CN101019833A - Oil-in-oil nonaqueous microemulsion used as medicine carrier and its medicine prepn - Google Patents
Oil-in-oil nonaqueous microemulsion used as medicine carrier and its medicine prepn Download PDFInfo
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Abstract
The present invention discloses oil-in-oil nonaqueous microemulsion used as medicine carrier and its medicine preparation. The oil-in-oil nonaqueous microemulsion consists of oil phase I, oil phase II, surfactant and co-surfactant, and can dissolve water insoluble medicines to prepare microemulsion. The nonaqueous microemulsion has the advantages of no hydrolysis and long effective period, slow or controlled release of medicine, nanometer level dispersion of water insoluble medicine and obviously raised bioavailability. For example, the present invention can obtain bioavailability of puerarin microemulsion and puerarin sol as high as 40.41 % and 52.68 % separately.
Description
Technical field
The invention belongs to a kind of pharmaceutical preparation carrier, specifically is a kind of oil-in-oil nonaqueous microemulsion as pharmaceutical carrier, and it can be used as the solvent or the carrier of one or more medicines or active component, and is prepared into the dispersive pharmaceutical preparation of nanoscale thus.
Background technology
Microemulsion is by two kinds of (or two or more) immiscible liquid, under the effect of parents' chemical compound, forms appearance transparent or translucent, isotropic, thermodynamically stable liquid liquid dispersion.Microemulsion under the ordinary meaning is moisture microemulsion, generally is made up of water, oil, surfactant and cosurfactant.Microemulsion is a kind of of nanometer disperse system, and its size is between 10～100nm.In pharmaceuticals industry; microemulsion formulation can improve insoluble drug dissolubility in water; improve bioavailability of medicament; the protection biochemical drug is avoided the destruction of gastro-intestinal Fluid and is decomposed; thereby; microemulsion has bigger using value as pharmaceutical carrier with in drug delivery system, caused that medical worker shows great attention to.Have many medicines water insoluble in pharmacy, it can not well be scatter in gastrointestinal tract, makes medicine well not absorbed by gastrointestinal tract, and bioavailability is low, and curative effect is not good enough.For medicine can be disperseed in gastrointestinal tract and absorb fully, pharmacy worker can be dispersed in medicine in the microemulsion, and medicine is nanoscale and disperses, and impels medicine and gastrointestinal contact area to increase, make the absorption of medicine increase, improved the thing availability significantly.
Yet, existing microemulsion system, it generally all is moisture microemulsion, the medicine that is insoluble in water must be dissolved in the middle of the oil phase of oil-in-water microemulsion, need select different oil phases to dissolve to different medicines, but the oil phase of can the fulfilling medicinal condition and can successfully prepare moisture microemulsion again is not a lot, numerous poorly water soluble drugs is impossible in the middle of can being dissolved in these limited oil phases, most poorly water soluble drugs can be made microemulsion and can can't make the micro emulsion drug carrying body by dissolved medicinal oil phase again because of can not find, so moisture microemulsion has limited the scope of application of micro emulsion drug carrying system.In view of the above, the present invention has selected two kinds of immiscible medicinal oil phases to be prepared into oily oil-in (O/O) microemulsion, promptly water-free non-water microemulsion according to the essential condition that microemulsion forms.Because biphase all is organic faciess, so the more or less freely microemulsion that is prepared into.Therefore non-water microemulsion has enlarged alternative medicinal oil phase scope greatly.At present, non-water microemulsion has some research reports aspect chemical industry, but used prescription is not a pharmaceutic adjuvant, and toxicity is bigger.
Need to prove that non-water microemulsion of the present invention is different from pharmaceutical carriers such as existing self-microemulsion, micro emulsion composition or microemulsion preconcentrate, their minimum problems that has two each and every one aspects: (1) contains the high surfaces activating agent, especially self-microemulsion, the amount of its surfactant is usually above more than 30%; (2) need could form microemulsion by gastro-intestinal Fluid and gastrointestinal wriggling, so microemulsion particle diameter and particle size distribution are difficult to determine that particle diameter and particle size distribution then are the important quality index of microemulsion system.
Summary of the invention
The purpose of this invention is to provide a kind of oil-in-oil nonaqueous microemulsion and pharmaceutical preparation thereof as pharmaceutical carrier, a kind of water-less environment is provided and is the non-toxic pharmaceutical carrier of biocompatibility, be used for dissolving or dispersion medicine or active component, be prepared into the pharmaceutical preparation of nano-grade medicine thus.
By this non-water microemulsion, the inventor has prepared absolute bioavailability up to non-water microemulsion of the puerarin more than 40% and soft capsule thereof.
The non-water microemulsion of oily oil-in of the present invention has as the advantage of pharmaceutical carrier: (1) has enlarged the kind scope of alternative medicinal oil phase greatly, makes more medicine can be prepared into microemulsion or colloidal sol, and this is difficult to realize for aqueous microemulsion; (2) because the biphase organic facies that is has certain sympathy, make that the preparation of microemulsion is more or less freely, and can obtain stable height, the wide microemulsion system of the biphase compatibility; (3) the non-water microemulsion of oily oil-in of the present invention also can make the consumption of surfactant reduce to seldom under appropriate composition, also can be zero, and this is another characteristics of the present invention; (4) can extremely easily further be prepared into the solid nano granule by non-water microemulsion of the present invention.
The non-water micro emulsion drug carrying of oil oil-in system is a kind of brand-new medicine-carried system that the inventor progressively generates in putting into practice work, because foreign minister is not moisture in it, it has as pharmaceutical carrier: (1), for the medicine that is easy to hydrolysis, with non-water microemulsion is carrier, can avoid hydrolysis, the effect duration of prolong drug; (2), for absorbing medicine rapidly, be carrier with non-water microemulsion, its absorption is slowed down, thereby reach the effect of slow release or controlled release; (3), for water-insoluble drug, be carrier with non-water microemulsion, can make medicine arrive nanoscale and disperse, thereby improve drug bioavailability.
Technical scheme of the present invention is as follows:
A kind of oil-in-oil nonaqueous microemulsion agent as pharmaceutical carrier of the present invention, its prescription comprise does not at least dissolve each other or sl. sol. two oil phases, comprises that also any one or two kinds of in two kinds of surfactant and the cosurfactants contain.
A kind of oil-in-oil nonaqueous microemulsion as pharmaceutical carrier is characterized in that, its prescription comprises at least and not dissolving each other or sl. sol. two oil phases, also comprises any one or two kinds of in surfactant and the cosurfactant.Its distribution of weight ratio scope is:
Oil phase 1 10-89 part
Oil phase 2 10-89 parts
Surfactant 0-35 part
Cosurfactant 0-40 part
Surfactant, cosurfactant can not be 0 simultaneously.
Wherein, oil phase 1 is an acceptable medicinal oil in the pharmacy, be selected from animal oil, vegetable oil, oleic acid and ester thereof, linoleic acid and ester thereof, isopropyl palmitate fat, myristic acid isopropyl ester, MCT Oil, liquid paraffin, simethicone, liquid paraffin,light, the mixture of one or more in above-mentioned:
Oil phase 2 is for the bigger organic solvent of acceptable polarity in the pharmacy and be not dissolved in or be dissolved in oil phase 1, is selected from alcohols, 1,2-alkanol, ketone, glycerol, Polyethylene Glycol, the mixture of one or more in above-mentioned;
Surfactant is an acceptable medicinal surfactant in the pharmacy, be selected from phospholipid, Tweens, spans, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer, card pool nurse, bile salts, higher fatty acid salt, the mixture of one or more in above-mentioned;
Cosurfactant is the chemical compound of acceptable in the pharmacy, be selected from ethanol, propanol, isopropyl alcohol, cholesterol, oleyl alcohol, propylene glycol, glycerol, acetone, ethyl acetate, amino acids, ethyl lactate, higher fatty acids and ester thereof, the mixture of one or more in above-mentioned.
Described oil-in-oil nonaqueous microemulsion as pharmaceutical carrier, it is characterized in that, be selected from vegetable oil, include but not limited to soybean oil, Oleum Arachidis hypogaeae semen, Oleum Brassicae campestris, low erucic acid rapeseed oil, Semen Maydis oil, Oleum Gossypii semen, Oleum Helianthi, Oleum Ricini, Oleum sesami, Oleum Cocois, olive oil, almond oil, Petiolus Trachycarpi oil, laurel fat; Higher fatty acids and ester thereof include but not limited to oleic acid, ethyl oleate, olein class, linoleic acid, glyceryl linoleate class; Described alcohols includes but not limited to ethanol, propanol; Described 1, the 2-alkanol includes but not limited to 1,2-propylene glycol, 1,2-pentanediol; Described ketone includes but not limited to acetone; Described amino acids includes but not limited to glycine, lysine; Described phospholipid, higher fatty acid salt include but not limited to soybean lecithin or Ovum Gallus domesticus Flavus lecithin, calcium oleate, magnesium oleate.
Described oil-in-oil nonaqueous microemulsion as pharmaceutical carrier is characterized in that, oil phase 1 adopts following combination with oil phase 2:
(1), oil phase 1 is selected from vegetable oil, glyceryl dioleate and glycerol trioleate, dilinoleic acid glyceride and Trilinoleyl glyceride, liquid paraffin, liquid paraffin,light, simethicone, the mixture of one or more in them; Oil phase 2 is selected from ethanol, 1,2-alkanol, glycerol, Polyethylene Glycol, the mixture of one or more in them; Or
(2), oil phase 1 is selected from: MCT Oil, myristic acid isopropyl ester, isopropyl palmitate fat, the mixture of one or more in them; Oil phase 2 is selected from 1,2-alkanol, glycerol, Polyethylene Glycol, the mixture of one or more in them; Or
(3), oil phase 1 is selected from: oleic acid, glyceryl monooleate, linoleic acid, single glyceryl linoleate, the mixture of one or more in them; Oil phase 2 is selected from glycerol, Polyethylene Glycol, the mixture of one or more in them.
More optimum organization, oil phase 1 are selected from one or more mixture of vegetable oil (comprising soybean oil, Oleum Brassicae campestris, Oleum Arachidis hypogaeae semen); Oil phase 2 is selected from one or more mixture of ethanol, propylene glycol; Surfactant is selected from phospholipid; Cosurfactant is selected from one or more mixture of ethyl lactate, oleic acid and ester thereof.
Oil phase 1: oil phase 2: surfactant: the distribution of weight ratio scope of cosurfactant: 10-89: 10-89: 0-35: 0-40; Preferred weight allocation proportion scope: 30-70: 15-45: 5-25: 0-20; Preferred weight allocation proportion scope: 15-45: 30-70: 5-25: 0: 20.
Stir to clarify transparent or semitransparent solution a little after they are mixed according to a certain percentage or mix, this is non-water microemulsion.
Described oil-in-oil nonaqueous microemulsion as pharmaceutical carrier is characterized in that the distribution of weight ratio scope of oil phase 1, oil phase 2 and surfactant, cosurfactant is:
Oil phase 1 30-70 part
Oil phase 2 20-50 parts
Surfactant 0-25 part
Cosurfactant 0-30 part.
Described oil-in-oil nonaqueous microemulsion as pharmaceutical carrier is characterized in that the distribution of weight ratio scope of aqueous favoring, oil phase and surfactant, cosurfactant is:
Oil phase 1 20-50 part
Oil phase 2 30-70 parts
Surfactant 0-25 part
Cosurfactant 0-30 part.
Described oil-in-oil nonaqueous microemulsion as pharmaceutical carrier is characterized in that aqueous favoring, oil phase and the surfactant of comparatively optimizing, the distribution of weight ratio scope of cosurfactant are:
Oil phase 1 40-60 part
Oil phase 2 30-40 parts
Surfactant 10-25 part
Cosurfactant 15-30 part.
Described oil-in-oil nonaqueous microemulsion as pharmaceutical carrier is characterized in that aqueous favoring, oil phase and the surfactant of comparatively optimizing, the distribution of weight ratio scope of cosurfactant are:
Oil phase 1 30-40 part
Oil phase 2 40-60 parts
Surfactant 10-25 part
Cosurfactant 20-30 part.
Described oil-in-oil nonaqueous microemulsion as pharmaceutical carrier is characterized in that aqueous favoring, oil phase and the surfactant of comparatively optimizing, the distribution of weight ratio scope of cosurfactant are:
Oil phase 1 20-35 part
Oil phase 2 20-35 parts
Surfactant 0-15 part
Cosurfactant 20-30 part.
The described pharmaceutical preparation that is used as the oil-in-oil nonaqueous microemulsion of pharmaceutical carrier is characterized in that wherein containing oil-in-oil nonaqueous microemulsion carrier and medicinal active ingredient puerarin, and the distribution of weight ratio scope of the two is:
Medicinal non-water micro emulsion carrier; 6-15 part
Puerarin: 1-5 part
The described pharmaceutical preparation that is used as the oil-in-oil nonaqueous microemulsion of pharmaceutical carrier is characterized in that wherein containing oil-in-oil nonaqueous microemulsion carrier and medicinal effective site propolis, and the distribution of weight ratio scope of the two is:
Medicinal non-water micro emulsion carrier: 8-15 part
Propolis: 1-8 part
The propolis colloidal sol that is transformed into by this microemulsion.
The described pharmaceutical preparation that is used as the oil-in-oil nonaqueous microemulsion of pharmaceutical carrier is characterized in that wherein containing oil-in-oil nonaqueous microemulsion carrier and one or more active ingredients, and the distribution of weight ratio scope of the two is:
Medicinal non-water micro emulsion carrier: 5-20 part
One or more active ingredients: 1-10 part
Active ingredient comprises chemicals, biochemical drug, Chinese medicine extract, effective ingredient in Chinese, the chemical analysis with nutrition or health care, pesticide.
The described pharmaceutical preparation that is used as the oil-in-oil nonaqueous microemulsion of pharmaceutical carrier is characterized in that it is microemulsion, colloidal sol or nano-powder form; Its dosage form includes but not limited to powder, granule, tablet, capsule, soft capsule, pill, drop pill, medicated wine, syrup, oral solution, injection, infusion solution, injection lyophilized powder, suppository, microcapsule, ointment, aerosol, membrane.
The present invention also comprises and is used for pharmaceutically acceptable additive in addition, includes but not limited to: antiseptic, antioxidant, viscosity modifier, excipient, lubricant, binding agent, disintegrating agent or the like.
For example, suitable pharmaceutic adjuvant can be added to this pharmaceutical composition,, then this powder or granule be inserted in the hard capsule, prepare hard capsule thus this mixture process powdered or graininess; Antioxidant and other suitable adjuvants are joined pharmaceutical composition,, make soft capsule with the content of this mixture as soft capsule; Suitable additive is added in the pharmaceutical composition, and compacting can prepare tablet in flakes thus.They can be used as industries such as pharmaceutical preparation, cosmetics, health product, food, industrial or agricultural.
The non-water microemulsion of the present invention has three big advantages: (1), for the medicine that is easy to hydrolysis is carrier with non-water microemulsion, can avoid hydrolysis, the effect duration of prolong drug; (2), for absorbing medicine rapidly, be carrier with non-water microemulsion, its absorption is slowed down, thereby reach the effect of slow release or controlled release; (3), for water-insoluble drug, be carrier with non-water microemulsion, can make medicine arrive nanoscale and disperse, thereby improve drug bioavailability significantly.
The present invention has been used to above-mentioned non-water microemulsion to prepare the nanometer system of medicines such as puerarin microemulsion, puerarin colloidal sol, propolis.Wherein the bioavailability of puerarin microemulsion, puerarin colloidal sol is up to 40.41% and 52.68%.
Description of drawings
Fig. 1 is embodiment 7 gained puerarin colloidal sol transmission electron microscope pictures.
The specific embodiment
Following examples are used to further specify the present invention, but never are the restrictions to its scope.
Example 1
| Component | Amount (g) |
| Soybean oil | 5.0 |
| Propylene glycol | 2.1 |
| Ethyl lactate | 1.2 |
| Phospholipid | 2.2 |
| Olein | 1.5 |
Above-mentioned each component is mixed in proportion the back gentle agitation
Example 2
| Component | Amount (g) |
| Paraffin | 4.5 |
| Propylene glycol | 2.0 |
| Ethyl lactate | 1.2 |
| Ethanol | 1.0 |
| Sorbester p17 | 1.8 |
| Polysorbate60 | 0.6 |
Example 3
| Component | Amount (g) |
| MCT Oil | 4.5 |
| Glycerol | 1.3 |
| PEG400 | 1.2 |
| Oleic acid | 3.8 |
Example 4
| Component | Amount (g) |
| Salad oil | 5.2 |
| Ethanol | 4.7 |
| Glycerol | 0.8 |
| Phospholipid | 2.4 |
| Oleic acid | 2.6 |
Example 5
| Component | Amount (g) |
| The myristic acid isopropyl ester | 3.4 |
| Glycerol | 6.6 |
| PEG400 | 1.3 |
| Polyoxyethylene hydrogenated Oleum Ricini | 2.8 |
| Glycine | 0.9 |
Example 6
Puerarin microemulsion soft capsules according to the preparation of the prescription of example 1
| Component | Amount (g) |
| Puerarin | 1.3 |
| Example 1 | 12.0 |
| Vitamin E | 0.2 |
Said components is mixed in proportion, be stirred to transparent, promptly get the puerarin soft capsule content, the rubber of soft capsule adopts gelatin, glycerol, water and modified component to make according to a conventional method, can also add materials such as some antioxidant, coloring agent, opacifier in the rubber.The content of getting above-mentioned soft capsule is filled in soft capsule promptly.
Example 7
Puerarin colloidal sol soft capsule according to the preparation of the prescription of example 4
| Component | Amount (g) |
| Puerarin | 1.0 |
| Example 4 | 13.7 |
| Vitamin E | 0.25 |
Said components is mixed in proportion, be stirred to transparently, being decompressed to does not have the alcohol flavor, promptly gets puerarin colloidal sol content, the rubber of soft capsule adopts gelatin, glycerol, water and modified component to make according to a conventional method, can also add materials such as some antioxidant, coloring agent, opacifier in the rubber.The content of getting above-mentioned soft capsule is filled in soft capsule promptly.
Embodiment 8 propolis sol systems
| Component | Amount (g) |
| Propolis | 1.0 |
| Example 4 | 10.0 |
| Vitamin E | 0.2 |
Said mixture is mixed in proportion, and must mix the clarification system, and being decompressed to does not have the alcohol flavor, gets propolis nano-particle sol system.
Embodiment 9 kurarinone microemulsion
| Component | Amount (g) |
| Kurarinone | 1.3 |
| Example 2 | 12.0 |
| Vitamin E | 0.2 |
Test example 1: absorption test in the body
In order to investigate the bioavailability that is included in puerarin preparation of the present invention, below the invention preparation among the embodiment 6, the invention preparation among the embodiment 7, puerarin suspensoid, puerarin glucose injection (Jiangsu is raised and given river pharmaceutical factory) are carried out in the body bioavailability investigate.Wherein, the puerarin suspensoid is with mixed the getting of an amount of distilled water of puerarin crude drug adding.
Puerarin suspensoid medication and blood sampling time are got 66 of Kunming mouses, be divided into 11 groups (6 of every groups) at random, respectively corresponding 1 time point of each group, fasting is 12 hours before the experiment, but can't help water, irritate stomach respectively by single dose 0.2mg/g and give mice puerarin suspension, after administration 10,20,25,30,35,40,50,60,75,90,120min plucks eyeball and gets blood, blood sample is placed the centrifuge tube of the 1.5ml that handles with heparin sodium, the centrifugal 10min separated plasma of 3000r/min immediately, get upper plasma be stored in preserve in subzero 20 ℃ of refrigerators to be measured.
Puerarin glucose injection medication and blood sampling time are got 55 of Kunming mouses, be divided into 10 groups (6 of every groups) at random, respectively corresponding 1 time point of each group, fasting is 12 hours before the experiment, but can't help water, irritate stomach respectively by single dose 0.01mg/g and give mice puerarin suspension, after administration 1,5,10,15,20,30,40,60,80,100min plucks eyeball and gets blood, blood sample is placed the centrifuge tube of the 1.5ml that handles with heparin sodium, the centrifugal 10min separated plasma of 3000r/min immediately, get upper plasma be stored in preserve in subzero 20 ℃ of refrigerators to be measured.
Invention preparation medication among the embodiment 6 and blood sampling time are got 78 of Kunming mouses, be divided into 13 groups (6 of every groups) at random, respectively corresponding 1 time point of each group, fasting is 12 hours before the experiment, but can't help water, irritate stomach respectively by single dose 0.2mg/g and give the preparation of the invention among the mice embodiment 1, after administration 10,20,30,40,50,60,90,120,180,240,360,480,720min plucks eyeball and gets blood, blood sample placed the 1.5ml that handles with heparin sodium from pipe, the centrifugal 10min separated plasma of 3000r/min immediately, get upper plasma be stored in preserve in subzero 20 ℃ of refrigerators to be measured.
Invention preparation medication among the embodiment 7 and blood sampling time are got 78 of Kunming mouses, be divided into 13 groups (6 of every groups) at random, respectively corresponding 1 time point of each group, fasting is 12 hours before the experiment, but can't help water, irritate stomach respectively by single dose 0.2mg/g and give the preparation of the invention among the mice embodiment 7, after administration 10,20,30,40,50,60,90,120,240,360,480,720,1440min plucks eyeball and gets blood, blood sample placed the 1.5ml that handles with heparin sodium from pipe, the centrifugal 10min separated plasma of 3000r/min immediately, get upper plasma be stored in preserve in subzero 20 ℃ of refrigerators to be measured.
The processing of plasma sample, analyze accurate getting in the centrifuge tube that blood plasma 0.2ml puts 1.5ml, the accurate 0.2ml 0.58mol/ml Thyronorman alcoholic solution protein precipitation that adds, mix 3min on the eddy mixer, the centrifugal 10min of 12000r/min, get in the small sample bottle that supernatant is transferred to high performance liquid chromatograph, measure its blood drug level with high-efficient liquid phase technique, the results are shown in following table 1.
Chromatographic condition:
---chromatographic column:
---mobile phase: methanol: 0.1% Chinese holly Citron aqueous acid (30: 70)
---flow velocity: 1.0ml/min
---column temperature: 40 ℃
---detect wavelength: 250nm
---sampling volume: 30 μ l
Above-mentioned gained data are handled through pharmacokinetics software 3P87, and the gained data are as follows: puerarin injection, and puerarin suspensoid, embodiment 1 three's AUC is respectively:
AUC
Puerarin injection=276.75＜ug/ml 〉
*Min
AUC
The puerarin suspensoid=135.77＜ug/ml 〉
*Min
AUC
Example 6=2236.77＜ug/ml 〉
*Min
AUC
Example 7=2915.76＜ug/ml 〉
*Min
The bioavailability of puerarin suspensoid: 135.77/ (276.75*20) * 100%=2.45%
Puerarin microemulsion bioavailability in the example 6: 2236.77/ (276.75*20) * 100%=40.41%
Puerarin colloidal sol bioavailability in the example 7: 2915.76/ (276.75*20) * 100%=52.68%
Mouse experiment shows: in the example 6 and the puerarin of example 7 and significant raising has been arranged with respect to the bioavailability of puerarin suspensoid, the degree of its raising is astonishing.
Subordinate list 1
| Embodiment 6 | Blood sampling time (min) | 10 | 20 | 30 | 40 | 50 | 60 | 90 | 120 | 180 | 240 | 360 | 480 | 720 |
| Blood drug level (μ g/ml) | 2.5257 | 4.1632 | 5.3011 | 5.6319 | 5.3796 | 5.2070 | 4.6050 | 4.1754 | 3.5309 | 3.0653 | 2.3551 | 1.9369 | 0.8394 | |
| Embodiment 7 | Blood sampling time (min) | 10 | 20 | 30 | 40 | 50 | 60 | 90 | 120 | 180 | 300 | 480 | 720 | 1440 |
| Blood drug level (μ g/ml) | 1.8803 | 2.5515 | 2.9655 | 3.1129 | 3.3210 | 3.1103 | 2.8367 | 2.6359 | 2.4227 | 2.1246 | 1.7832 | 1.4126 | 0.6912 | |
| Injection | Blood sampling time (min) | 1 | 5 | 10 | 15 | 20 | 30 | 40 | 60 | 80 | 100 | |||
| Blood drug level (μ g/ml) | 20.938 | 14.688 | 8.6779 | 5.9539 | 4.6590 | 2.0549 | 0.9263 | 0.5572 | 0.3027 | 0.0134 | ||||
| The puerarin suspensoid | Blood sampling time (min) | 10 | 20 | 25 | 30 | 35 | 40 | 50 | 60 | 75 | 90 | 120 | ||
| Blood drug level (μ g/ml) | 0.5434 | 1.9490 | 2.1620 | 2.2169 | 1.9036 | 1.5505 | 1.2387 | 0.9425 | 0.7387 | 0.6740 | 0.3574 |
Claims (9)
1. the oil-in-oil nonaqueous microemulsion as pharmaceutical carrier is characterized in that, its prescription comprises at least and not dissolving each other or sl. sol. two oil phases, also comprises any one or two kinds of in surfactant and the cosurfactant; Its distribution of weight ratio scope is:
Oil phase 1 10-89 part
Oil phase 2 10-89 parts
Surfactant 0-35 part
Cosurfactant 0-40 part
Surfactant, cosurfactant can not be 0 simultaneously;
Wherein, oil phase 1 is an acceptable medicinal oil in the pharmacy, be selected from animal oil, vegetable oil, oleic acid and ester thereof, linoleic acid and ester thereof, isopropyl palmitate fat, myristic acid isopropyl ester, MCT Oil, liquid paraffin, simethicone, liquid paraffin,light, the mixture of one or more in above-mentioned;
Oil phase 2 for the bigger organic solvent of acceptable polarity in the pharmacy and be not dissolved in or micro dissolution in oil phase 1, be selected from alcohols, 1,2-alkanol, ketone, glycerol, Polyethylene Glycol, the mixture of one or more in above-mentioned;
Surfactant is an acceptable medicinal surfactant in the pharmacy, be selected from phospholipid, Tweens, spans, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer, card pool nurse, bile salts, higher fatty acid salt, the mixture of one or more in above-mentioned;
Cosurfactant is the chemical compound of acceptable in the pharmacy, be selected from ethanol, propanol, isopropyl alcohol, cholesterol, oleyl alcohol, propylene glycol, glycerol, acetone, ethyl acetate, amino acids, ethyl lactate, higher fatty acids and ester thereof, the mixture of one or more in above-mentioned.
2, the oil-in-oil nonaqueous microemulsion as pharmaceutical carrier according to claim 1, it is characterized in that, be selected from vegetable oil, include but not limited to soybean oil, Oleum Arachidis hypogaeae semen, Oleum Brassicae campestris, low erucic acid rapeseed oil, Semen Maydis oil, Oleum Gossypii semen, Oleum Helianthi, Oleum Ricini, Oleum sesami, Oleum Cocois, olive oil, almond oil, Petiolus Trachycarpi oil, laurel fat; Higher fatty acids and ester thereof include but not limited to oleic acid, ethyl oleate, olein class, linoleic acid, glyceryl linoleate class; Described alcohols includes but not limited to ethanol, propanol; Described 1, the 2-alkanol includes but not limited to 1,2-propylene glycol, 1,2-pentanediol; Described ketone includes but not limited to acetone; Described amino acids includes but not limited to glycine, lysine; Described phospholipid, higher fatty acid salt include but not limited to soybean lecithin or Ovum Gallus domesticus Flavus lecithin, calcium oleate, magnesium oleate.
According to the described oil-in-oil nonaqueous microemulsion of claim 1-2, it is characterized in that 3, oil phase 1 adopts following combination with oil phase 2 as pharmaceutical carrier:
(1), oil phase 1 is selected from vegetable oil, glyceryl dioleate and glycerol trioleate, dilinoleic acid glyceride and Trilinoleyl glyceride, liquid paraffin, liquid paraffin,light, simethicone, the mixture of one or more in them; Oil phase 2 is selected from ethanol, 1,2-alkanol, glycerol, Polyethylene Glycol, the mixture of one or more in them; Or
(2), oil phase 1 is selected from: MCT Oil, myristic acid isopropyl ester, isopropyl palmitate fat, the mixture of one or more in them; Oil phase 2 is selected from 1,2-alkanol, glycerol, Polyethylene Glycol, the mixture of one or more in them; Or
(3), oil phase 1 is selected from: oleic acid, glyceryl monooleate, linoleic acid, single glyceryl linoleate, the mixture of one or more in them; Oil phase 2 is selected from glycerol, Polyethylene Glycol, the mixture of one or more in them.
4, according to the described oil-in-oil nonaqueous microemulsion of one of claim 1 to 3, it is characterized in that the distribution of weight ratio scope of oil phase 1, oil phase 2 and surfactant, cosurfactant is as pharmaceutical carrier:
Oil phase 1 30-70 part
Oil phase 2 20-50 parts
Surfactant 0-25 part
Cosurfactant 0-30 part.
5, according to the described oil-in-oil nonaqueous microemulsion of one of claim 1 to 3, it is characterized in that the distribution of weight ratio scope of aqueous favoring, oil phase and surfactant, cosurfactant is as pharmaceutical carrier:
Oil phase 1 20-50 part
Oil phase 2 30-70 parts
Surfactant 0-25 part
Cosurfactant 0-30 part.
6, contain the described pharmaceutical preparation that is used as the oil-in-oil nonaqueous microemulsion of pharmaceutical carrier of one of claim 1 to 5, it is characterized in that wherein containing oil-in-oil nonaqueous microemulsion carrier and medicinal active ingredient puerarin, the distribution of weight ratio scope of the two is:
Medicinal non-water micro emulsion carrier: 6-15 part
Puerarin: 1-5 part.
7, contain the described pharmaceutical preparation that is used as the oil-in-oil nonaqueous microemulsion of pharmaceutical carrier of one of claim 1 to 5, it is characterized in that wherein containing oil-in-oil nonaqueous microemulsion carrier and medicinal effective site propolis, the distribution of weight ratio scope of the two is:
Medicinal non-water micro emulsion carrier: 8-15 part
Propolis: 1-8 part
The propolis colloidal sol that is transformed into by this microemulsion.
8, contain the described pharmaceutical preparation that is used as the oil-in-oil nonaqueous microemulsion of pharmaceutical carrier of one of claim 1 to 5, it is characterized in that wherein containing oil-in-oil nonaqueous microemulsion carrier and one or more active ingredients, the distribution of weight ratio scope of the two is:
Medicinal non-water micro emulsion carrier: 5-20 part
One or more active ingredients: 1-10 part
Active ingredient comprises chemicals, biochemical drug, Chinese medicine extract, effective ingredient in Chinese, the chemical analysis with nutrition or health care, pesticide.
9, contain the described pharmaceutical preparation that is used as the oil-in-oil nonaqueous microemulsion of pharmaceutical carrier of one of claim 6 to 8, it is characterized in that it is microemulsion or makes colloidal sol or the nano-powder form; Its dosage form includes but not limited to powder, granule, tablet, capsule, soft capsule, pill, drop pill, medicated wine, syrup, oral solution, injection, infusion solution, injection lyophilized powder, suppository, microcapsule, ointment, aerosol, membrane.
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| CN200710020157A CN101019833B (en) | 2007-02-16 | 2007-02-16 | Oil-in-oil nonaqueous microemulsion used as medicine carrier and its medicine preparation |
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| CN200710020157A CN101019833B (en) | 2007-02-16 | 2007-02-16 | Oil-in-oil nonaqueous microemulsion used as medicine carrier and its medicine preparation |
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| CN101019833A true CN101019833A (en) | 2007-08-22 |
| CN101019833B CN101019833B (en) | 2010-05-19 |
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