5mg edelfosine, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(14) 5%edelfosine, formulated by 50mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection
(15) 10%edelfosine, formulated by 100mg edelfosine, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(16) 15%edelfosine, formulated by 15mg edelfosine, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 20%edelfosine, formulated by 200mg edelfosine, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline;
(18) 25%edelfosine, formulated by 250mg edelfosine, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 30%edelfosine, formulated by 300mg edelfosine, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(20) 35%edelfosine, formulated by 350mg edelfosine, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Medicine in the above-mentioned anticancer sustained-release gel injection is drug powder and sustained-release micro-spheres, and its gelling temperature is 31 ℃-37 ℃, and be 4-16 week release time in the animal body.When gel solution concentration is lower than 5%-12%, the gelation reaction instability, viscosity is too low; When gel solution concentration was higher than 30%-40%, gelation reaction was subjected to drug influence obvious, and viscosity is too big, was unfavorable for injection.
Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000.
Above amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1300-1600, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-6: 1.
Embodiment 12
With the rat is subjects, with 2 * 105 breast cancer tumour cell subcutaneous injections in its hypochondrium, treat to be divided into 4 groups behind tumor growth to 1 cm diameter, contain 20%, 10%, 0.1% and the anticancer sustained-release gel injection of 0%edelfosine among the intratumor injection 0.1ml embodiment 5 respectively.Measure gross tumor volume every day, the result shows that the edelfosine anticancer sustained-release gel injection can significantly suppress tumor growth, and its tumor-inhibiting action is obvious dose dependent.30% concentration is safety still.Intratumor injection slow releasing injection operation most convenient, easy.
Embodiment 13
With the rat is subjects, with 2 * 105 prostate tumor cells subcutaneous injections in its hypochondrium, treat to be divided into 4 groups behind tumor growth to 0.5 cm diameter, contain 20%, 10%, 0.1% and the anticancer sustained-release gel injection of 0%edelfosine among the intratumor injection 0.5ml embodiment 5 respectively.Measure gross tumor volume every day, the result shows that the edelfosine anticancer sustained-release gel injection can significantly suppress tumor growth, and its tumor-inhibiting action is obvious dose dependent.20% concentration is safety still.Effective, the operation most convenient, easy of intratumor injection slow releasing injection.Good effect not only, toxic and side effects is also little.
Embodiment 14, contain tumor-inhibiting action in the body of anti-cancer medicine sustained-release injection
With the rat is subjects, with 2 * 10
5Individual oophoroma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 20 days is divided into it following 7 groups (seeing Table 1).Medicine is selected from embodiment 10, through intratumor injection.Dosage is 0.1ml, only is equivalent to 5mg-25mg/.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(5) | Contrast | 52±12 | |
| 2(5) | 5％edelfosine | 46±8.2 | ＜0.05 |
| 3(5) | 10％edelfosine | 40±6.8 | ＜0.01 |
| 4(5) | 15％edelfosine | 36±5.0 | ＜0.01 |
| 5(5) | 20％edelfosine | 28±6.0 | ＜0.001 |
| 6(5) | 25％edelfosine | 22±4.0 | ＜0.001 |
| 7(5) | 30％edelfosine | 18±3.0 | ＜0.001 |
Above result shows that anti-cancer medicine sustained-release injection all has the obvious suppression effect to the oophoroma tumor growth of tumour cell under this concentration, and is dose-effect relationship.
The tumor-inhibiting action of embodiment 15, anti-cancer medicine sustained-release injection
With the rat is subjects, with 2 * 10
5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 6 groups (seeing Table 2).Slow releasing injection is selected from embodiment 10, places in tumor.Cancer therapy drug dosage only is 0.2ml/, only is equivalent to 0.2mg-10mg/.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 30th day.
Table 2
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(5) | Contrast | 52±12 | |
| 2(5) | 1％edelfosine | 44±9 | ＜0.05 |
| 3(5) | 4％edelfosine | 38±8.6 | ＜0.001 |
| 4(5) | 10％edelfosine | 32±6.8 | ＜0.001 |
| 5(5) | 20％edelfosine | 28±4.6 | ＜0.001 |
| 6(6) | 30％edelfosine | 22±3.6 | ＜0.001 |
Above result shows that used anti-cancer medicine sustained-release injection all has the obvious suppression effect to the hepatocarcinoma growth of tumour cell when this concentration, and is dose dependent.
The tumor-inhibiting action of embodiment 16, anti-cancer medicine sustained-release injection
With the rat is subjects, with 2 * 10
5Pulmonary carcinoma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 6 groups (seeing Table 3).Slow releasing injection is selected from embodiment 10, places in tumor.Cancer therapy drug dosage only is 0.5ml/, only is equivalent to 0.5mg-35mg/.The treatment back was measured the gross tumor volume size on the 30th day, compared therapeutic effect, calculated tumor control rate according to following formula:
Tumor control rate (%)=((matched group gross tumor volume treatment group gross tumor volume)/matched group gross tumor volume) * 100 (%).
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(5) | Contrast | 50±10 | |
| 2(5) | 1％edelfosine | 46±8.0 | ＜0.05 |
| 3(5) | 4％edelfosine | 40±6.6 | ＜0.001 |
| 4(5) | 10％edelfosine | 34±4.6 | ＜0.001 |
| 5(5) | 20％edelfosine | 28±4.2 | ＜0.001 |
| 6(6) | 30％edelfosine | 22±3.8 | ＜0.001 |
Above result shows that used anti-cancer medicine sustained-release injection all has the obvious suppression effect to the hepatocarcinoma growth of tumour cell when this concentration, and is dose dependent.
The tumor-inhibiting action of embodiment 17 anti-cancer medicine sustained-release injections
With the rat is subjects, with 2 * 10
5Esophageal carcinoma tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 6 groups (seeing Table 4).Slow releasing injection is selected from embodiment 11, places in tumor.Cancer therapy drug dosage only is 0.2ml/, only is equivalent to 2mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 4) on the 30th day.
Table 4
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(5) | Contrast | 54±12 | |
| 2(5) | 1％edelfosine | 46±10 | ＜0.05 |
| 3(5) | 4％edelfosine | 42±6.6 | ＜0.001 |
| 4(5) | 10％edelfosine | 36±5.8 | ＜0.001 |
| 5(5) | 20％edelfosine | 32±4.4 | ＜0.001 |
| 6(6) | 30％edelfosine | 22±3.8 | ＜0.001 |
Above result shows that used anti-cancer medicine sustained-release injection all has the obvious suppression effect to the hepatocarcinoma growth of tumour cell when this concentration, and is dose dependent.
The tumor-inhibiting action of embodiment 18, anticancer medicine slow-release preparation containing
With the rat is subjects, with 2 * 10
5Individual cervical cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 6 groups (seeing Table 5).First group is contrast, and the 2nd to 6 group is the treatment group, and slow releasing injection is selected from embodiment 11, places in tumor.Cancer therapy drug dosage only is 0.2ml/, only is equivalent to 2mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 5) on the 30th day.
Table 5
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(5) | Contrast | 48±10 | |
| 2(5) | 1％edelfosine | 42±8.4 | ＜0.05 |
| 3(5) | 4％edelfosine | 36±6.6 | ＜0.001 |
| 4(5) | 10％edelfosine | 32±5.6 | ＜0.001 |
| 5(5) | 20％edelfosine | 22±5.0 | ＜0.001 |
| 6(6) | 30％edelfosine | 18±4.8 | ＜0.001 |
Above result shows that used anti-cancer medicine sustained-release injection all has the obvious suppression effect to the hepatocarcinoma growth of tumour cell when this concentration, and is dose dependent.
The tumor-inhibiting action of embodiment 19, anticancer medicine slow-release preparation containing
With the rat is subjects, with 2 * 10
5Individual gastric cancer tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 6 groups (seeing Table 6).First group is contrast, and the 2nd to 6 group is the treatment group, and slow releasing injection is selected from embodiment 11, places in tumor.Cancer therapy drug dosage only is 0.25ml/, only is equivalent to 12.5mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 6) on the 30th day.
Table 6
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(5) | Contrast | 46±10 | |
| 2(5) | 1％edelfosine | 42±8.2 | ＞0.05 |
| 3(5) | 4％edelfosine | 38±6.6 | ＜0.05 |
| 4(5) | 10％edelfosine | 28±6.0 | ＜0.01 |
| 5(5) | 20％edelfosine | 22±5.0 | ＜0.001 |
| 6(6) | 30％edelfosine | 18±4.4 | ＜0.001 |
Above result shows that used anti-cancer medicine sustained-release injection all has the obvious suppression effect to the hepatocarcinoma growth of tumour cell when this concentration, and is dose dependent.
The tumor-inhibiting action of embodiment 20, anticarcinogen agent slow releasing agent
With the rat is subjects, with 2 * 10
5Individual rectal cancer tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 6 groups (seeing Table 7).First group is contrast, and the 2nd to 6 group is the treatment group, and slow releasing injection is selected from embodiment 8 (micropowder) and 9 (microspheres), places in tumor.Cancer therapy drug dosage only is 0.25ml/, only is equivalent to 12.5mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 7) on the 30th day.
Table 7
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(5) | Contrast | - | |
| 2(5) | 2%edelfosine (micropowder) | 38 | ＜0.05 |
| 3(5) | 2%edelfosine (microsphere) | 44 | ＜0.01 |
| 4(5) | 5%edelfosine (micropowder) | 50 | ＜0.05 |
| 5(5) | 5%edelfosine (microsphere) | 60 | ＜0.01 |
| 6(5) | 10%edelfosine (micropowder) | 58 | ＜0.01 |
| 7(5) | 10%edelfosine (microsphere) | 72 | ＜0.01 |
| 8(5) | 15%edelfosine (micropowder) | 62 | ＜0.01 |
| 9(5) | 15%edelfosine (microsphere) | 74 | ＜0.01 |
| 10(5) | 20%edelfosine (micropowder) | 76 | ＜0.01 |
| 11(5) | 20%edelfosine (microsphere) | 82 | ＜0.001 |
Above result shows that used anti-cancer medicine slow release gel injection all has the obvious suppression effect to many gastric cancer growth of tumour cell when this concentration, and wherein microsphere is than the micropowder better effects if.
The tumor-inhibiting action of embodiment 21, anticancer medicine slow-release preparation containing
With the rat is subjects, with 2 * 10
5Individual breast cancer tumour cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 8).First group is contrast, and the 2nd to 11 group is the treatment group, and release injectable is placed in tumor from embodiment 8 (micropowder) and 9 (microspheres) and 10 (micropowder and microsphere).Cancer therapy drug dosage only is 0.25ml/, only is equivalent to 12.5mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 8) on the 30th day.
Table 8
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(5) | Contrast | - | |
| 2(5) | 5%edelfosine (micropowder) | 44 | ＜0.05 |
| 3(5) | 5%edelfosine (microsphere) | 52 | ＜0.05 |
| 4(5) | 5%edelfosine (micropowder and microsphere) | 602 | ＜0.01 |
| 5(5) | 10%edelfosine (micropowder) | 58 | ＜0.05 |
| 6(5) | 10%edelfosine (microsphere) | 66 | ＜0.01 |
| 7(5) | 10%edelfosine (micropowder and microsphere) | 72 | ＜0.001 |
| 8(5) | 20%edelfosine (micropowder) | 66 | ＜0.01 |
| 9(5) | 20%edelfosine (microsphere) | 74 | ＜0.01 |
| 10(5) | 20%edelfosine (micropowder and microsphere) | 82 | ＜0.001 |
Above result shows that used anti-cancer medicine slow release gel injection all has the obvious suppression effect to the renal carcinoma growth of tumour cell when this concentration, and wherein microsphere is better than the micropowder effect, and micropowder and microsphere are best.
The tumor-inhibiting action of embodiment 22, anticancer medicine slow-release preparation containing
With the rat is subjects, with 2 * 10
5Individual breast cancer tumour cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 21 days is divided into it following 11 groups (seeing Table 9).First group is contrast, and the 2nd to 11 group is the treatment group, and release injectable is placed in tumor from embodiment 8 (micropowder) and 9 (microspheres) and 10 (micropowder and microsphere).Cancer therapy drug dosage only is 0.25ml/, only is equivalent to 12.5mg-20mg/.The treatment back was measured gross tumor volume size, comparison of tumor suppression ratio (seeing Table 9) on the 30th day.
Table 9
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(5) | Contrast | - | |
| 2(5) | 1%edelfosine (micropowder) | 30 | ＜0.05 |
| 3(5) | 1%edelfosine (microsphere) | 34 | ＜0.05 |
| 4(5) | 1%edelfosine (micropowder and microsphere) | 40 | ＜0.01 |
| 5(5) | 5%edelfosine (micropowder) | 44 | ＜0.05 |
| 6(5) | 5%edelfosine (microsphere) | 48 | ＜0.01 |
| 7(5) | 5%edelfosine (micropowder and microsphere) | 54 | ＜0.001 |
| 8(5) | 15%edelfosine (micropowder) | 64 | ＜0.01 |
| 9(5) | 15%edelfosine (microsphere) | 76 | ＜0.01 |
| 10(5) | 15%edelfosine (micropowder and microsphere) | 82 | ＜0.001 |
Above result shows that used anti-cancer medicine slow release gel injection all has the obvious suppression effect to the renal carcinoma growth of tumour cell when this concentration, and wherein microsphere is better than the micropowder effect, and micropowder and microsphere are best.
Discover that further used anti-cancer medicine slow release gel injection all has the obvious suppression effect to growth of tumour cell such as carcinoma of the colon and rectum, ovarian cancer, the cerebral tumor, bladder cancer
In a word, growth all has the obvious suppression effect to used anti-cancer medicine sustained-release injection to kinds of tumor cells.Its inhibitory action to tumor is tangible dose-effect relationship.
Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
The present invention disclosed and the protection the content see claim.
Claims (10)
1. slow-releasing anticarcinogen injection that contains octadecyl methyl glyceryl phosphocholine (edelfosine) is characterized in that slow releasing injection contains following constituent:
A: octadecyl methyl glyceryl phosphocholine 0.01-40%
B: amphipathic copolymer 5%-40%
C: solvent 60%-90%
D: regulator 0-15%
More than be weight percentage,
Wherein, edelfosine exists with the form of sustained-release micro-spheres or microsphere and micropowder in the slow releasing agent injection, be that cancer therapy drug partly or entirely is wrapped in the sustained-release micro-spheres, the part drug release that is wrapped in the microsphere is slow, help controlling the tumor cell that enters rest period, the medicine that exists with the micropowder form in sustained-release gel helps discharging very fast relatively, helps controlling the cell faster that rises in value, and the two is united and helps steadily slowly release of medicine;
Amphipathic copolymer is the block structure of polyester and Polyethylene Glycol, is selected from polylactic acid poly ethylene glycol polylactic acid, Vicryl Rapide Polyethylene Glycol Vicryl Rapide, Polyethylene Glycol polylactic acid poly ethylene glycol or Polyethylene Glycol Vicryl Rapide Polyethylene Glycol;
Regulator is selected from a kind of or its combination in sugar, salt, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40, Tween 80, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, collagen protein, gelatin, the albumin glue.
2. the slow-releasing anticarcinogen injection according to claim 1, but it is characterized in that solvent is the aqueous solution of injecting in the body after the sterilization, is selected from distilled water, water for injection, physiology towards liquid, cell culture fluid, body fluid, tissue fluid, buffer, phosphate buffer.Wherein, the percentage ratio of solvent in the hydrogel of amphipathic nature block polymer and solvent composition is 60%-99%.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the mean molecule quantity of amphipathic nature block polymer is selected from 500-5000,5000-20000,20000-30000.
4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is selected from 10-15 in the Vicryl Rapide: 1,5-10: 1 or 1-5: 1.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the mean molecule quantity of Polyethylene Glycol can be 200-20000.
6. it is one of following that the slow-releasing anticarcinogen injection according to claim 1, the preparation method that it is characterized in that described slow-releasing anticarcinogen injection are selected from:
(1) prepares amphipathic aqueous copolymers solution with solvent earlier, add a certain amount of cancer therapy drug then, become anticancer sustained-release gel injection behind the dissolving mixing.-10 ℃ or following storing for future use.Injection in redissolution, the body before using;
(2) prepare amphipathic aqueous copolymers solution and cancer therapy drug respectively, packing stores separately, injection is preceding to be stored in low temperature or freezing state then with making anticancer sustained-release gel injection behind amphipathic aqueous copolymers solution and the abundant mixing of cancer therapy drug, uses after intensification is redissolved before using;
(3) the preparation cancer therapy drug is made medicaments injection earlier, is mixed into anticancer sustained-release gel injection with a certain amount of amphipathic copolymer then.-10 ℃ or following storing for future use.Injection in the body after redissolving before using;
(4) prepare cancer therapy drug aqueous solution and amphipathic copolymer respectively, packing stores separately, with making anticancer sustained-release gel injection behind cancer therapy drug aqueous solution and the abundant mixing of amphipathic copolymer, be stored in low temperature or freezing state then before injection, use the redissolution back of heating up before using;
(5) a certain amount of amphipathic copolymer is mixed with a certain amount of cancer therapy drug, add solvent then and make slow-releasing anticarcinogen injection.Be stored in low temperature or freezing state, use the redissolution back of heating up before using; Or
(6) a certain amount of amphipathic copolymer is mixed with a certain amount of cancer therapy drug, separately or mix back packing, transportation, store, before clinical practice, add solvent and fully mix and be stored in low temperature, heat up before using and redissolve the back and use to freezing state.
7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that described slow-releasing anticarcinogen injection contains one of following ingredients:
(1) 1%edelfosine, formulated by 10mgedelfosine, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 5%edelfosine, formulated by 50mgedelfosine, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 10%edelfosine, formulated by 100mgedelfosine, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 2%edelfosine, formulated by 20mgedelfosine, 260mg amphipathic nature block polymer and 740ul normal saline;
(5) 15%edelfosine, formulated by 150mgedelfosine, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(6) 20%edelfosine, formulated by 200mgedelfosine, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
(7) 25%edelfosine, formulated by 250mgedelfosine, 230mg amphipathic nature block polymer, 70mg mannitol and 700ul normal saline;
(8) 30%edelfosine, formulated by 300mgedelfosine, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer.
Above amphipathic nature block polymer is a Vicryl Rapide Polyethylene Glycol Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1200-1600, accounts for 18% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 3-6: 1.
8. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that described slow-releasing anticarcinogen injection contains one of following ingredients:
(1) 0.05%edelfosine, formulated by 1mgedelfosine, 300mg amphipathic nature block polymer and 700ul water for injection;
(2) 1%edelfosine, formulated by 10mgedelfosine, 280mg amphipathic nature block polymer and 720ul distilled water;
(3) 2%edelfosine, formulated by 20mgedelfosine, 250mg amphipathic nature block polymer and 750ul normal saline;
(4) 4%edelfosine, formulated by 40mgedelfosine, 230mg amphipathic nature block polymer and 770ul water for injection;
(5) 10%edelfosine, formulated by 100mgedelfosine, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(6) 20%edelfosine, formulated by 200mgedelfosine, 260mg amphipathic nature block polymer and 740ul normal saline;
(7) 0.5%edelfosine, formulated by 5mgedelfosine, 280mg amphipathic nature block polymer, 200mg mannitol and 700ul water for injection;
(8) 1%edelfosine, formulated by 10mgedelfosine, 260mg amphipathic nature block polymer, 30mg mannitol, 710ul distilled water;
(9) 5%edelfosine, formulated by 50mgedelfosine, 230mg amphipathic nature block polymer, 40mg mannitol and 730ul normal saline;
(10) 10%edelfosine, formulated by 100mgedelfosine, 200mg amphipathic nature block polymer, 50mg mannitol and 750ul water for injection;
(11) 8%edelfosine, formulated by 80mgedelfosine, 260mg amphipathic nature block polymer and 740ul phosphate buffer;
(12) 1%edelfosine, formulated by 10mgedelfosine, 200mg amphipathic nature block polymer, 20mg sorbitol and 780ul normal saline;
(13) 1.25%edelfosine, formulated by 12.5mgedelfosine, 230mg amphipathic nature block polymer, 0.07g mannitol and 700ul normal saline;
(14) 5%edelfosine, formulated by 50mg amphipathic nature block polymer, 10mg mannitol and 790ul water for injection;
(15) 10%edelfosine, formulated by 100mgedelfosine, 220mg amphipathic nature block polymer and 780ul phosphate buffer;
(16) 15%edelfosine, formulated by 15mgedelfosine, 200mg amphipathic nature block polymer, 10mg sorbitol and 790ul normal saline.
(17) 20%edelfosine, formulated by 200medelfosine, 230mg amphipathic nature block polymer, 90mg mannitol and 780ul normal saline;
(18) 25%edelfosine, formulated by 250mgedelfosine, 230mg amphipathic nature block polymer, 20mg mannitol and 750ul water for injection;
(19) 30%edelfosine, formulated by 300mgedelfosine, 220mg amphipathic nature block polymer, 20mg mannitol and 760uml phosphate buffer; Or
(20) 35%edelfosine, formulated by 350mgedelfosine, 250mg amphipathic nature block polymer, 60mg sorbitol, 690ul normal saline.
Medicine in the above-mentioned anticancer sustained-release gel injection is drug powder and sustained-release micro-spheres, and its gelling temperature is 33 ℃-37 ℃, and be 4-16 week release time in the animal body; Adjuvant in the sustained-release micro-spheres is polylactic acid/ethanol copolymer, and wherein, lactic acid (LA) can be 75/25 (W/W) with the blend ratio of glycolic (GA), and the molecular weight of the copolymer of lactic acid and glycolic (PLGA) can be 15000-38000; Amphipathic nature block polymer is Vicryl Rapide-Polyethylene Glycol-Vicryl Rapide, and wherein the molecular weight of Polyethylene Glycol is 1300-1600, accounts for 20% of amphipathic nature block polymer weight; In the Vicryl Rapide, the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is 4-6: 1.
9. the anticancer sustained-release gel injection according to claim 1 is characterized in that the injection of described anticancer slow-release is in subcutaneous, intracavity, abdominal cavity, thoracic cavity, canalis spinalis, in the tumor, in tumor week, tremulous pulse, lymph node and inject in the bone marrow.
10. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that described slow releasing injection is used to prepare former or the cancer of transfer or the anti-cancer drug preparation of sarcoma or carcinosarcoma that treatment originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008103021998A CN101347409A (en) | 2008-06-19 | 2008-06-19 | Sustained-release injection containing octadecyl dimethyl-4-piperidine phosphate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008103021998A CN101347409A (en) | 2008-06-19 | 2008-06-19 | Sustained-release injection containing octadecyl dimethyl-4-piperidine phosphate |
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| Publication Number | Publication Date |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013107839A3 (en) * | 2012-01-20 | 2013-11-14 | Technische Universität Graz | Phospholipid compounds for use in skin cancer treatment |
| CN112999432A (en) * | 2021-03-15 | 2021-06-22 | 上海交通大学 | Preparation method of flexible brain nerve electrode coating and electrode assembled by same |
-
2008
- 2008-06-19 CN CNA2008103021998A patent/CN101347409A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013107839A3 (en) * | 2012-01-20 | 2013-11-14 | Technische Universität Graz | Phospholipid compounds for use in skin cancer treatment |
| CN112999432A (en) * | 2021-03-15 | 2021-06-22 | 上海交通大学 | Preparation method of flexible brain nerve electrode coating and electrode assembled by same |
| CN112999432B (en) * | 2021-03-15 | 2022-05-20 | 上海交通大学 | Preparation method of flexible brain nerve electrode coating and electrode assembled by same |
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