CN1507854A - Amphotericin B Liposome and preparing method thereof - Google Patents
Amphotericin B Liposome and preparing method thereof Download PDFInfo
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- CN1507854A CN1507854A CNA021551901A CN02155190A CN1507854A CN 1507854 A CN1507854 A CN 1507854A CN A021551901 A CNA021551901 A CN A021551901A CN 02155190 A CN02155190 A CN 02155190A CN 1507854 A CN1507854 A CN 1507854A
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Abstract
The present invention relates to an amphotericin B liposome and its preparation method. It is formed from (wt%) 1.4-1.8% of amphotericin B, 50-89% of lecithin, 0.6-3.2% of sodium deoxycholate and 6-48% of cane sugar. Its preparation method is simple, not only reduces the toxicity of original drug, but also retains the medicinal effect for resisting fungi.
Description
Technical field:
The present invention relates to pharmaceutical preparation and preparation method, be specifically related to a kind of AM Bison and preparation method.
Background technology:
Amphotericin B is the macro ring polyene antibiotics, at present is the medicine of effective anti-deep fungal infection in clinical use.In recent years, the sickness rate of deep mycosis has the trend of increasing, and the state of an illness is serious mostly, the case fatality rate height, especially in the seriousness disease (as malignant tumor, hematopathy) immunologic function obviously descends on the basis, and easier generation when prolonged application broad ectrum antibiotic, adrenocortical hormone or radiotherapy, chemotherapy.But because the both sexes toxin has more serious toxic and side effects, and clinical maximum tolerated dose curative effect can not bring into play, thereby limited its use.For toxicity and the untoward reaction that reduces amphotericin B, researcher changes it into liposome both at home and abroad, can reduce its toxic and side effects on the basis that does not lessen the curative effect.The design of existing liposome prescription is comparatively complicated, and some prescription particle diameter is difficult to remain on below 3 μ, has influenced the performance of curative effect.
Summary of the invention:
It is cheap and easy to get that technical problem to be solved by this invention provides a kind of adjuvant, prepare easy, the encapsulation ratio height, the liposome particle diameter is little, the new type amphoteric mycin B liposome of stable curative effect.
AM Bison disclosed by the invention is the 1.4-1.8% amphotericin B by percentage by weight, 50-89% lecithin, and 0.6-3.2% sodium deoxycholate and 6-48% sucrose are formed, particle diameter≤1 μ.
Described lecithin is selected from the natural phosphatidyl choline that extracts from egg yolk, its nitrogen content 〉=17.0mg/mg, phosphorus content are 3.5-4.0, acid number≤4.0, and saponification number is 170-210, iodine number is 60-70.
Another technical problem to be solved by this invention is the preparation method that discloses above-mentioned liposome.
The preparation of AM Bison disclosed by the invention comprises the following steps:
Take by weighing after lecithin adds anhydrous alcohol solution by recipe quantity, use the rotary evaporator film forming; Other takes by weighing the amphotericin B dissolution of sodium hydroxide, mixes with lecithin after the phosphate buffer that will be dissolved with sodium deoxycholate and sucrose is again transferred pH to 7-8, and with the high pressure homogeneous pump pulverizing, through the inclined to one side fluorine membrane filtration of 0.22 μ, fill, lyophilization are promptly.Encapsulation ratio 〉=90%, particle diameter≤1 μ.
Used phosphate buffer is the phosphate buffer of pH7.04 in the preparation method of the present invention, as potassium dihydrogen phosphate and sodium hydrate buffer solution.
Great mass of data shows that encapsulation ratio height and particle diameter are to reduce toxicity for a short time, improve the essential condition of curative effect.The adjuvant sodium deoxycholate of selecting for use in the present invention's prescription is the adjuvant of common amphotericin B preparation, clinical use through decades, prove that it has good water solublity, and can guarantee that amphotericin B makes electric charge row property mutually behind the liposome because of the natural phospholipid film forming, increase the mutually exclusive of electric charge, confirm that through batch data more than ten and electromicroscopic photograph its liposome is twin nuclei.Thereby guarantee liposome particle diameter≤1 μ.
Liposome of the present invention is a double-decker, this structure can strengthen stability of drug, make both sexes toxin B in hydrophobic layer, keep maximum content as far as possible, reduce with body in combining of cholesterol and increase combination to fungal cell's ergosterol, thereby bring into play maximum sterilizing ability.
Carry out the relevant toxicity and the test of pesticide effectiveness with liposome of the present invention, the result is as follows: the I toxicological test
One, acute toxicity test in mice
(1) test objective: carry out two kinds of administrations of mice with AM Bison of the present invention (L-AmpB) lyophilized formulations: the acute toxicity test of vein and lumbar injection, observe the reaction of animals situation, observed seven days continuously, record animal toxicity response situation and dead animal distribute, and measure the acute toxicity test of not sealing liposome both sexes toxin B (F-AmpB) intravenous injection approach, calculate LD
50Value.
(2) result of the test:
1, to behind the F-AmpB, performance is excited, twitches, and heart beating and accelerated breathing are until death.2.55mg/kg after the administration dead immediately 4, the symptom performance is the same.
Dead one of L-AmpB group 7.0mg/kg that afternoon, the toxicity reveal any symptoms is dull, alarms hair, breathing and palpitating speed and death, the animal postmortem, the perusal important organ is not seen obvious pathological changes, both LD
50Measurement result sees Table 1, table 2.Table 1L-AmpB intravenous injection LD
50
| Dosage (mg/kg) | Log10 dose (X) | Number of animals (only) | Dead animal number (only) | Probit (Y) | Mortality rate (%) | LD 50And 95% fiducial limit (mg/kg) |
| ?3.66 | ?1.2974 | ?10 | ?1 | ?3.718 | ?10 | ?5.07 (4.57-5.63) |
| ?4.30 | ?1.4586 | ?10 | ?4 | ?4.747 | ?40 | |
| ?5.06 | ?1.6213 | ?10 | ?4 | ?4.747 | ?40 | |
| ?5.95 | ?1.7833 | ?10 | ?6 | ?5.253 | ?60 | |
| ?7.00 | ?1.9459 | ?10 | ?10 | ?7.620 | ?100 |
Table 2F-AmpB intravenous injection LD50
| The unclear amount of agent (mg/kg) | Log10 dose (X) | Number of animals (only) | Dead animal number (only) | Probit (Y) | Mortality rate (%) | LD 50And 95% fiducial limit (mg/kg) |
| ??1.57 | ??0.4510 | ??10 | ??0 | ??2.380 | ??0 | ??2.61 ??(2.41-2.81) |
| ??1.84 | ??0.6097 | ??10 | ??0 | ??2.380 | ??0 | |
| ??2.17 | ??0.7747 | ??10 | ??1 | ??3.718 | ??10 | |
| ??2.55 | ??0.9360 | ??10 | ??5 | ??5.000 | ??50 | |
| ??3.00 | ??1.0986 | ??10 | ??8 | ??5.842 | ??80 |
2, mice performance is dull behind the L-AmpB lumbar injection, does not eat, and breathes fast and rapid, until death.The main device of animal postmortem is not seen pathological changes, according to death condition, obtains the LD50 value, sees Table 3.
Table 3F-AmpB intravenous injection LD
50
| Dosage (mg/kg) | Log10 dose (X) | Number of animals (only) | Dead animal number (only) | Probit (Y) | Mortality rate (%) | LD 50And 95% fiducial limit (mg/kg) |
| 26.0 | ?1.4510 | ?10 | ?0 | ?2.380 | ?0 | ?2.61 (38.86-49.01) |
| 33.3 | ?1.5224 | ?10 | ?2 | ?4.158 | ?20 | |
| 41.6 | ?1.6119 | ?10 | ?4 | ?4.747 | ?40 | |
| 52 | ?1.7160 | ?10 | ?8 | ?5.824 | ?80 | |
| 65 | ?1.8129 | ?10 | ?9 | ?6.282 | ?90 |
(3) conclusion:
1, intravenous injection approach
L-AmpB LD
50Be 5.07 (4.57-5.63) mg/kg.
F-AmpB LD
50Be 2.61 (2.41-2.81) mg/kg.
L-AmpB is littler about 2 times than the acute toxicity of F-AmpB.
2, the LD of lumbar injection approach
50Be 43.63 (38.86-49.01) mg/kg.
Two, to the influence of renal function
According to the maximal dose 3.0mg/kg of AM Bison (L-AmpB) pharmacodynamics and maximum tolerated dose (MTD) 2.0mg/kg of free amphotericin B (F-AmpB), through mouse tail vein injection, reach seven days one day after respectively at administration and carry out the renal function detection, after the administration seven days, though the creatinine of L-AmpB and F-AmpB is high slightly than matched group, L-AmpB and matched group be p＜0.05 relatively, F-AmpB and matched group be p＜0.01 relatively, but all in normal range, L-AmpB is than the big 1.0mg/kg dosage of F-AmpB, and flesh liver L-AmpB is lower than F-AmpB in the blood.So renal function is not exerted an influence.
Three, the zest of tame rabbit ear vein is observed
The dosage that three groups of rabbit give intravenous injection L-AmpB and F-AmpB is 1.0mg and solvent control group, intravenous drip once a day, continuous seven days, observe and do histological examination, L-AmpB and group of solvents are identical: not seeing has the obvious stimulation reaction, and three tame rabbit ear veins of F-AmB group see that all blood vessel wall is imperfect, and thrombosis is arranged.
Four, to rabbit erythrocyte hemolytic test
L-AmpB adds in the 2% rabbit erythrocyte suspension by various dose, places 30min, 60min, 120min, 180min, the rabbit erythrocyte is not had haemolysis for 37 ℃.
Five, to the hypersensitive test of Cavia porcellus
Cavia porcellus behind sensitizing injection was divided into two groups at random, gave decisive injection L-AmpB respectively through 14 days and 21 days, and two treated animals there is no allergic phenomena.
II drug effect and pharmacokinetics test
One, to the therapeutical effect of mice systemic infection Candida albicans
The survival rate of L-AmpB and F-AmpB equal dose (1.0mg/kg) is respectively 55% and 35%, though it is variant, but P＞0.05, and when the dosage of L-AmpB brought up to 3.0mg/kg or 2.0mg/kg, can obviously increase curative effect, survival rate 85% and 75%, P＜0.01 of comparing with F-AmpB1.0mg/kg.After animal of each group survival continued to raise 60 days, get nephridial tissue and prepare homogenate, the L-AmpB3.0mg/kg group is only arranged, negative through fungal culture, and that other respectively organizes fungal culture is all positive.Show that L-AmpB is more effective to the drug action specific ionization amphotericin B that infects the Candida albicans mice, with the L-AmpB basically identical of bibliographical information with synthetic membrane material preparation.
Two, L-AmpB infects the experimental therapy effect of Cryptococcus histolyticus to mouse intracranial
L-AmpB and L-FmpB infect protection test to novel coccus; represent with median effective dose (ED50); result of the test L-AmpBED50 is 0.8252mg/kg; the ED50 of F-AmpB is 0.8373mg/kg; both ED50 are similar, but F-AmpB 3.0mg/kg group, and animal is all dead in the tail vein injection 48 hours; and L-AmpB does not have death, and prompting L-AmpB toxicity is less.
Three, L-AmpB treatment cutaneous leishmaniasis
L-AmpB becomes the active drug of internal organs, mucosa and cutaneous leishmaniasis, L-AmpB is lower than F-AmpB toxicity, little single belt negative charge liposome in vitro tests (the leishmaniasis substance is cultivated and the Mus leishmaniasis), F-AmpB is active bigger 3-6 times than L-AmpB's, BALB/c skin infection model in vivo, be dosage correlation by vein L-AmpB6.25mg/kg and 50mg/kg curative effect, at the F-AmpB of nontoxic dose also inefficacy, so prompting L-AmpB can be used for the treatment of cutaneous leishmaniasis.
Four, L-AmpB treatment histoplasma maris disease
L-AmpB experimentizes and treats and can finely tolerate, and its reason is that the L-AmpB concentration mainly concentrates on infection site, but points out L-AmpB treated tissue endochylema bacterium disease clinically.
Five, L-AmpB in-vitro antibacterial experimental result
L-AmpB measures extracorporeal antifungal activity, and according to the methodology difference, the quantitative test that antifungal is renderd a service has obvious difference.This experiment belongs to 15 kind of 107 strain pathogenic bacterium antibacterial activity to 10, is to use not agar dilution mensuration MIC, and the result shows the external anti-fungus spectra of AmpB and MIC and bibliographical information basically identical, parallels at antibacterial range and sensitivity with L-AmpB.
L-AmpB3.0mg/kg has tangible curative effect to the animal model of mice systemic infection Candida albicans in sum; and can obtain the radical cure effect; L-AmpB and F-AmpB infect Cryptococcus histolyticus protection experimental result to mouse intracranial; both are close with ED50; but the dosage group of identical 3.0mg/kg, animal was all dead in F-AmpB organized 48 hours, and L-AmpB does not all have death; show that toxicity is less, both show extracorporeal antifungal activity and show difference.
Six, pharmacokinetic studies
Behavior when more in depth understanding in animal body medicine of L-AmpB, adopt the HPLC method to measure blood drug level, the result shows: L-AmpB and F-AmpB all meet three Room open models, wherein the T1/2 of L-AmpB is long more than three times than F-AmpB1/2, blood on each sampling time point, L-AmpB are than the high 3-5 of F-AmpB doubly.
Seven, pharmacokinetics of monolayer L-AmpB rabbit and security study
Give 20 intravenous rabbits injection monolayer L-AmpB0.5,1.0,5 and 10 μ g/kg, 12 rabbits give F-AmpB0.5 in addition, 1.0 and 1.5mg/kg (iv), but F-AmpB high dose group, acute cardiac toxicity takes place and death in 2 rabbits; Single dose L-AmpB1.0mg/kg serum peak concentration Cmax26 ± 2.4 μ g/ml and AUC0-∞ 60 ± 16 μ g.h/ml, and single dose F-AmpB1.0mg/kg, very low 4.7 ± 0.2 μ g/ml of Cmax, L-AmpB compares P＜0.001 with F-AmpB, and low 30.6 ± 2.2 μ g.h/ml of F-AmpB AUC0-∞, both compare P=0.07; Give L-AmpB5.0 μ g/kg, Cmax (287 ± 14 μ g/ml) and AUC0-∞ (2223 ± 246 μ g.h/ml).
Long-term L-AmpB5.0mg/kg/day * 28day or the F-AmpB1.0mg/kg/day * 28day of giving, L-AmpB peak concentration every day 122.8 ± 5.8 μ g/ml, paddy concentration 34.9 ± 1.8 μ g/ml, and the F-AmpB kurtosis reduces only 1.766 ± 0.11 μ g/ml, paddy concentration 0.46 ± 0.04 μ g/ml, both compare P≤0.001.Give L-AmpB5.0mg/kg/day for a long time, find that AmpB obviously accumulates in the internal organs of reticuloendothelial system, as liver 239 ± 39 μ g/g, bigger seven times than F-AmpB (1.0mg/kg/day) 33 ± 6 μ g/g, P=0.002, but than low 14 times of F-AmpB (12.7 ± 4.6 μ g/g), nephrotoxicity only 1/4 takes place in L-AmpB at kidney concentration L-AmpB (0.87 ± 0.61 μ g/g), and nephrotoxicity all takes place all animals of F-AmpB.Liver transaminase raises (liver toxicity), and L-AmpB only 1 rabbit takes place, so L-AmpB can reach safe higher peak concentration C max and AUC0-∞, and reduces nephrotoxicity.
After this product gives rat intravenous injection with 1.0mg/kg and two kinds of dosage of 3.0mg/kg, show that in the tissue distribution result of some internal organs the AmpB content of L-AmpB3.0mg/kg group in each tissue is all high than the L-AmpB1.0mg/kg group with HPLC method detection 0.5h, 4h and 24h, 0.5h concentration is the highest in the lung, secondly be liver: liver concentration is the highest during 4h, lung takes second place, and is followed successively by spleen, the heart, brain again.The distribution sequence of 24h: lung, spleen, liver, kidney, the heart, brain.Distribute close substantially with the L-AmpB of the synthetic film material preparation of bibliographical information.
The medicine kinetoplast intracellular metabolite distribution experimentation of L-AmpB shows the carrier of liposome as AmpB, has its feature: it is more that half-life prolongation and AmpB are distributed in reticuloendothelial system, helps mycotic treatment.
Above-mentioned evidence, AM Bison of the present invention has significantly reduced the toxicity of former medicine, has kept its antifungal drug effect simultaneously again.
Description of drawings:
Fig. 1 embodiment 1, AM Bison laser particle size test pattern
The specific embodiment:
Embodiment 1
| Amphotericin B | 0.20g |
| Lecithin | 10g |
| Sodium deoxycholate | 0.2g |
| Sucrose | 2g |
| 0.04N sodium hydroxide | 50ml |
| Potassium dihydrogen phosphate and sodium hydrate buffer solution pH7.04 | 150ml |
Take by weighing 10g lecithin and add the 80ml dehydrated alcohol, after the dissolving, use the rotary evaporator film forming; Other takes by weighing amphotericin B 0.2g, use the 50ml0.04N dissolution of sodium hydroxide, the phosphate buffer that will be dissolved in 0.2g sodium deoxycholate and 2g sucrose is again transferred pH to 7-8, mix with lecithin the back, pulverizes with high pressure homogeneous pump, through the inclined to one side fluorine membrane filtration of 0.22 μ, 100 of fills, lyophilization, that is, grain is through＜0.412 μ.AM Bison laser particle size test pattern (see figure 1).
Embodiment 2
Take by weighing 14g lecithin and add the 100ml dehydrated alcohol, after the dissolving, use the rotary evaporator film forming; Other takes by weighing amphotericin B 0.22g, use the 43m10.04N dissolution of sodium hydroxide, the phosphate buffer that will be dissolved in 0.15g sodium deoxycholate and 1.5g sucrose is again transferred pH to 7-8, mix with lecithin the back, pulverizes with high pressure homogeneous pump, through the inclined to one side fluorine membrane filtration of 0.22 μ, 100 of fills, lyophilization, that is, grain is through＜0.558 μ.
| Amphotericin B | 0.22g |
| Lecithin | 14g |
| Sodium deoxycholate | 0.15g |
| Sucrose | 1.5g |
| 0.04N sodium hydroxide | 43ml |
| Potassium dihydrogen phosphate and sodium hydrate buffer solution pH7.04 | 157ml |
Embodiment 3
| Amphotericin B | 0.24g |
| Lecithin | 18g |
| Sodium deoxycholate | 0.4g |
| Sucrose | 4g |
| 0.04N sodium hydroxide | 55ml |
| Potassium dihydrogen phosphate and sodium hydrate buffer solution pH7.04 | 145ml |
Take by weighing 18g lecithin and add the 170ml dehydrated alcohol, after the dissolving, use the rotary evaporator film forming; Other takes by weighing amphotericin B 0.24g, use the 55ml0.04N dissolution of sodium hydroxide, the phosphate buffer that will be dissolved in 0.4g sodium deoxycholate and 4g sucrose is again transferred pH to 7-8, mix with lecithin the back, pulverizes with high pressure homogeneous pump, through the inclined to one side fluorine membrane filtration of 0.22 μ, 100 of fills, lyophilization, that is, grain is through＜0.478 μ.
Claims (4)
1, a kind of AM Bison is characterized in that this liposome is the 1.4-1.8% amphotericin B by percentage by weight, 50-89% lecithin, and 0.6-3.2% sodium deoxycholate and 6-48% sucrose are formed, particle diameter≤1 μ.
2 ,-and kind of liposome as claimed in claim 1, it is characterized in that wherein said lecithin is selected from the natural phosphatidyl choline that extracts from egg yolk, its nitrogen content 〉=17.0mg/mg, phosphorus content is 3.5-4.0, acid number≤4.0, saponification number are 170-210, and iodine number is 60-70.
3, a kind of preparation method of liposome as claimed in claim 1 is characterized in that the preparation of this liposome comprises the following steps:
Take by weighing after lecithin adds anhydrous alcohol solution by recipe quantity, use the rotary evaporator film forming; Other takes by weighing the amphotericin B dissolution of sodium hydroxide, mixes with lecithin after the phosphate buffer that will be dissolved with sodium deoxycholate and sucrose is again transferred pH to 7-8, and with the high pressure homogeneous pump pulverizing, through the inclined to one side fluorine membrane filtration of 0.22 μ, fill, lyophilization are promptly; Encapsulation ratio 〉=90%, particle diameter≤1 μ.
4, a kind of preparation method of liposome as claimed in claim 3 is characterized in that wherein said phosphate buffer is the phosphate buffer of pH7.04.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021551901A CN1507854A (en) | 2002-12-17 | 2002-12-17 | Amphotericin B Liposome and preparing method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021551901A CN1507854A (en) | 2002-12-17 | 2002-12-17 | Amphotericin B Liposome and preparing method thereof |
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| CN1507854A true CN1507854A (en) | 2004-06-30 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100372524C (en) * | 2006-02-28 | 2008-03-05 | 中国人民解放军第二军医大学 | Amphotericin B nano preparation |
| CN100418537C (en) * | 2005-07-15 | 2008-09-17 | 同济大学 | Amphotericin B slow-releasing microsphere, and its prepn. method |
| CN102746352A (en) * | 2011-04-20 | 2012-10-24 | 上海新先锋药业有限公司 | Technology for purifying medicines for treating deep fungal infection |
| CN107412165A (en) * | 2017-08-02 | 2017-12-01 | 上海上药新亚药业有限公司 | A kind of preparation method of AM Bison |
-
2002
- 2002-12-17 CN CNA021551901A patent/CN1507854A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100418537C (en) * | 2005-07-15 | 2008-09-17 | 同济大学 | Amphotericin B slow-releasing microsphere, and its prepn. method |
| CN100372524C (en) * | 2006-02-28 | 2008-03-05 | 中国人民解放军第二军医大学 | Amphotericin B nano preparation |
| CN102746352A (en) * | 2011-04-20 | 2012-10-24 | 上海新先锋药业有限公司 | Technology for purifying medicines for treating deep fungal infection |
| CN102746352B (en) * | 2011-04-20 | 2016-03-30 | 上海新亚药业有限公司 | A kind of purifying process for the treatment of deep fungal infection medicine |
| CN107412165A (en) * | 2017-08-02 | 2017-12-01 | 上海上药新亚药业有限公司 | A kind of preparation method of AM Bison |
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