CN1088777A - The preparation method that is used for the chemotherapeutic preparation of directly administering to cancer nidus - Google Patents
The preparation method that is used for the chemotherapeutic preparation of directly administering to cancer nidus Download PDFInfo
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- CN1088777A CN1088777A CN 92114977 CN92114977A CN1088777A CN 1088777 A CN1088777 A CN 1088777A CN 92114977 CN92114977 CN 92114977 CN 92114977 A CN92114977 A CN 92114977A CN 1088777 A CN1088777 A CN 1088777A
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Abstract
The present invention is the preparation method that is used for the chemotherapeutic preparation of directly administering to cancer nidus, belongs to anti-cancer drug preparation technology.The present invention is under the prerequisite of the liposome of not choosing the whole body administration, again at the Cell cycle non-specific cancer therapy drug, drug level doubles when administration, curative effect can improve several times to tens times characteristics, and the two class targeting administration rates that provide level off to the preparation method of suspension type slow releasing injection and Injectable sustained release liposome of 100% carcinoma entity direct injection.
Description
The invention belongs to anti-cancer drug preparation technology.
Cancer is worldwide generally acknowledged obstinate disease, existing tens of kinds more than of the cancer therapy drug that the approval of countries in the world government is used.Great majority all are whole body administration therapeutic methods such as oral, quiet notes, intracavity, intramuscular injection.This kind chemotherapy has the growth of inhibition and killing action to carcinoma really.But when carcinoma is suppressed or is partly killed, human normal tissue (hemopoietic system, detoxification system, genitourinary system etc.) also is subjected to wrecking greatly and injuring accordingly, cause at last human normal tissue never can resist the efficacy of a drug injury and be forced to drug withdrawal midway.Because carcinoma is organized and thoroughly do not killed, cause carcinoma recurrence in a period of time after the chemotherapy, transfer etc. to become certainty.Therefore people place on hope in the research of targeting good anticancer preparation liposome.The preparation method of existing liposome has membrane process, reverse evaporation, injection method, surfactant dilution method, squeezing and pressing method etc.But the liposome that conventional method is made (solution) all exists, and envelop rate is low, storage period is short, easily unload the problem that leakage waits, after freezing, the spray drying liposome dry product of gained also exist easy adhesion, moisture absorption, become sour rotten and redissolve with distilled water when using after the difficult problem such as press filtration homogenize of still needing.Simultaneously to say objectively liposome is not only carcinoma to be had bigger affinity, and is very high in abundances such as the abundant tissue of phagocyte such as liver, spleen, bone, marrow lungs yet.Therefore say that the targeting of liposome also is relative.Corresponding toxicities after the administration also is unavoidable.
The objective of the invention is to can be used under the preceding topic of whole body administration not discharging this liposome, at the Cell cycle non-specific cancer therapy drug, drug level doubles when administration, curative effect can improve several times to its characteristics of tens times, provides two classes and is more suitable for suspension type slow releasing injection and Injectable sustained release liposome in carcinoma entity direct administration targeting administration rate nearly 100%.
The chemotherapeutic preparation that is used for the direct administration of carcinoma kitchen range of the present invention mainly comprises suspension type slow releasing injection and three kinds of Liposomal formulations.Its selected medicine for those have cancer therapy drug that cytotoxicity can directly play a role in the carcinoma entity as: cell cycle nonspecific agent (CCNSA) biases toward cancer entity direct injection.The alkylating agent class: cyclophosphamide, ifosfamide, chlorambucil, melphalan, mustine hydrochlcride, plug replace group etc.; Nitrous urine class; First ring nitrous urine carmustine, hexamethylene nitrous urine etc.; Antitumor antibiotics class: dactinomycin, amycin, epirubicin, daunorubicin, mitomycin etc.; Miscellany: mitoxantrone, methylbenzyl hydrazine, cisplatin, carboplatin, arsenious acid and salt thereof etc.Cell cycle specific agents (biasing toward the whole body administrable) has vinca alkaloids, camptothecine, white element of ghost, fluorouracil, tegafur, ammonia first talk endlessly cry of certain animals, cytosine arabinoside, Bo bleomycin, Bleomycin, tetrahydroform, the thin basic purine of 6-etc.
Wherein the preparation method of suspension type slow releasing injection is: (can select medicine nonspecific drug solvent for use vegetable oil, benzyl benzyl formate, ethyl oleate etc.) after suspending agent (can select single, double Aluminium Tristearate Micronized sterile for use) gives processing respectively, suspending agent is dissolved in forms oleogel in the solvent, get final product to qualified, sterilization packing medicine and the abundant mixing of factice (or being dissolved in factice) reuse colloid mill are levigate then.
The preparation method of three kinds of Liposomal formulations wherein: be divided into cationic according to its charged situation medicine (selecting the medicine or the water-insoluble drug of stabilized aqueous solution in the above-mentioned two big class medicines for use), anionic two big class medicines, and add according to the classification of its medicine at aqueous phase and can make medicine dissolves (salify) in water acid buffer agent accordingly (as citric acid, succinic acid, acetic acid or oxalic acid etc.) or ealkaline buffer (as sodium carbonate, sodium bicarbonate, sodium phosphate, dibastic sodium phosphate etc.), oil phase (can be selected axunge for use, vegetable oil, the benzyl benzyl formate, ethyl oleate, chloroform etc.), the oil phase suspending agent (can be selected list for use, two, Aluminium Tristearate Micronized steriles etc.) matrix material (can be selected phosphatidylcholine for use, the lecithin phatidylcholine, the fabaceous lecithin phatidylcholine, the hydrogenated soybean lecithin phatidylcholine, two lauroyl lecithin phatidylcholines, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, two spermaceti phospholipid, the distearyl phosphatidyl glycerol, thioester, the cholesterol coprostenol, cholestane, Dihydrocholesterol, alpha-tocopherol etc.), the spray drying anticoagulant of high-viscosity polymer, entity injection slow releasing agent (can be selected sodium alginate for use, methylcellulose, carboxymethyl cellulose, polyethylene is than each alkane ketone, amylopectin and glue class etc.) above-mentioned former, adjuvant is standby after giving processing, medicine is dissolved in the internal layer water buffer, transfer PH4 or 9 standby, phospholipid with suspending agent and 1/3 amount, cholesterol is dissolved in oil phase (oils and fats respectively, the chloroform mixed liquor) in, under agitation add above-mentioned pastille buffer in the oil phase then, carry out emulsifying and form w/o type Emulsion, again this W/O breast is removed most of organic solvent with gentle method, form spissated W/O Emulsion, this is concentrated the newborn fluidity that contains total amount 2/3 phospholipid and cholesterol that adds under the state that stirs transfer in PH6.5～7.5 aqueous solutions, form the compound breast of W/O/W type, 1. residual organic solvent is removed in evaporation after the homogenize, promptly get the envelop rate height that can be used for the whole body administration, unload the low liposome solutions of leak rate; 2. if with this liposome solutions and the abundant mix homogeneously of high viscosity copolymer solution, promptly get the Injectable sustained release liposome solutions that can be used for directly administering to cancer nidus; 3. if compound breast of W/O/W type after the above-mentioned homogenize and high viscosity copolymer solution are carried out spray drying simultaneously, promptly get anti, the antioxidative liposome microgranule of surperficial formation one layer of polymeric thin film.
But the present invention is owing to be on the basis of not discharging the whole body administration, be based on the direct administration of carcinoma entity, therefore have following characteristics: 1. two kinds of dosage form administrations all have the carcinoma entity to get pharmaceutical quantities accurate, controlled, local drug concentration height, curative effect height, the height that takes effect, overall side effect are little, 2. two kinds of dosage forms have all been taked means such as thickening, slow release, so good, the medicine of polarization from focus unload leakage less, long action time, 3. since this liposome interior, in, outer three layers all adopted special mode to handle.Therefore the liposome made of this law is not only applicable to industrialized great production, and solved that liposome (solution) preservation term lack, is easily unloaded with Louing, envelop rate is low, the gained dry product exists after freezing, the spray drying easy adhesion, moisture absorption, become sour and when using with using a difficult problem such as particular device press filtration homogenize after the distilled water redissolution.
Prescription of the present invention, process example are:
Example 1: prescription: cyclophosphamide 45g, aluminum monostearate 20g, neuter flower oil generation is to 1000ml.
Technology: with standby learning from else's experience below cyclophosphamide comminution by gas stream to the 5 μ m by filtration, the neuter flower oil generation of sterilization, heat to 120 ℃ with 8% factice that the aluminum monostearate that steeps with oil immersion is made into, be incubated 1 hour, it is standby that the above-mentioned neuter flower oil generation of reuse is diluted to 2% oleogel mix homogeneously.With drug powder therewith oleogel fully mix, the reuse colloid mill is levigate to get final product to qualified, sterilization, packing.
Example 2: prescription and technology are: the PH that the 4g amycin is added 60ml be in 4 the 0.15M citrate buffer solution fully the dissolving back constitute standby neutral Oleum Glycines gel, 12g distearoylphosphatidylcholine phatidylcholine and the cholesterol (1: 09 mole ratio) that 30g is contained 2% aluminum monostearate of water and be dissolved in respectively in the 120g chloroform and constitute oil phase.Above-mentioned water is added in the oil phase, use the homogenizer homogenize, with w/o type Emulsion, this breast is evaporated 55～70% chloroforms under the decompression state below 50 ℃, get spissated w/o type Emulsion, this breast is contained transferring in the 600ml aqueous solution of PH7 through sodium bicarbonate of 24g distearoylphosphatidylcholine phatidylcholine and cholesterol (1: 0.7 mole ratio) in adding under the condition of stirring, be emulsified into W/O/W type multiple emulsion, then with this compound breast and the 600ml aqueous solution that contains the 6g methylcellulose evenly after spray drying immediately, get final product the liposome microgranule (about 130 grams) of surperficial formation one deck methylcellulose thin film packing promptly.
Annotate: during use, the redissolution of liposome microgranule can utilize methylcellulose easily molten in cold water, and insoluble characteristic in the water of temperature more than 45 ℃ can get homodisperse liposome suspension.
Claims (8)
1, the preparation method that is used for the chemotherapeutic preparation of the direct administration of carcinoma kitchen range, it is characterized in that selecting for use those to have the Cytotoxic cancer therapy drug that can directly play a role (as: cell cycle nonspecific agent (CCNSA) (bias toward carcinoma entity direct injection with) in the cancer entity has the alkylating agent class: cyclophosphamide, ifosfamide, chlorambucil, melphalan mustine hydrochlcride, plug are for group etc.; Nitrous urine class; First ring nitrous urine, carmustine, hexamethylene nitrous urine etc.; Antitumor antibiotics class: dactinomycin, amycin, epirubicin, daunorubicin mitomycin etc.; Miscellany: mitoxantrone, methylbenzyl hydrazine, cisplatin, carboplatin, arsenious acid and salt thereof etc.Cell cycle specific agents (biasing toward the whole body administrable) has vinca alkaloids, camptothecine, podophyllin class, tegafur, fluorouracil, methotrexate, cytosine arabinoside bleomycin, Bleomycin, tetrahydroform, 6-to dredge basic purine etc.) among at least a medicine be that raw material combines with specific adjuvant, be processed into suspension type slow releasing injection and three kinds of Liposomal formulations of the chemotherapeutics of directly administering to cancer nidus.
2, suspension type slow releasing injection as claimed in claim 1, it is characterized in that solvent can select vegetable oil for use, the benzyl benzyl formate, at least a in the ethyl oleate, suspending agent is selected for use in list two, the Aluminium Tristearate Micronized sterile at least a, the amount ratio of suspending agent and solvent is 0.5: 100～5: 100, and medicine mix suspension grain degree is controlled at 5 μ m following (or being dissolved in the factice)
3, the preparation of three kinds of liposomees as claimed in claim 1, it is characterized in that medicine is dissolved in the corresponding buffer (internal layer water) according to its charged situation transfers PH(to make it to become water soluble salt), phospholipid with axunge (or oleogel) and 1/3 amount, constitute oil phase in the cholesterol solution chloroform, above-mentioned water is joined in the middle of the oil phase, carry out emulsifying and form w/o type Emulsion, this Emulsion is removed most of organic solvent with gentle method form spissated breast, this W/O is concentrated breast to add the PH that contains total amount 2/3 phospholipid and cholesterol and approximates in 7 the aqueous solution under the state that stirs, form the compound breast of W/O/W type after the emulsifying, this compound breast can be got three kinds of different liposomees with different disposal methods: 1. with this compound breast, after the homogenize, residual organic solvent is removed in evaporation, gets final product to such an extent that be used for the envelop rate height of whole body administration, unload the low liposome solutions of leak rate.2. incite somebody to action 1. gained liposome solutions and the abundant mix homogeneously of high viscosity copolymer solution, promptly get the Injectable sustained release liposome solutions that can be used for the direct medicine of carninomatosis kitchen range.3. if compound breast of W/O/W type after the above-mentioned homogenize and high viscosity copolymer solution are carried out spray drying simultaneously, get final product anti, the antioxidative liposome microgranule of surperficial formation one layer of polymeric thin film.
4, the preparation method of three kinds of Liposomal formulations as claimed in claim 3, the buffer agent of aqueous phase should be selected according to the charged situation of its medicine in it is characterized in that, when medicine when being cationic, then need select for use acid buffer agent (as citric acid succinic acid, acetic acid, oxalic acid etc.) with its composition water soluble salt when medicine is anion, then select ealkaline buffer (as sodium carbonate, sodium bicarbonate, sodium phosphate, dibastic sodium phosphate etc.) for use.
5, the preparation method of the preparation of three kinds of liposomees as claimed in claim 3, it is characterized in that the double-deck molecular material of liposome can select phosphatidylcholine for use, the lecithin phatidylcholine, the fabaceous lecithin phatidylcholine, the hydrogenated soybean lecithin phatidylcholine, two lauroyl lecithin phatidylcholines, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, two spermaceti phospholipid, the distearyl phosphatidyl glycerol, thioester, cholesterol, coprostenol, cholestane, Dihydrocholesterol, alpha-tocopherol etc., its total consumption is equivalent to 0.5～15% of spray drying proliposome solution, in, outer lipid ratio is about 1: 2: wherein the ratio of phospholipid and cholesterol should be between 1: 0.2～1: 1, and the cholesterol level of internal layer lipid layer should be bigger than skin.
6, the preparation method of the preparation of three kinds of liposomees as claimed in claim 3, the oil reservoir only remaining micro-axunge or the oleogel that it is characterized in that the compound breast of spraying (evaporation) back W/O/W type, so formed special liposome bilayer, axunge between this bilayer or factice fat can stop unloading leakage of water soluble drug effectively.Wherein oleogel is made of suspending agent such as list, two, Aluminium Tristearate Micronized sterile etc. and oil phase such as vegetable oil, benzyl benzyl formate, ethyl oleate etc.The ratio of axunge or oleogel and liposome material should be between 0-500%, and the consumption of suspending agent should be 0.5～5% of an oil phase in the oleogel.
7, the preparation method of Injectable sustained release liposome as claimed in claim 3, it is characterized in that in the requirement 3 that 2. 3. the used high-viscosity polymer of liposome can select for use sodium alginate, methylcellulose, carboxymethyl cellulose, polyethylene than each alkane ketone, amylopectin and glue class etc., its consumption should be looked the kind of polymer, redissolving the back cancer entity required slow release degree of injection and fixed 3. spray drying process can carry out spray drying method after evenly with the high-viscosity polymer liquid mixing, also can carry out spray drying method by different spray guns ejections with the chamber by two kinds of liquid.
8, the preparation method of the preparation of three kinds of liposomees as claimed in claim 3, the foreign minister's aqueous solution that it is characterized in that containing 2/3 lipid should transfer to 7 with PH before emulsifying W/O/W breast about (slightly get final product on the contrary), so that the part medicine that spills when making preparation W/O/W newborn can return the internal layer water when spray drying in internal layer water PH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92114977 CN1088777A (en) | 1992-12-18 | 1992-12-18 | The preparation method that is used for the chemotherapeutic preparation of directly administering to cancer nidus |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92114977 CN1088777A (en) | 1992-12-18 | 1992-12-18 | The preparation method that is used for the chemotherapeutic preparation of directly administering to cancer nidus |
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| CN1088777A true CN1088777A (en) | 1994-07-06 |
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| CN 92114977 Pending CN1088777A (en) | 1992-12-18 | 1992-12-18 | The preparation method that is used for the chemotherapeutic preparation of directly administering to cancer nidus |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1299773C (en) * | 2004-10-14 | 2007-02-14 | 孔庆忠 | Anti-cancer medicine composition |
| CN100356920C (en) * | 2004-12-27 | 2007-12-26 | 北京文卓医药生物制品技术开发有限公司 | Alkaloid liposome in vinca and production technique |
| CN100464783C (en) * | 2004-11-22 | 2009-03-04 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition containing antineoplastic antibiotics |
| CN100522141C (en) * | 2004-05-19 | 2009-08-05 | 新疆维吾尔自治区包虫病临床研究所 | Prosoma liposome preparation, its production method and using method |
| CN101653439B (en) * | 2006-04-21 | 2010-12-01 | 中国科学院上海应用物理研究所 | Application of C60-benzoic nitrogen mustard in preparing antitumor medicament |
| CN101057842B (en) * | 2006-04-21 | 2010-12-08 | 中国科学院上海应用物理研究所 | Application of C60-benzoic acid nitrogen mustard in preparing medicine for anti tumor |
| CN101455641B (en) * | 2007-12-11 | 2010-12-22 | 复旦大学附属肿瘤医院 | Anti-cancer medicine liposome preparation sensitive to ray |
| CN101513390B (en) * | 2009-03-24 | 2012-06-27 | 沈阳药科大学 | Hydrochloric acid boanmycin liposomes and preparation method thereof |
| CN1895262B (en) * | 2005-07-11 | 2013-09-18 | 胡文波 | Emulsion for injecting epirubicin and its production |
| US9107824B2 (en) | 2005-11-08 | 2015-08-18 | Insmed Incorporated | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
| US9186322B2 (en) | 2002-08-02 | 2015-11-17 | Insmed Incorporated | Platinum aggregates and process for producing the same |
| CN107043456A (en) * | 2017-04-19 | 2017-08-15 | 川北医学院 | To oxygen cyclohexanone and L melphalans copolymer and its application |
| US11291644B2 (en) | 2012-09-04 | 2022-04-05 | Eleison Pharmaceuticals, Llc | Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin |
-
1992
- 1992-12-18 CN CN 92114977 patent/CN1088777A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9186322B2 (en) | 2002-08-02 | 2015-11-17 | Insmed Incorporated | Platinum aggregates and process for producing the same |
| CN100522141C (en) * | 2004-05-19 | 2009-08-05 | 新疆维吾尔自治区包虫病临床研究所 | Prosoma liposome preparation, its production method and using method |
| CN1299773C (en) * | 2004-10-14 | 2007-02-14 | 孔庆忠 | Anti-cancer medicine composition |
| CN100464783C (en) * | 2004-11-22 | 2009-03-04 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition containing antineoplastic antibiotics |
| CN100356920C (en) * | 2004-12-27 | 2007-12-26 | 北京文卓医药生物制品技术开发有限公司 | Alkaloid liposome in vinca and production technique |
| CN1895262B (en) * | 2005-07-11 | 2013-09-18 | 胡文波 | Emulsion for injecting epirubicin and its production |
| US9107824B2 (en) | 2005-11-08 | 2015-08-18 | Insmed Incorporated | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
| CN101057842B (en) * | 2006-04-21 | 2010-12-08 | 中国科学院上海应用物理研究所 | Application of C60-benzoic acid nitrogen mustard in preparing medicine for anti tumor |
| CN101653439B (en) * | 2006-04-21 | 2010-12-01 | 中国科学院上海应用物理研究所 | Application of C60-benzoic nitrogen mustard in preparing antitumor medicament |
| CN101455641B (en) * | 2007-12-11 | 2010-12-22 | 复旦大学附属肿瘤医院 | Anti-cancer medicine liposome preparation sensitive to ray |
| CN101513390B (en) * | 2009-03-24 | 2012-06-27 | 沈阳药科大学 | Hydrochloric acid boanmycin liposomes and preparation method thereof |
| US11291644B2 (en) | 2012-09-04 | 2022-04-05 | Eleison Pharmaceuticals, Llc | Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin |
| CN107043456A (en) * | 2017-04-19 | 2017-08-15 | 川北医学院 | To oxygen cyclohexanone and L melphalans copolymer and its application |
| CN107043456B (en) * | 2017-04-19 | 2019-05-17 | 川北医学院 | To oxygen cyclohexanone and Phenylalanin-Lost copolymer and its application |
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