CN1634064A - Itraconazole structurization emulsion composition and its preparing method - Google Patents
Itraconazole structurization emulsion composition and its preparing method Download PDFInfo
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- CN1634064A CN1634064A CN 200410098418 CN200410098418A CN1634064A CN 1634064 A CN1634064 A CN 1634064A CN 200410098418 CN200410098418 CN 200410098418 CN 200410098418 A CN200410098418 A CN 200410098418A CN 1634064 A CN1634064 A CN 1634064A
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- itraconazole
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Abstract
The invention discloses an itraconazole structurization emulsion composition and its preparing method, characterized in that is a kind of cooperative composition, which comprises itraconazol, triglyceride, tension conditioning agent and water. The composition has the advantages of continuous release and smaller toxic and side actions.
Description
Technical field
The present invention relates to a kind of Itraconazole structurization emulsion composition and preparation method thereof, it is characterized in that it is a kind of cooperative compositions, wherein comprises itraconazole, fatty acid triglycercide, tension regulator and water.Compare with the itraconazole kind of listing, have and advantage such as continue to discharge, toxicity is little.
Background technology
Itraconazole is the synthetic antifungal agent of second filial generation triazole type, and its capsule and oral liquid are applied to clinical already.The appearance of itraconazole injection is to the new selection of deep fungal infection treatment having increased.
Main component: itraconazole
Chemical name: (±)-cis-4-[4-[4-[4-[[2-(2, the 4-Dichlorobenzene base)-2-(1H-1,2,4-triazole-1-methyl)-1,3-dioxolanes-4-yl] methoxyl group] phenyl]-the 1-piperazine] phenyl]-2,4-dihydro-2-(1-first propyl group)-3H-1,2,4-triazole-3-ketone
Molecular formula: C
35H
38Cl
2N
8O
4
Molecular weight: 705.64
Structural formula:
Be distributed in behind the Itraconazole injection intravenously administrable in the tissues such as each body fluid and kidney, liver, bone, stomach, spleen and muscle, susceptible position of some funguses such as skin, sebum, lung and female genital tract isoconcentration are higher, and lipotropy high because of protein binding rate and medicine can keep a couple of days it in tissue.In addition, a small amount of distribution is also arranged in horny layer and the hair, trace is only arranged in the milk.Itraconazole mainly at liver through CYP3A4 (a kind of gene hypotype of hepatocyte metabolic enzyme Cytochrome P450) metabolism, main metabolites is for having active R 63373, mainly through bile and homaluria.
The untoward reaction of Itraconazole injection has: side effect of digestive tract, and serum creatinine increases, erythra such as maculopapule, urticaria, edema, central nervous system's reaction it should be noted that Itraconazole injection can cause hepar damnification and heart failure.Animal experiment shows that it has negative inotropic action to cardiac muscle.
The present invention is the oil-in-water type structured emulsion, and toxicity is low, particle diameter is little, is particularly suitable for intravenously administrable, also can local topical or orally use.Because product is in that significantly not lose itraconazole active and do not destroy under the condition of emulsion stability, aseptic filtration or moist heat sterilization, so that the asepticize of the present composition has obtained guarantee.The present composition also has long shelf life, is suitable for stable commercially available prod.
Retrieve domestic and international pertinent literature, do not see that useful prescription provided by the invention and preparation method prepare the report of Itraconazole structurization emulsion.
Summary of the invention
The invention discloses a kind of Itraconazole structurization emulsion composition and preparation method thereof, it is characterized in that it is a kind of cooperative compositions, wherein comprises itraconazole, fatty acid triglycercide, tension regulator and water.Wherein every 1g fatty acid triglycercide contains one or both among 0.01-0.5g phospholipid or the poloxamer188; Fatty acid triglycercide is selected from one or more in the oil, as the oil phase (the highest 30%w/v compositions) of Oleum Glycines, Oleum Ricini, safflower oil, Oleum Camelliae, olive oil and medium chain triglyceride; Can also contain stabilizing agent, stabilizing agent can be cholesterol, fatty acid (carbon atom is from 6-20) or its sodium salt, cholic acid or deoxycholic acid and sodium salt thereof, and the weight ratio in system is: 0.1-1.5%, as oleic acid, capric acid etc.Tension regulator comprises one or both in glycerol, mannitol, the glucose; Phospholipid is selected from soybean phospholipid or egg yolk lecithin.
Itraconazole structurization emulsion, its preparation method comprises:
1) itraconazole is dispersed in the oil phase mix homogeneously;
2) tension regulator is dissolved in aqueous phase, mix homogeneously;
3) emulsifying agent is dispersed in aqueous phase, mix homogeneously;
4) regulate water PH to about 8-11;
5) under stirring condition, oil phase is joined aqueous phase, obtain coarse-texture Emulsion;
6) with coarse-texture Emulsion homogenizing to particle diameter less than 1.0 microns;
Filter, the structured emulsion of under nitrogen atmosphere homogenizing being crossed is filled in the glass container, closes glass container, the glass container that sealing is closed, and pass through the filling glass container that the autoclaving asepticize seals, sterile filling is promptly.
Wherein oil phase or water or biphase 75 ℃ of the maximum temperatures that in emulsion process, maintain.
That Itraconazole structurization emulsion, its route of administration comprise is oral, local application and muscle or intravascular injection.
In main embodiment of the present invention, itraconazole is dispersed in the oil phase, and Itraconazole powder is coated by oil.Lecithin as emulsifying agent is dispersed in aqueous phase.
The present invention will be set forth by the mode of embodiment.These embodiment only are illustratives, never are to be used for restriction originally
Scope of invention.
Embodiment one:
Itraconazole (0.5%w/v); Oil phase Oleum Glycines (20%w/v); Emulsifying agent purification lecithin (1.2%w/v); Tension regulator glycerol (2.25%w/v) and water (in right amount to 100% (volume)).
Prepare by following method: the present invention is by being dispersed in itraconazole in the vegetable oil; Prepare water by in water, adding glycerol; Then purification lecithin is dispersed in aqueous phase; Regulate water PH to 10.0; Under stirring condition, add the oil that contains itraconazole to aqueous phase, obtain thick Emulsion; Thick Emulsion to the particle diameter of homogenize is lower than 1 micron; Filter by being lower than 1 micron filter membrane, join in the glass container under nitrogen atmosphere, close glass container, the glass that sealing is closed carries out asepticize by autoclaving to the filling containers that seals and handles.
Embodiment two:
Itraconazole (0.5%w/v); Oil phase Oleum Glycines (20%w/v); Emulsifying agent purification lecithin (1.0%w/v), poloxamer188 (1.0%w/v); Tension regulator glycerol (2.0%w/v) and water (in right amount to 100% (volume)).
Prepare by following method: the present invention is by being dispersed in itraconazole in the vegetable oil; Prepare water by in water, adding glycerol; Then purification lecithin and poloxamer188 (are dispersed in aqueous phase; Regulate water PH to 10.0; Under stirring condition, add the oil that contains itraconazole to aqueous phase, obtain thick Emulsion; Thick Emulsion to the particle diameter of homogenize is lower than 1 micron; Filter by being lower than 1 micron filter membrane, join in the glass container under nitrogen atmosphere, close glass container, the glass that sealing is closed carries out asepticize by autoclaving to the filling containers that seals and handles.
Embodiment three:
Itraconazole (0.8%w/v); Oil phase Oleum Glycines (20%w/v); Emulsifying agent purification lecithin (1.0%w/v), poloxamer188 (1.0%w/v); Tension regulator glycerol (2.8%w/v); Oleic acid (0.5%w/v) and water (in right amount to 100% (volume)).
Prepare by following method: the present invention is by being dispersed in itraconazole and oleic acid in the vegetable oil; Prepare water by in water, adding glycerol; Then purification lecithin and poloxamer188 (are dispersed in aqueous phase; Regulate water PH to 10.0; Under stirring condition, add the oil that contains itraconazole to aqueous phase, obtain thick Emulsion; Thick Emulsion to the particle diameter of homogenize is lower than 1 micron; Filter by being lower than 1 micron filter membrane, join in the glass container under nitrogen atmosphere, close glass container, the glass that sealing is closed carries out asepticize by autoclaving to the filling containers that seals and handles.
Embodiment four:
Itraconazole (0.5%w/v); Oil phase Oleum Glycines (20%w/v); Emulsifying agent purification lecithin (1.2%w/v); Cholesterol 0.6%; Tension regulator glycerol (2.25%w/v) and water (in right amount to 100% (volume)).
Prepare by following method: the present invention is by being dispersed in itraconazole and cholesterol in the vegetable oil; Prepare water by in water, adding glycerol; Then purification lecithin is dispersed in aqueous phase; Regulate water PH to 10.0; Under stirring condition, add the oil that contains itraconazole to aqueous phase, obtain thick Emulsion; Thick Emulsion to the particle diameter of homogenize is lower than 1 micron; Filter by being lower than 1 micron filter membrane, join in the glass container under nitrogen atmosphere, close glass container, the glass that sealing is closed carries out asepticize by autoclaving to the filling containers that seals and handles.
Embodiment five:
Itraconazole (0.8%w/v); Oil phase Oleum Glycines (20%w/v); Emulsifying agent purification lecithin (1.0%w/v); Poloxamer188 (1.0%w/v); Cholesterol 0.6%; Tension regulator glycerol (2.5%w/v) and water (in right amount to 100% (volume)).
Prepare by following method: the present invention is by being dispersed in itraconazole and cholesterol in the vegetable oil; Prepare water by in water, adding glycerol; Then purification lecithin and poloxamer188 are dispersed in aqueous phase; Regulate water PH to 10.0; Under stirring condition, add the oil that contains itraconazole to aqueous phase, obtain thick Emulsion; Thick Emulsion to the particle diameter of homogenize is lower than 1 micron; Filter by being lower than 1 micron filter membrane, join in the glass container under nitrogen atmosphere, close glass container, the glass that sealing is closed carries out asepticize by autoclaving to the filling containers that seals and handles.
Effect experiment:
We have studied the toxicity situation by the Emulsion of the inventive method preparation, are variable with the pattern of adding itraconazole and purification lecithin wherein.Emulsion toxicity reflection according to the preparation of the method for specific embodiment sees the following form:
| Embodiment | Itraconazole | Lecithin | Toxicity |
| ????I) | Oil phase | Water | Do not demonstrate the cardiac toxicity sign |
| ????II) | Water | Water | Demonstrate the cardiac toxicity sign |
| ????III) | Oil phase | Oil phase | Demonstrate the cardiac toxicity sign |
In the preparation process of technology, investigate lecithin and be dispersed in oil phase or water, carried out mice, rat and the research of Canis familiaris L. toxic.Toxicity research clearly illustrates that the Emulsion that is made by the inventive method is a kind of cooperative compositions.
Example I
The recipe quantity of structured emulsion is:
1) itraconazole 1.0g
2) Oleum Glycines 40.0g
3) purification lecithin 2.4g
4) glycerol 4.5g
5) oleic acid 1.0g
6) sodium hydroxide is an amount of, regulates pH10.0, and it is an amount of to add water, to 200ml.
Utilize aerojet grinder micronization Itraconazole powder, obtain particle size range less than 10 microns powder.
By 1g itraconazole (micronization) being dispersed in the 40g Oleum Glycines preparation oil phase.
, and then be dispersed in the 2.4g lecithin preparation water by the 4.5g glycerol is joined in the 150ml water.Utilize sodium hydrate aqueous solution to regulate pH to 10.0.
Under high-speed stirred, the above-mentioned oil phase that makes is joined aqueous phase.Utilize water that volume is transferred to 200ml.The Emulsion that forms is passed the high-pressure uniform device.Repeat uniform treatment, detect with laser particle analyzer, 50% particle diameter is 0.3 μ m.
Detailed step according to example I provides carries out toxicity research with the sterile product that obtains, and the result does not produce the cardiac toxicity sign.This shows, purification lecithin is joined water, is that the present invention recommends.
Example II
The recipe quantity of structured emulsion is:
1) itraconazole 1.0g
2) Oleum Glycines 40.0g
3) purification lecithin 2.4g
4) glycerol 4.5g
5) oleic acid 1.0g
6) sodium hydroxide is an amount of, regulates pH10.0, and it is an amount of to add water, to 200ml.
Utilize aerojet grinder micronization Itraconazole powder, obtain particle size range less than 10 microns powder.
By 1g itraconazole (micronization), 2.4g lecithin and 4.5g glycerol are distributed in 150ml pH to 10.0 water, stir, join in the 40g Oleum Glycines, under high-speed stirred, the above-mentioned oil phase that makes is joined aqueous phase.Utilize water that volume is transferred to 200ml.The Emulsion that forms is passed the high-pressure uniform device.Repeat uniform treatment, detect with laser particle analyzer, 50% particle diameter is 0.3 μ m.
Detailed step according to example II provides carries out toxicity research with the sterile product that obtains, and the result produces the cardiac toxicity sign.This shows, itraconazole and purification lecithin are joined water, is not that the present invention recommends.
EXAMPLE III
The recipe quantity of structured emulsion is:
1) itraconazole 1.0g
2) Oleum Glycines 40.0g
3) purification lecithin 2.4g
4) glycerol 4.5g
5) oleic acid 1.0g
6) sodium hydroxide is an amount of, regulates pH 10.0, and it is an amount of to add water, to 200ml.
Utilize aerojet grinder micronization Itraconazole powder, obtain particle size range less than 10 microns powder.
By 1g itraconazole (micronization) and 2.4g lecithin being dispersed in the 40g Oleum Glycines preparation oil phase.
By the 4.5g glycerol is joined in the 150ml water.Utilize sodium hydrate aqueous solution to regulate pH to 10.0.
Under high-speed stirred, the above-mentioned oil phase that makes is joined aqueous phase.Utilize water that volume is transferred to 200ml.The Emulsion that forms is passed the high-pressure uniform device.Repeat uniform treatment, detect with laser particle analyzer, 50% particle diameter is 0.3 μ m.
Detailed step according to EXAMPLE III provides carries out toxicity research with the sterile product that obtains, and the result produces the cardiac toxicity sign.This shows, purification lecithin is joined oil phase, is not that the present invention recommends.
Found that in the methods of the invention, when itraconazole is suspended in the oil phase, then do not observe these signs.This may be because the oil tank effect (reservoir effect) that Emulsion oil droplet and Kuppfer cell cause.This low rate of release can cause having the monomer itraconazole in the blood plasma behind the injectable emulsion, thereby reduces toxicity.
Itraconazole is dispersed in the observed result that oil phase and lecithin is dispersed in aqueous phase and shows that the Emulsion that toxicity is very low has very strong interaction between oil droplet and itraconazole.Therefore, Itraconazole emulsion can be considered to the storage tank of the itraconazole of monomeric form, and because the preparation stability height, so as long as a spot of free itraconazole just can continue to discharge.The itraconazole of monomeric form can stably combine with fungal cell's ergosterol, and to the cholesterol inertia of host mammal cell, therefore the toxicity that causes is lower.In the itraconazole preparation of routine, the oligomer of existence self association during the free high emission levels of itraconazole in blood plasma can cause circulating.These oligomers interact with the cholesterol that contains host cell membrane, thereby cause higher toxicity.This has just explained with conventional formulation and has compared, the low principle of Itraconazole emulsion toxicity of the present invention.
Claims (10)
1, a kind of Itraconazole structurization emulsion composition and preparation method thereof is characterized in that it is a kind of cooperative compositions, wherein comprises itraconazole, fatty acid triglycercide, tension regulator and water.
2, according to the Itraconazole structurization emulsion of claim 1, wherein every 1g fatty acid triglycercide contains one or both among 0.01-0.5g phospholipid or the poloxamer188.
3, be selected from the oil one or more according to the fatty acid triglycercide of claim 1, as the oil phase (the highest 30%w/v compositions) of Oleum Glycines, Oleum Ricini, safflower oil, Oleum Camelliae, olive oil and medium chain triglyceride.
4, according to the structured emulsion of claim 1, can also contain stabilizing agent, stabilizing agent can be cholesterol, fatty acid or its sodium salt, cholic acid or deoxycholic acid and sodium salt thereof, and the weight ratio in system is: 0.1-2.5%.
5,, comprise in glycerol, mannitol, the glucose one or both according to the tension regulator of claim 1.
6,, be selected from soybean phospholipid or egg yolk lecithin according to the phospholipid in the claim 2.
7,, be fatty acid carbons atom one or more from 6-20 according to the stabilizing agent in the oil of being scattered in the claim 4.As oleic acid, capric acid etc.
8, according to the structured emulsion of claim 1, its preparation method is as follows:
Itraconazole is dispersed in the oil phase, and Itraconazole powder is coated by oil, and the lecithin that is used as emulsifying agent is dispersed in aqueous phase.Concrete preparation method comprises:
1) itraconazole is dispersed in the oil phase mix homogeneously;
2) tension regulator is dissolved in aqueous phase, mix homogeneously;
3) emulsifying agent is dispersed in aqueous phase, mix homogeneously;
4) regulate water PH to about 8-11;
5) under stirring condition, oil phase is joined aqueous phase, obtain coarse-texture Emulsion;
6) with coarse-texture Emulsion homogenizing to particle diameter less than 1.0 microns;
7) filter, the structured emulsion of under nitrogen atmosphere homogenizing being crossed is filled in the glass container, closes glass container, the glass container that sealing is closed, and pass through the filling glass container that the autoclaving asepticize seals, sterile filling is promptly.
9, the preparation method in according to Claim 8, wherein oil phase or water or the biphase maximum temperature of keeping in emulsion process are no more than 75 ℃.
10, according to the Itraconazole structurization emulsion of claim 1, that its route of administration comprises is oral, local application, muscle or intravenous injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410098418 CN1634064A (en) | 2004-12-10 | 2004-12-10 | Itraconazole structurization emulsion composition and its preparing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410098418 CN1634064A (en) | 2004-12-10 | 2004-12-10 | Itraconazole structurization emulsion composition and its preparing method |
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| CN1634064A true CN1634064A (en) | 2005-07-06 |
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| CN 200410098418 Pending CN1634064A (en) | 2004-12-10 | 2004-12-10 | Itraconazole structurization emulsion composition and its preparing method |
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