Non-toxic ion liquid, preparation method and application thereof
Technical field
The invention belongs to new ion liquid synthetic reaching in chemical material and the manufacturing field as a kind of new solvent, solubility promoter or tensio-active agent application in medicine, agricultural chemicals.
Background technology
Ionic liquid (Ionic Liquids) is meant by organic alkyl imidazole, quaternary amine, positive ion such as alkyl pyridine and different negative ion as, chlorion, BF
4 -, PF
6 -, CF
3CO
2 -, N (CN)
- 2Deng the low melting point organic molten salt of forming, they have many is liquid under room temperature even low temperature, therefore is referred to as ionic liquid at room temperature again.They have and do not have vapour pressure, and are thermally-stabilised good, (reaching as high as 300-400 ℃), good electrical conductivity; To organic compound, mineral compound, organometallics, gas is as H
2, CO, O
2Solvability is widely arranged; Can be also and organic solvent, water is miscible, or insoluble formation two-phase or heterogeneous reaction system; The most attractive is its polarity, the length that hydrophilic, close ester can be by alkyl carbon chain with select different negative ions to regulate, programmable solvent therefore is otherwise known as.Ionic liquid, has been used widely in the research fields such as electrochemistry at organic synthesis, novel material as new green solvent, and it has mainly been used: 1, replace volatile organic solvent, reduce environmental pollution; 2, solid-carried catalyst reduces the consumption of catalyzer; 3, improve Activity of Chemical Reaction and selectivity; 4, as electrochemical material such as battery etc.Above-mentioned ionic liquid is as 1-methyl-3-butyl imidazole hexafluorophosphate, in water, can produce hydrolysis and generate volatile deleterious HF and POF3, (R.P.Swalowski, J.D.Holbery, andR.D.Rogers, Green Chem., 2003,5,361.) 1-methyl-its acute toxicity of 3-butyl imidazole a tetrafluoro borate LD
50=1.4g/kg (female rats), LD
50=1.37g/kg (male rat) (J.Pernak, et.al., Ind.Eng.Chem.Res.2001,40,2379.), so these ionic liquids commonly used all are to have necessarily toxicly, can not be used for medicine or use as foodstuff additive.To at present, also there is not relevant ionic liquid to be used to prepare medicine or pesticides new formulation or as the report of foodstuff additive as a kind of new solvent, solubility promoter or tensio-active agent.In pharmaceutical industry, there are many medicines to be insoluble in water, are difficult to be absorbed by the body and utilize.Therefore solve the solvability of insoluble medicine in water, the raising bioavailability of medicament remains difficult point and the hot issue in the pharmaceutical industry.The method of often taking now is that medicine is dissolved in the oil phase, adds then that tensio-active agent is made emulsion or microemulsion improves bioavailability of medicament.But need to add a large amount of oil phases, simultaneously, also need add tensio-active agent.Some has side effect to human body these additives.Owing to tensio-active agent, the solubility promoter kind is very limited simultaneously, complicated process of preparation, and cost is higher.And can not solve all insoluble medicines deliquescent problem in water.
Summary of the invention
The purpose of this invention is to provide a kind of non-toxic ion liquid, it is used to prepare novel pharmaceutical formulation as new solvent, solubility promoter or tensio-active agent, can improve the solubleness of insoluble medicine in water, makes insoluble medicine
Design of the present invention is such.Because ionic liquid is programmable solvent, therefore by selecting different zwitterions good solvability to be arranged to insoluble medicine.Using as pharmaceutical auxiliary agent simultaneously need be nontoxic.It is used for preparation medicine or pesticides new formulation as new solvent, solubility promoter or tensio-active agent, can well improve the solubleness of a lot of insoluble medicines in water, insoluble medicine can be dissolved in water, thereby can better improve bioavailability of medicament.Particularly, non-toxic ion liquid of the present invention partly is made up of positively charged ion and negatively charged ion two, the raw material that its design philosophy is that to select at present be nontoxic or is used for medicine or foodstuff additive synthesizes ionic liquid, positively charged ion is made of the quaternary ammonium salts positively charged ion, negatively charged ion is made of carboxylic acid and derivative thereof, and structural formula is expressed as follows:
Carboxylic-acid negatively charged ion R=C in the formula
1-C
17Alkyl or its contain hydroxyl, carboxy derivatives as acetate, lactic acid, propionic acid, butyric acid, oxysuccinic acid, citric acid, tartrate, lauric acid, oleic acid, palmitinic acid, stearic acid etc.The many food or drug additive and life-time service of being used for of these organic carboxyl acids prove nontoxic.
Wherein, R in the quaternary ammonium salts positively charged ion
1, R
2, R
3, R
4Can be H, identical or different C
1-C
8Alkyl or its contain hydroxyl, carboxy derivatives.As: H ,-CH
3.-CH
2CH
3.-CH
2CH
2OH ,-CH
2CH
2COOH ,-(CH
2)
3CH
3Deng.Quaternary ammonium salts such as choline chloride 60 are the food or the drug additives of generally recognized as safe.
Above-mentioned non-toxic ion liquid can obtain by following two kinds of preparation methods:
The preparation method one:
Generate corresponding ionic liquid and water by quaternary amine alkali and organic carboxyl acid direct reaction, then water is prepared by the high vacuum underpressure distillation.Alkyl imidazole alkali exchanges by basic resin and prepares.Reaction formula is as follows:
The preparation method two:
In organic solvent, carry out ion-exchange, generate ionic liquid and inorganic salt by corresponding salt.Inorganic salt evaporate organic solvent and prepare ionic liquid by removing by filter, and reaction formula is as follows:
The security of above-mentioned non-toxic ion liquid is by to the small white mouse oral administration, measures its acute toxicity LD
50Estimate, concrete outcome is seen embodiment subordinate list 1.
Above-mentioned non-toxic ion liquid can well dissolve many in water the medicine of indissoluble, solution, microemulsion or submicron emulsion that simultaneously can insoluble medicine formation soluble in water is transparent or semitransparent.Its particle diameter is 50-300nm.Thereby can improve the bioavailability of insoluble medicine.Concrete implementation and operation is as follows:
Get one or more mixed liquid of ionic liquid, its ratio is by being added 0.1-100 times of medicines.Also can add some chaotropic agents such as ethanol, propylene glycol, glycerine, polyoxyethylene glycol etc., or tensio-active agent such as anionic surfactant such as sodium lauryl sulphate, sodium sulfonate, bile acide etc., amphoterics Yelkin TTS, nonionic surface active agent such as spans, Tweens and sucrose fatty ester mix use.Its add-on is add 0.1-100 times of medicine.
Insoluble medicine is dissolved in the above-mentioned solution, and insoluble medicine comprises, Western medicine class such as taxanes, camptothecine and derivative thereof, amphotericin B, rapamycin, encircle rhzomorph A, Chinese medicine class scutellarin, Chinese medicine miscellany and volatile oil such as Mountain Spicy Tree Fruit volatilization wet goods and all are insoluble in the medicine of water.Consumption is decided according to preparation type.
Add distilled water then while stirring, or add behind the ionic liquid solution contain medicine by the equal breast of excusing from death ripple or equal newborn machine, water consumption is 1-5000 times of medicine.Can form transparent or semitransparent solution, microemulsion or submicron emulsion.Its particle diameter is 50-300nm.
The aqueous solution of prepared insoluble medicine can be used as oral liquid, injection liquid, infusion solutions, sprays, the administering mode that eye drop etc. are different.Embodiment is seen in concrete operations.
The technique effect that the present invention obtains is:
(1) ionic liquid of mentioning in the present invention and the background technology compare have its general ion liquid physicochemical property such as liquid range wide, thermally-stabilised good, to organic, mineral compound has good solvability, and nontoxic;
(2) non-toxic ion liquid of the present invention can be used as solvent, solubility promoter, or tensio-active agent is used for the solvability that field of medicaments increases the medicine that is insoluble in water.
(3) non-toxic ion liquid of the present invention is as solvent, solubility promoter, or tensio-active agent is used for field of medicaments, increases when being insoluble in the solvability of water medicine, has good solubilising and hydrotropy effect.Compare with other tensio-active agent or solubilizing agent, better effects if, preparation technology is simple, and cost is low.Be easy to realize industrialization.
Embodiment
The following example has further disclosed technical scheme of the present invention.Embodiment has only illustrated conception of the present invention, does not limit the present invention.Can carry out many changes according to thought of the present invention and scope.
Embodiment 1
The ion liquid preparation of L-lactoylcholine
Synthesize by ion liquid synthetic method one: in the methanol solution of 32ml bursine 45%, drip the 9.6ml90%L-lactic acid solution.Stir after 0.5 hour, purified after, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless L-lactoylcholine of 22.0g. ionic liquid.
Embodiment 2
The ion liquid preparation of DL-lactoylcholine
Synthesize by ion liquid synthetic method one: in the methanol solution of 32ml bursine 45%, drip 11.0ml80% DL-lactic acid solution.Stir after 0.5 hour, purified after, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless DL-lactoylcholine of 22.3g. ionic liquid.
Embodiment 3
The preparation of isopropylformic acid cholinium ion liquid
Synthesize by ion liquid synthetic method one: in the methanol solution of 20ml bursine 45%, drip the 6.14g isopropylformic acid.Stir after 0.5 hour, purified after, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless isopropylformic acid cholinium ion of 15.4g liquid.
Embodiment 4
The preparation of n-caproic acid cholinium ion liquid
Synthesize by ion liquid synthetic method one: in the methanol solution of 18.6 bursines 45%, drip the 9.04g n-caproic acid.Stir after 0.5 hour, purified after, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless n-caproic acid cholinium ion of 18.4g. liquid.
Embodiment 5
The preparation of lauric acid cholinium ion liquid
Synthesize by ion liquid synthetic method one: in the methanol solution of 10ml bursine 45%, add 6.95g lauric acid solid.After the stirring and dissolving, purified, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless lauric acid cholinium ion of 12.1g. liquid.Become waxy solid after the cooling.
Embodiment 6
The ion liquid preparation of choline stearate
Synthesize by ion liquid synthetic method one: in the methanol solution of 10ml bursine 45%, add the hard ester acid of 9.9g solid.After the stirring and dissolving, purified, 45 ℃ of high vacuum evaporated under reduced pressure solvents get 13.2g.The hard ester acid of colourless waxy solid cholinium ion liquid.
Embodiment 7
The preparation of palmitinic acid cholinium ion liquid
Synthesize by ion liquid synthetic method one: in the methanol solution of 10ml bursine 45%, add 8.9g palmitinic acid solid.After the stirring and dissolving, purified, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless waxy solid palmitinic acid of 12.3g. cholinium ion liquid.
Embodiment 8
Choline stearate preparation method of ionic liquid 2
Synthesize by ion liquid synthetic method two: in the 14.00g choline chloride 60, add acetone and the 22.2g sodium stearate solid of 100ml.Stir after 24 hours, remove sodium-chlor after filtration, behind the purifying, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the hard ester acid of the colourless waxy solid of 29.5g. cholinium ion liquid.
Embodiment 9
The choline acetate preparation method of ionic liquid
Synthesize by ion liquid synthetic method two: in the 14.00g choline chloride 60, add acetone and the 8.2g sodium-acetate solid of 100ml.Stir after 24 hours, remove sodium-chlor after filtration, behind the purifying, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless choline acetate ionic liquid of 16.0g..
Above-mentioned ionic liquid is through its acute toxicity of the oral mensuration of small white mouse LD
50The results are shown in table 1:
Subordinate list 1. ion liquid acute toxicity LD
50Measurement result
Ionic liquid |
LD
50(g/kg)
|
1.L-lactoylcholine 2.DL-lactoylcholine 3. isopropylformic acid choline 4. n-caproic acid choline 5. lauric acid choline 6. choline stearates 7. palmitinic acid choline 8. choline acetates |
(5.3 female), 6.4 (heros) 5.5 5.3 5.4 5.6 6.4 6.2 6.5 |
Following examples are used for illustrating the application of above-mentioned non-toxic ion liquid in the preparation novel pharmaceutical formulation.
Embodiment 10
The aqueous solution combination formula 1 of cyclosporin A:
Composition weight (mg)
Cyclosporin A 61.6
L-lactoylcholine 780
Choline stearate 200
Water 2000
This component is a solution, is diluted with water to 100ml, can form microemulsion, and particle diameter is 249.9 nanometers.
Embodiment 11
The aqueous solution combination formula 2 of cyclosporin A (also can add other tensio-active agent preparation in the prescription):
Composition weight (mg)
Cyclosporin A 71.8
L-lactoylcholine 600
Sodium laurylsulfonate 200
Water 2000
This component is a solution, is diluted with water to 100ml, can form microemulsion, and particle diameter is 260 nanometers.
Embodiment 12
The aqueous solution combination formula 1 of amphotericin B:
Composition weight (mg)
Amphotericin B 100
DL-lactoylcholine 1000
Palmitinic acid choline 200
Water 1000
This component is a solution, is diluted with water to 100ml, can form microemulsion, and particle diameter is 193.4 nanometers.
Embodiment 13
The aqueous solution combination formula 2 of amphotericin B (also can add other solubility promoter in the prescription):
Composition weight (mg)
Amphotericin B 47
Isopropylformic acid choline 500
PEG400 200
Water 500
This component is a solution, is diluted with water to 50ml, can form microemulsion, and particle diameter is 230 nanometers.
Embodiment 14
The aqueous solution combination formula 2 of scutellarin (also can add other solubility promoter in the prescription):
Composition weight (mg)
Scutellarin 200
Choline acetate 500
Sucrose fatty ester 20
Water 500
This component is a solution, is diluted with water to 50ml, can form microemulsion, and particle diameter is 270 nanometers.