CN104000781B - Amrubicin liposome and its preparation method - Google Patents
Amrubicin liposome and its preparation method Download PDFInfo
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- CN104000781B CN104000781B CN201310056867.4A CN201310056867A CN104000781B CN 104000781 B CN104000781 B CN 104000781B CN 201310056867 A CN201310056867 A CN 201310056867A CN 104000781 B CN104000781 B CN 104000781B
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Abstract
The present invention relates to amrubicin liposome and preparation technology thereof. This liposome comprises the amrubicin of therapeutic dose, and appropriate phosphatide, cholesterol etc. The present invention simultaneously provides the preparation method of the formulation freeze-dried preparation that this liposome can be prepared. This formulation is applicable to the treatment of malignant tumour, reduces the toxic side effect of cancer therapy drug amrubicin to a certain extent.
Description
Technical field
The present invention relates to a kind of amrubicin lipidosome freeze-dried preparation and its preparation method.
Background technology
Amrubicin (amrubicin); chemistry (7S by name; 9S)-9-ethanoyl-9-amino-7-[(2-deoxidation-B-D-red type-pyranopentose base) oxygen base]-7,8,9; 10-tetrahydrochysene-6; 11-dihydroxyl-5,12-tetracene diketone, this product is the complete synthesis third generation anthracycline antibiotics of Sumitomo Pharmaceuticals Co., Ltd of Japan exploitation and strong TOP-001 inhibitor; for the treatment of nonsmall-cell lung cancer and small cell lung cancer, and listed in 2002 at Japan registration. Clinical dosage, in Amrubicin Hydrochloride, is grown up 1 time on the 1st, each 45mg/m2(body surface area), is dissolved in 20ml physiological saline or 5% glucose injection, continuous 3 days intravenous injections, then stop medicine 3��4 weeks, then carry out next course for the treatment of treatment (Yuan Yongrong, Chang Ping. lung cancer medication Amrubicin Hydrochloride [J]. Shandong medicine thing, 2004,23:61).
Amrubicin and active metabolite amrubicinol thereof, mainly through suppressing the activity of type �� topoisomerase, finally cause the fracture of DNA and inhibition tumor cell is bred. I-II clinical trial phase determines that the maximum tolerated dose (MTD) of this product is 50mg/m2/ d. II clinical trial phase data show, this product to nonsmall-cell lung cancer have efficiency reach 27.9%(wherein complete remission rate be 1.6%), to small cell lung cancer have efficiency reach 75.8%(wherein complete remission rate be 9.1%) (Yuan Yongrong, Chang Ping. lung cancer medication Amrubicin Hydrochloride [J]. Shandong medicine thing, 2004,23:61). U.S. clinical Society of Oncology 2011 reports: a research report of Jotte etc. shows, amrubicin (AMR) treats small cell lung cancer (SCLC) compared with Hycamtin (Topo), can significantly improve remission rate. AMR group lifetime longer [dangerous is 0.88 than (HR)], intractable patient's subgroup (HR is 0.77) all the more so.
After amrubicin administration, proto-drug concentration rapid reduction, the basic held stationary of the concentration of its metabolite amrubicinol. Whole body internal organs all have drug distribution, and the drug level in marrow, digestive tube parietal cell, skin, kidney, suprarenal gland, liver, spleen, lung is higher, and heart cell drug level is lower. Its main metabolic organ is liver, metabolic enzyme mainly carbonyl reductase, NADPH-P450 reductase enzyme, NADPH hydrogen-quinone reductase. Bile, urine and ight soil are its Major excretion channel. (Lu Hongyang, Chen Lili etc. amrubicin treatment small cell lung cancer research progress [J]. China's lung cancer impurity, 2010,13:544-549).
In clinical trial and application, it has been found that the toxic side effect of this product is bone marrow function suppression mainly. Wherein oligoleukocythemia and neutrophilic granulocyte reduce incidence all more than 90%, and anaemia incidence is more than 80%. (Yuan Yongrong, Chang Ping. lung cancer medication Amrubicin Hydrochloride [J]. Shandong medicine thing, 2004,23:61) therefore, by drug preparation technique to reach the toxic side effect improving amrubicin, increase the conformability of patient, facilitate the problem that clinical application has become urgently to be resolved hurrily.
The relevant patent of current amrubicin preparation aspect has: the anticancer medicine slow-release preparation containing of a kind of pain load amrubicin of Chinese patent [200610200279.3] and synergistic agent thereof. Have studied the microball preparation of amrubicin, this patent Example 1 is pointed out contain sustainable 10��15 days of medicine 10% amrubicin microball preparation release in vitro with prepared by polifeprosan, maintain release after mouse subcutaneous injection about 20��30 days. But microball preparation uses organic solvent to cause the organic residue in preparation undoubtedly due to a large amount of in preparation process, it is possible to reduce the conformability of patient further. Chinese patent [201010272910.7] reports amrubicin freeze-dried preparation and its preparation method etc. Proposing to affect the factor of amrubicin stability in this patent, be mainly pH value, temperature and moisture, amrubicin is prepared into freeze-dried preparation and strictly controls moisture 0��3.5% by this patent, and preparation temperature controls below 15 DEG C, and pH value regulates 2��5.
But untoward reaction is more after taking medicine for amrubicin at present, patient's poor compliance and carry out research report less, the present invention is by changing the regular dosage form of amrubicin administration, taking the current amrubicin liposome that at home and abroad there is not been reported as research object, in conjunction with dissolution rate test and toxicity test, tentatively show lipidosome freeze-dried preparation and under the prerequisite ensureing the higher dissolution in vitro of medicine, the toxicity of medicine can be reduced to a certain extent.
It is well known that liposome has low poison and good biocompatibility, in recent years, seeing that reporting in document and patent take liposome as the anticancer preparation of carrier repeatly, and existing procucts successfully list, such as Evacet and cisplatin liposome list abroad. In the recent period, the antitumor drug Doxil injection liquid (the many U.S. elements of trade(brand)name) of Shi Yao Group Co., Ltd independent development also successfully lists at home, and the research and development of this product obtain the your kind effort support of 863 Program. Under this inspiration, this seminar has researched and developed a kind of amrubicin lipidosome freeze-dried preparation and preparation technology thereof, and this technique can realize suitability for industrialized production. Dissolution in vitro test test shows that 4 hours dissolution rates can reach more than 70%. After the medicine amrubicin giving higher dosage, amrubicin lipidosome freeze-dried preparation group relatively control group can effectively improve survival of rats rate more than 1 times.
Summary of the invention
Medicine amrubicin described in the present invention, other comprising amrubicin, Amrubicin Hydrochloride or amrubicin becomes salt form, and such as methylsulfonic acid amrubicin, Ammonium Acetate is soft compares magnitude.
A kind of amrubicin lipidosome freeze-dried preparation provided in the present invention, contains the medicine amrubicin of dosage, phosphatide, cholesterol, contains tensio-active agent and sugar simultaneously.
At present, can be used as the phosphatide of liposomal preparation and be divided into natural phospholipid and the big class of synthetic phospholipid two, natural phospholipid is mainly based on Yelkin TTS (phosphatidylcholine), and synthetic phospholipid is mainly hydrogenated phospholipid class. Amrubicin liposome involved in the present invention, its phosphatide comprise following one or more: DPPC(dipalmitoyl phosphatidylcholine), DSPC(distearoyl phosphatidylcholine), DDPG (two palmityl phosphatidyl two glycerine).
Tensio-active agent described in invention is Pegylation ester class, comprise following one or more: methoxyl group PEG2000-bis-hard ester acyl phosphatidyl ethanol ammonium, cholesterol-PEG, triglyceride-PEG, the tree-shaped PEG of DSPE many arms PEG or DSPE.
Owing to, in the preparation process of lipidosome freeze-dried preparation, lyophilize unavoidably need to be carried out, and the stability of liposome is caused disadvantageous impact by low temperature environment. Document report (Tang Wenya; Deng Yihui etc. lipidosome freeze-dried protective material kind and study on mechanism progress [J] thereof. Shenyang Pharmaceutical University's journal; 2012; 29:560-569); after lipidosome freeze-dried preparation aquation, it is possible to the increase of particle diameter and unilamelar liposome can be caused to the transformation of multilamelar liposome. Show freeze-drying process can cause fusion, the gathering of duplicature to a certain extent, cause the seepage of content. The effective way addressed this problem is, the application of lyophilized vaccine. Can be used as the auxiliary material of lyophilized vaccine at present and have glucose, N.F,USP MANNITOL, maltose, trehalose, sucrose, lactose, Polylevulosan, amino acid etc. In this patent preferably but be not limited to trehalose as lyophilized vaccine; and find when the ratio of glycolipid ratio is 3.0��5.0 after carrying out process optimization; its protected effect is best; the retention rate of liposomal contents after freeze-drying be can effectively improve, the remarkable increase of rear liposomal particle size and unilamelar liposome prevented from redissolving to the transformation of multilamelar liposome.
The present invention further comprises following content:
(1) the amrubicin liposome described in, wherein amrubicin accounts for the 0.01%��1.2% of this pharmaceutical composition weight, it is preferable that 0.05%��1%.
(2) the amrubicin liposome described in, wherein phosphatide accounts for the 1%��10% of this pharmaceutical composition weight, it is preferable that 2%��8%.
(3) the amrubicin liposome described in, wherein cholesterol accounts for the 0.001%��5% of this pharmaceutical composition weight, it is preferable that 0.01%��3%.
(4) the amrubicin liposome described in, wherein tensio-active agent accounts for the 0.001%��2% of this pharmaceutical composition weight, it is preferable that 0.01%��1%.
(5) the amrubicin liposome described in, wherein sugar accounts for the 8%��40% of this pharmaceutical composition weight, it is preferable that 15%��30%.
(6) the amrubicin liposome described in, wherein ammonium sulfate accounts for the 0.003%��3% of this pharmaceutical composition weight, it is preferable that 0.005%��2%.
It is as follows that the present invention contains a kind of amrubicin lipidosome freeze-dried preparation preparation technology:
(1) one or more in dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, two palmityl phosphatidyl two glycerine and Pegylation lipid surfactant and cholesterol are dissolved in the solvent mixture of ethanol and Virahol or the trimethyl carbinol, lyophilize, is prepared into fat phase mixture.
(2) with phosphate buffered saline buffer preparation 0.05 ~ 0.5M L of pH2 ~ 4-1Ammonium sulfate solution, is added in fat phase mixture, stirs 0.5��4h, be prepared into blank liposome intermediate compound I at the temperature of 40��70 DEG C.
(3) through the whole grain of microjet for several times, pressure setting is 8000��18000psi to blank liposome intermediate compound I step (2) obtained, and obtains the uniform blank liposome intermediate II of particle diameter.
(4) the blank liposome intermediate II that step (3) obtains is carried out column chromatography, adopt sugar concentration to be 0.5��1M L-1, pH be 2��4 phosphoric acid salt sugar soln carry out wash-out, for the ammonium sulfate replaced in liposome foreign minister, obtain blank liposome solutions.
(5) according to the drug level described in claim 7 or 8, it is prepared into amrubicin or the Amrubicin Hydrochloride aqueous solution for injection of 20��100mg/ml. In blank liposome solution, at 20��40 DEG C, hatch 0.5��1h, obtain amrubicin liposome solutions.
(6) amrubicin liposome solutions step (5) obtained is degerming through 0.22 ��m of membrane filtration, is undertaken filling by suitable specification.
(7) filling for step (6) gained good liposome solutions carried out lyophilize, jump a queue, seal to obtain amrubicin liposome freeze-drying powder injection.
The mixed solvent of the ethanol described in step (1) and Virahol or the trimethyl carbinol, it is characterised in that: ethanol and Virahol or the trimethyl carbinol proportional range be 10:90��90:10. Sugar soln described in step (4) preferably but is not limited to trehalose. Lyophilize condition described in step (7) is pre-freezing temperature is-30��-40 DEG C, and the pre-freeze time is 1��4h. During lyophilize, vacuum pump pressure is 10��20pa, and freezing temp is-20��-30 DEG C, and freezing time is 7��15h. PH value conditioning agent described in step (2), (4) preferably but is not limited to phosphate buffer soln, also can select acetate buffer etc.
The following examples and test example are the explanation that the present invention carries out, but the present invention is not limited to following example
Embodiment 1
By dipalmitoyl phosphatidylcholine (DPPC): cholesterol: DSPE-PEG2000 is dissolved in 1:0.05:0.01 ratio in 1000mL ethanol and Virahol the solvent mixture (1:6), and lyophilize, obtains fat phase mixture. It is in 3 phosphate buffered saline buffers that ammonium sulfate is dissolved in pH, and obtaining concentration is 0.05M L-1Ammoniumsulphate soln, be added in the fat phase mixture after above-mentioned lyophilize, at 55 DEG C heating in water bath, stir 1.5 hours, obtain blank liposome intermediate I. Blank liposome intermediate I is through the whole grain of microjet three times, and pressure setting is 11000psi, obtains the uniform blank liposome intermediate II of particle diameter. Adopt column chromatography, it is the 0.5M L of 3 by blank liposome intermediate II pH-1Ammonium sulfate in treahalose phosphate salts solution displacement foreign minister, obtains blank liposome solutions. Preparing, with water for injection, the Amrubicin Hydrochloride solution that concentration is 5%, Amrubicin Hydrochloride add-on accounts for the 0.1% of preparation. Being poured into by said medicine solution in blank liposome solution, after being slowly uniformly mixed, to 35 DEG C of water-baths, Constant temperature hatch 1 hour, obtains Amrubicin Hydrochloride liposome solutions. Above-mentioned product, through 0.22 ��m of membrane filtration, degerming, obtains aseptic Amrubicin Hydrochloride liposome solutions. To it filling after carry out lyophilize (pre-freezing temperature :-30��-40 DEG C, the pre-freeze time be 1��4h. During lyophilize, vacuum pump pressure: 10pa, freezing temp :-20��-30 DEG C, freezing time is 7��15h. ), afterwards temperature being warming up to 0 DEG C by-20��-30 DEG C, heating-up time 4h��6h, then temperature is warming up to 25��30 DEG C by 0 DEG C, the heating-up time is 6h��8h, freeze-day with constant temperature about 8h in this temperature range. After dry, preparation adds lid sealing, is prepared into amrubicin lipidosome freeze-dried preparation.
Embodiment 2
By dipalmitoyl phosphatidylcholine (DPPC): two hard ester phosphatidyl cholines (DSPC): cholesterol: DSPE-PEG2000 is dissolved in 1000mL ethanol and trimethyl carbinol the solvent mixture (1:6) with the ratio of 0.7:0.3:0.5:0.2, lyophilize, obtains fat phase mixture. It is in 3 phosphate buffered saline buffers that ammonium sulfate is dissolved in pH, and obtaining concentration is 0.5M L-1Ammoniumsulphate soln, be added in the lipid mixt after above-mentioned lyophilize, at 55 DEG C heating in water bath, stir 1.5 hours, obtain blank liposome intermediate I. Blank liposome intermediate I is through the whole grain of microjet three times, and pressure setting is 11000psi, obtains the uniform blank liposome intermediate II of particle diameter. Adopt column chromatography, it is the 1M L of 3 by blank liposome intermediate II pH-1Ammonium sulfate in treahalose phosphate salts solution displacement foreign minister, obtains blank liposome solutions. Preparing, with water for injection, the Amrubicin Hydrochloride solution that concentration is 5%, Amrubicin Hydrochloride add-on accounts for the 1.0% of preparation. Being poured into by said medicine solution in blank liposome solution, after being slowly uniformly mixed, to 35 DEG C of water-baths, Constant temperature hatch 1 hour, obtains Amrubicin Hydrochloride liposome solutions. Above-mentioned product, through 0.22 ��m of membrane filtration, degerming, obtains aseptic Amrubicin Hydrochloride liposome solutions. To it filling after carry out lyophilize (pre-freezing temperature :-30��-40 DEG C, the pre-freeze time be 1��4h. During lyophilize, vacuum pump pressure: 15pa, freezing temp :-20��-30 DEG C, freezing time is 7��15h. ), afterwards temperature being warming up to 0 DEG C by-20��-30 DEG C, heating-up time 4h��6h, then temperature is warming up to 25��30 DEG C by 0 DEG C, the heating-up time is 6h��8h, freeze-day with constant temperature about 8h in this temperature range. After dry, preparation adds lid sealing, prepares amrubicin lipidosome freeze-dried preparation.
Test example 1
The sample 1 prepared according to the method for embodiment 1,2, sample 2 being got and be dissolved in the glucose solution of 5% in right amount respectively, precision pipettes above-mentioned sample solution 5ml in dialysis membrane, and this dialysis membrane is placed in the phosphate buffered saline buffer release medium of the pH7.4 of 100ml. Setting gas bath constant temperature oscillation actuator temperature 37 DEG C, revolution 60rpm. Respectively at 0,15,30,60,120,240min timing sampling 1mL, supplementing release medium 1mL, sample, through 0.22 ��m of filtering with microporous membrane, gets the content that continuous filtrate measures different time points medicine by HPLC method simultaneously. Calculating accumulative dissolution, result is as shown in Figure 1. As seen from Figure 1, sample of the present invention all reaches the dissolution rate of 70%, has good result of extraction.
Test example 2
The amrubicin freeze-dried lipidosome freeze-dried preparation method of embodiment 2 prepared, gets and is dissolved in 5% D/W in right amount, as test sample. Prepare the amrubicin 5% D/W sample in contrast that drug level is 0.5%. The wista rat of body weight 200 �� 20g is divided into 2 groups at random, often organizes 6, one group of control group, one group of sample sets. Tail intravenously administrable, dosage is 50mg/m2, the toxic reaction of observation experiment mouse after administration, the observation cycle is one week. Calculating the survival rate of rat, and adopt its significant difference of statistical calculations, result is as shown in table 1:
* P < 0.05 is compared with control group for examination group.
It may be seen that amrubicin freeze-dried lipidosome injection can obviously reduce drug toxicity compared with amrubicin 5% D/W from above-mentioned test example, significantly improve survival number of days and the survival rate of laboratory animal. Can obtain that a kind of toxicity reduces by the present invention, the higher amrubicin lipidosome freeze-dried preparation of dissolution rate and preparation technology thereof.
Claims (1)
1. an Amrubicin Hydrochloride lipidosome freeze-dried preparation, it is characterised in that be prepare by following component and step:
By dipalmitoyl phosphatidylcholine (DPPC): cholesterol: DSPE-PEG2000 is dissolved in 1000mL ethanol and Virahol the solvent mixture with 1:0.05:0.01 ratio, wherein ethanol: Virahol volume ratio is 1:6, and lyophilize obtains fat phase mixture;
Being dissolved in by ammonium sulfate in pH=3 phosphate buffered saline buffer, obtaining concentration is 0.05M L-1Ammoniumsulphate soln, be added in the fat phase mixture after above-mentioned lyophilize, at 55 DEG C heating in water bath, stir 1.5 hours, obtain blank liposome intermediate I;
Blank liposome intermediate I is through the whole grain of microjet three times, and pressure setting is 11000psi, obtains the uniform blank liposome intermediate II of particle diameter;
Adopt column chromatography, by the 0.5M L of blank liposome intermediate II pH=3-1Ammonium sulfate in treahalose phosphate salts solution displacement foreign minister, obtains blank liposome solutions;
Preparing, with water for injection, the Amrubicin Hydrochloride solution that concentration is 5%, Amrubicin Hydrochloride add-on accounts for the 0.1% of preparation; Being poured into by said medicine solution in blank liposome solution, after being slowly uniformly mixed, to 35 DEG C of water-baths, Constant temperature hatch 1 hour, obtains Amrubicin Hydrochloride liposome solutions; Above-mentioned product, through 0.22 ��m of membrane filtration, degerming, obtains aseptic Amrubicin Hydrochloride liposome solutions;
To it filling after carry out lyophilize, freezing procedure is: pre-freezing temperature :-30��-40 DEG C, and the pre-freeze time is 1��4h; During lyophilize, vacuum pump pressure: 10Pa, freezing temp :-20��-30 DEG C, freezing time is 7��15h; Then by-20��-30 DEG C, temperature being warming up to 0 DEG C, heating-up time 4h��6h, then by 0 DEG C, temperature is warming up to 25��30 DEG C, the heating-up time is 6h��8h, freeze-day with constant temperature 8h in this temperature range; After dry, preparation adds lid sealing, is prepared into amrubicin lipidosome freeze-dried preparation.
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| CN101897667A (en) * | 2009-05-26 | 2010-12-01 | 石药集团中奇制药技术（石家庄）有限公司 | Doxorubicin hydrochloride liposome injection and preparation technology thereof |
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| CN101897667A (en) * | 2009-05-26 | 2010-12-01 | 石药集团中奇制药技术（石家庄）有限公司 | Doxorubicin hydrochloride liposome injection and preparation technology thereof |
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