CN1698643A - Cidofovir liposome and preparation method thereof - Google Patents
Cidofovir liposome and preparation method thereof Download PDFInfo
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- CN1698643A CN1698643A CN 200510043586 CN200510043586A CN1698643A CN 1698643 A CN1698643 A CN 1698643A CN 200510043586 CN200510043586 CN 200510043586 CN 200510043586 A CN200510043586 A CN 200510043586A CN 1698643 A CN1698643 A CN 1698643A
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- cidofovir
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Abstract
The invention relates to a cidofovir liposome and preparation method wherein the cidofovir liposome comprises the following constituents (by weight percentage), cidofovir 1-10%, lecithin 40-68%, cholesterin 10-17%, sodium deoxycholate 0.5-3%, cane sugar 2-48.2%. The preparation comprises weighing prescription amount of lecithin and cholesterin, dissolving with anhydrous alcohol and mixing, evaporating with rotary evaporator to obtain lipid film, then dissolving cidofovir into phosphoric acid buffer, charging deoxysodium cholate and cane sugar as required by prescription, charging into prepared lipid film and mixing, disintegrating with high pressure homogenizer to obtain liposome, then carrying out microporous film filtering, degerming, canning, and freeze drying.
Description
(1) technical field
The present invention relates to Cidofovir liposome and preparation method thereof, belong to medical technical field.
(2) background technology
Cidofovir (cidofovir, HPMPC, GS-504) be the open loop nucleotide analog, can suppress viral dna polymerase, people CMV there is very strong inhibitory action, other herpesvirus such as herpes simplex virus (HSV) I type and II type, chickenpox one varicella zoster virus (VZV), E～B virus, herpes 6 type viruses (HHV-6) and adenovirus, human papilloma shape virus (HPV) are also had very strong activity.Cidofovir injection is by the exploitation of Gilead company, and in Nikkei drugs approved by FDA listing Mays 15 in 1996, commodity are called Vistide, are used for the treatment of the retinitis that the HIV sufferers cytomegalovirus causes.This medicine is at the medicine ganciclovir and the foscarnet sodium that obviously are better than aspect curative effect, toleration and the therapeutic index having gone on the market, however because cidofovir exists serious toxic and side effects, particularly nephrotoxicity, serious restriction its in Clinical Application.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, provide a kind of adjuvant be easy to get, prepare simple, encapsulation ratio is high, toxic and side effects is little, eutherapeutic novel Cidofovir liposome.
The present invention is a Cidofovir liposome, it is characterized in that, comprises following component, all is weight percentage: 1～10% cidofovir, and 40～68% lecithin, 10～17% cholesterol, 0.5～3% sodium deoxycholate and 2%～48.2% sucrose are formed.Lecithin is selected from natural phosphatidyl choline that extracts in the egg yolk or the soybean lecithin that extracts from Semen sojae atricolor.
Cidofovir liposome preparation method disclosed by the invention comprises the following steps:
1, takes by weighing lecithin, the cholesterol of recipe quantity, after mixing behind the anhydrous alcohol solution, make it become lipid soln.
2, above-mentioned lipid soln is evaporated with rotary evaporator, decompression removes ethanol, the preparation lipid film.
3, the cidofovir that takes by weighing recipe quantity is dissolved in the phosphate buffer of pH6～8, preparation cidofovir phosphate buffered solution.
4, in above-mentioned cidofovir phosphate buffered solution, add the sodium deoxycholate and the abundant mixed dissolution of sucrose of recipe quantity after, be added in the lipid film of preparation and mix, high pressure homogenizer is pulverized the preparation liposome, check that the liposome particle diameter is qualified, gel column is isolated liposome solutions, 0.45 μ m microporous filter membrane clarification filtration, 0.22 μ m filtering with microporous membrane degerming, canned, freezing, be drying to obtain.Envelop rate 〉=80%, particle diameter≤1um.
Carry out the relevant toxicity and the test of pesticide effectiveness with liposome of the present invention, the result is as follows:
Toxicity test
Get the Cidofovir liposome lyophilized formulations with the present invention and give rabbit and macaque intravenous administration respectively, observe the toxicity test of animal, and measure simultaneously that the cidofovir do not seal liposome is administered intravenously in rabbit and macaque compares, result of the test is as follows: the Cidofovir liposome single dose lethal maximal dose do not occur and is: rabbit＞189mg/kg; Macaque＞72mg/kg; The cidofovir single dose of not sealing liposome lethal maximal dose do not occur and is: rabbit＞100mg/kg; Macaque＞40mg/kg.Nephrotoxicity is a main toxic and side effects after the cidofovir medication, and the dosage that nephrotoxicity appears in Cidofovir liposome is: rabbit is 94mg/kg; Macaque is 208mg/kg; The dosage that nephrotoxicity appears in the cidofovir of not sealing liposome is: rabbit is 60mg/kg; Macaque is 150mg/kg.Cidofovir liposome is littler about 2 times than the single dose toxicity of the cidofovir of not sealing liposome as can be seen, and is also much smaller to nephrotoxicity.
The test of pesticide effectiveness
In the cell culture of MRC-5D, cidofovir suppresses the concentration (IC that CMV AD-169 experiment Strain 50% plaque forms
50) be 0.007 μ g/ml, suppress the average IC of the clinical isolated viral strain of 17 strains
50Be 0.069 μ g/ml, and Cidofovir liposome IC
50Be 0.0023 μ g/ml, Cidofovir liposome selection index (50% cytotoxicity concentration and IC
50Ratio) higher 30 times than cidofovir.After CMV AD-169 infects 48 hours, add Cidofovir liposome and still have very strong inhibitory action.Behind GPE cell infection Cavia porcellus CMV and the human diploid fibroblasts infected person CMV, the IC of Cidofovir liposome
50Be respectively 0.0073 and 0.017 μ g/ml.50% toxic concentration of these two kinds of cells is respectively toxic concentration is respectively 2.8 and 3.8mol/l, its selection index is all more than 400.
Above-mentioned evidence, Cidofovir liposome of the present invention has significantly reduced the toxicity of former cidofovir, has strengthened its antiviral drug effect.
(4) specific embodiment
Embodiment 1 Cidofovir liposome, component is as follows:
Cidofovir 1g
Lecithin 40g
Cholesterol 10g
Sodium deoxycholate 0.5g
Sucrose 48.5g
Preparation method is as follows:
Take by weighing lecithin 40g, add the 500ml dehydrated alcohol, add cholesterol 10g, stirring and dissolving is with rotary evaporator reduction vaporization film forming.Take by weighing the cidofovir of 1g, the phosphate buffer dissolving that adds 300ml PH6.86, mix with lecithin after adding 0.5g sodium deoxycholate and 48.5g sucrose, the preparation suspension, the high-pressure homogenization mixing prepares liposome, and gel column separates liposome solutions, uses the 0.22um micro-pore-film filtration behind the clarification filtration, canned, lyophilization promptly gets Cidofovir liposome.
Embodiment 2 Cidofovir liposomes, component is as follows:
Cidofovir 5g
Lecithin 52g
Cholesterol 12g
Sodium deoxycholate 1g
Sucrose 30g
Preparation method is with embodiment 1,
Embodiment 3 Cidofovir liposomes, component is as follows:
Cidofovir 10g
Lecithin 68g
Cholesterol 17g
Sodium deoxycholate 3g
Sucrose 2g
Preparation method is with embodiment 1.
Embodiment 4 penetrates and uses Cidofovir liposome, and component is as follows:
Cidofovir 37.5g
Lecithin 200g
Cholesterol 40.5g
Sodium deoxycholate 10g
Sucrose 5g
Preparation method is as follows:
Take by weighing lecithin 200g and add the 1000ml dehydrated alcohol, the 40.5g cholesterol, stirring and dissolving is with rotary evaporator reduction vaporization film forming.Take by weighing the 37.5g cidofovir, add in the 350mlPH7.04 phosphate buffer and dissolve, add in the lipid film that is added to preparation behind 10g sodium deoxycholate and the 5g sucrose mixed dissolution and mix, high pressure homogenizer is pulverized the preparation liposome, and after inspection liposome particle diameter was qualified, gel column was isolated liposome solutions, 0.45um filtering with microporous membrane clarification, 0.22um the microporous filter membrane degerming, canned 100 bottles, lyophilization promptly gets the injection Cidofovir liposome.
Embodiment 5 Cidofovir liposome sheets, component is as follows:
Cidofovir liposome 100g
Starch 10g
Microcrystalline Cellulose 15g
Micropowder silica gel 3g
Magnesium stearate 1g
The 5%PVP aqueous solution is an amount of
Preparation method is as follows:
Take by weighing Cidofovir liposome dry powder 100g and cross 100 mesh sieves, take by weighing starch, microcrystalline Cellulose is crossed 100 mesh sieves, after fully mixing, add the 5%PVP aqueous solution and do soft material in right amount, cross 20 mesh sieves, 50 ℃ of vacuum dryings 1 hour, 20 mesh sieve granulate, tabletting behind adding 3g micropowder silica gel and the 1g magnesium stearate mixing, hydroxypropyl cellulose bag film-coat promptly.
Embodiment 6 Cidofovir liposome capsules, component is as follows:
Cidofovir liposome 150g
Microcrystalline Cellulose 20g
Micropowder silica gel 3g
The 5%PVP alcoholic solution is an amount of
Take by weighing Cidofovir liposome 150g and cross 100 mesh sieves, take by weighing microcrystalline Cellulose 20g, cross 100 mesh sieves, mixing, add the 5%PVP alcoholic solution and do soft material in right amount, cross 20 mesh sieves, 50 ℃ of vacuum dryings 1 hour, 20 mesh sieve granulate add the 3g micropowder silica gel, incapsulate to get final product.
Embodiment 7 Cidofovir liposome granules, component is as follows:
Cidofovir liposome 200g
Dextrin 100g
Cyclamate 0.5g
Take by weighing Cidofovir liposome 200g, add dextrin 100g, cyclamate 0.5g, with ethanol system soft material, 16 mesh sieve system granules, 40 ℃ of vacuum dryings, 12 mesh sieve granulate are distributed into bag and get final product.
Claims (2)
1, the present invention is a Cidofovir liposome, comprises following component, all is weight percentage: 1～10% cidofovir, 40～68% lecithin, 10～17% cholesterol, 0.5～3% sodium deoxycholate, 2%～48.2% sucrose.
2, the preparation method of the described Cidofovir liposome of claim 1 is characterized in that, the preparation of this liposome comprises the following steps:
1) takes by weighing lecithin, the cholesterol of recipe quantity, after mixing behind the anhydrous alcohol solution, make it become lipid soln.
2) will give an oral account lipid soln and evaporate with rotary evaporator, decompression removes ethanol, the preparation lipid film.
3) cidofovir that takes by weighing recipe quantity is dissolved in the phosphate buffer of pH6～8, preparation cidofovir phosphate buffered solution.
4) in above-mentioned cidofovir phosphate buffered solution, add the sodium deoxycholate and the abundant mixed dissolution of sucrose of recipe quantity after, be added in the lipid film of preparation and mix, high pressure homogenizer is pulverized the preparation liposome, check that the liposome particle diameter is qualified, gel column is isolated liposome solutions, 0.45 μ m microporous filter membrane clarification filtration, 0.22 μ m filtering with microporous membrane degerming, canned, freezing, be drying to obtain.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510043586 CN1698643A (en) | 2005-05-27 | 2005-05-27 | Cidofovir liposome and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510043586 CN1698643A (en) | 2005-05-27 | 2005-05-27 | Cidofovir liposome and preparation method thereof |
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| CN1698643A true CN1698643A (en) | 2005-11-23 |
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| CN 200510043586 Pending CN1698643A (en) | 2005-05-27 | 2005-05-27 | Cidofovir liposome and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014520834A (en) * | 2011-07-15 | 2014-08-25 | フェマロン エス．ペ．エール．エル． | Compositions and methods for the treatment of HPV |
| WO2020168358A3 (en) * | 2019-02-11 | 2020-10-01 | Chemistryrx | Pyrimidine derivative containing compositions |
-
2005
- 2005-05-27 CN CN 200510043586 patent/CN1698643A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014520834A (en) * | 2011-07-15 | 2014-08-25 | フェマロン エス．ペ．エール．エル． | Compositions and methods for the treatment of HPV |
| WO2020168358A3 (en) * | 2019-02-11 | 2020-10-01 | Chemistryrx | Pyrimidine derivative containing compositions |
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