CN103271955B - Brucea javanica oil emulsion composition - Google Patents
Brucea javanica oil emulsion composition Download PDFInfo
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- CN103271955B CN103271955B CN201310199191.4A CN201310199191A CN103271955B CN 103271955 B CN103271955 B CN 103271955B CN 201310199191 A CN201310199191 A CN 201310199191A CN 103271955 B CN103271955 B CN 103271955B
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- fructus bruceae
- oil emulsion
- water
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- emulsifying agent
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- 235000010889 Rhus javanica Nutrition 0.000 title claims abstract description 68
- 239000000839 emulsion Substances 0.000 title claims abstract description 60
- 239000000203 mixture Substances 0.000 title claims abstract description 37
- 241001533159 Brucea javanica Species 0.000 title claims abstract 14
- 238000002347 injection Methods 0.000 claims abstract description 64
- 239000007924 injection Substances 0.000 claims abstract description 64
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 47
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- 239000012178 vegetable wax Substances 0.000 claims abstract description 13
- 239000009969 fructus bruceae Substances 0.000 claims description 107
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 85
- 235000013399 edible fruits Nutrition 0.000 claims description 61
- 239000000470 constituent Substances 0.000 claims description 41
- 239000004615 ingredient Substances 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 18
- 239000008215 water for injection Substances 0.000 claims description 15
- 235000013365 dairy product Nutrition 0.000 claims description 11
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 8
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 7
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 6
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- 239000005642 Oleic acid Substances 0.000 description 6
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 6
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- 229940079593 drug Drugs 0.000 description 6
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Landscapes
- Medicines Containing Plant Substances (AREA)
Abstract
The invention relates to a brucea javanica oil emulsion composition. The composition is characterized by containing the following components: 50-300ml of brucea javanica fat-soluble components, 0.5-15g of brucea javanica water-soluble components, 5-100g of emulsifying agent and a defined amount of glycerin. The invention also relates to a preparation method and application of the brucea javanica oil emulsion composition. The composition has the beneficial effects that the brucea javanica oil emulsion injection provided by the invention is prepared from water-soluble components and fat-soluble components extracted from brucea javanica according to a certain ratio; compared with the single-use fat-soluble components, the composition can be used for obviously improving the treatment effect and has the function of protecting mucosae; acute toxicity tests show the product has high safety; and the quality, stability and use safety of medicaments in the use and storage processes can be obviously improved by controlling the contents of free fatty acids and vegetable wax in brucea javanica oil.
Description
Technical field
The present invention relates to Oleum Fructus Bruceae dairy compositions and preparation thereof and application.
Background technology
Tumor is a kind of commonly encountered diseases, frequently-occurring disease, and wherein malignant tumor is the class disease that current harm humans health is the most serious.In the industry the treatment of malignant tumor mainly still be take to operation, radiotherapy, chemotherapy as main at present, but many chemical anticarcinogenic drugs often involve normal cell when acting on target cell, cause serious side reaction.And plant amedica, Chinese medicine have unique advantage at anticancer, anti-tumor aspect, China's medicinal organism resource is very abundant, and its biological active substances is to find and the natural treasure-house of research new drug.From natural product, extract active substance, be developed to the new drug with antitumor curative effect, there is significant application value and wide development prospect.
Fructus Bruceae is the dry mature fruit of Simarubaceae brucea plant Fructus Bruceae Brucea javanica (L.) Merr.Gather during fruit maturation autumn, removes impurity, dries.The Fructus Bruceae beginning is loaded in the < < A Supplement to the Compendium of Materia Medica > > that Qing Dynasty's ZHAO Xue-Min is shown.
Fructus Bruceae containing water-soluble composition and liposoluble constituent two classes, being widely used at present clinical is liposoluble constituent, wherein mainly contain the compositions such as glycerol trioleate, oleic acid, linoleic acid, linolenic acid, stearic acid, Palmic acid, myristic acid, gadoleic acid, behenic acid, arachidonic acid are also compositions common in Oleum Fructus Bruceae in addition.At present commonplace Oleum Fructus Bruceae (or claiming Fructus Bruceae total fatty oil) is ligroin extraction, also can for example, through simply refining (decolouring processing, washing processing, the hargil removal of impurity be processed), extract is for the preparation of pharmaceutical preparation, and the preparation of commonplace use is Java brucea fruit oil emulsion injection.
But existing Java brucea fruit oil emulsion injection is being heated, in the process of freezing and long-term storage, all can cause breakdown of emulsion or layering, cause expiration date of drug to shorten, this stability problem has seriously limited the using and promoting clinically of this product, and these all illustrate that Fructus Bruceae is needing to break through aspect its component research and development and stability study.
Summary of the invention
In order to address the deficiencies of the prior art, inventor is by studies have shown that in a large number, the Java brucea fruit oil emulsion injection that the water soluble ingredient extracting from Fructus Bruceae and liposoluble constituent are made with certain proportioning, through animal experiment, show, compare alone liposoluble constituent, there is better therapeutic effect, and mucosa is had to protective effect; Control Oleum Fructus Bruceae free fatty acid and vegetable wax content, can significantly improve medicine use and preservation process in the safety of quality, stability and drug use.
The present invention relates to a kind of Oleum Fructus Bruceae dairy compositions, the component that described compositions contains following proportion relation:
Fructus Bruceae liposoluble constituent 50-300ml, preferably 80-200ml, most preferably 80ml;
Fructus Bruceae water soluble ingredient 0.5-15g, preferably 0.5-8g, most preferably 1g;
Emulsifying agent 5-100g, preferably 30-60g, most preferably 30g;
Glycerol is appropriate, preferably 15ml.
Wherein, emulsifying agent can mix for a kind of or its arbitrary proportion in Ovum Gallus domesticus Flavus lecithin or soybean phospholipid.
Preferably, described Fructus Bruceae liposoluble constituent is Oleum Fructus Bruceae, more preferably refining Oleum Fructus Bruceae.Described Oleum Fructus Bruceae is the normally used Oleum Fructus Bruceae in this area, that is, by petroleum ether, the dry mature fruit of Fructus Bruceae is extracted and the fatty oil that obtains.Described refining Oleum Fructus Bruceae is described Oleum Fructus Bruceae after decolouring is processed, and removes 1) residual organic solvent, free fatty and other low boiling impurities and/or 2) obtain after senior ester, vegetable wax, alkaloid and other high-boiling-point impurities.Particularly, Fructus Bruceae liposoluble constituent can adopt the preparation method comprising the steps to prepare:
Oleum Fructus Bruceae decolours after processing through active carbon and Kaolin, through secondary molecular distillation, carries out separation; Described secondary molecular distillation refers to,
First, carry out first order molecular distillation, adopt molecular distillation equipment, for example wiped film molecular distillation equipment, gets the Oleum Fructus Bruceae after decolouring, be for example 300g, at distillation equipment system pressure 0.7Pa, feeding preheating temperature 30-35 ℃, vapo(u)rizing temperature 70-110 ℃, feed rate 2.5ml/min, distills under the condition of rotating speed 140-160r/min.Retain heavy phase fluid, remove light phase fluid, described light phase fluid comprises residual organic solvent, free fatty and other low boiling impurities.When carrying out first order molecular distillation, the temperature of condensed water can be 20 ℃;
Then, carry out second level molecular distillation, adopt molecular distillation equipment, wiped film molecular distillation equipment for example, get the heavy phase fluid after one-level molecular distillation, at distillation equipment system pressure 0.4Pa, feeding preheating temperature 30-50 ℃, vapo(u)rizing temperature 130-220 ℃, feed rate 2.0ml/min, distills under the condition of rotating speed 160-200r/min, leaves and takes light phase fluid as Fructus Bruceae liposoluble constituent, remove heavy phase fluid, this heavy phase fluid comprises senior ester, vegetable wax, alkaloid and other high-boiling-point impurities.When carrying out second level molecular distillation, the temperature of condensed water can be 10 ℃.
As preferably, in above-mentioned Fructus Bruceae liposoluble constituent, the content of unsaturated fatty acid is not less than 80%, and free fatty acid content is less than or equal to 1%, and vegetable wax content is less than or equal to 0.5%.
Preferably, described Fructus Bruceae water soluble ingredient is the extract that utilizes water, C1-4 alcohol or both arbitrary proportion mixture; Preferably the extract of water and alcohol mixture, for example, be 60-95% ethanol extraction; More preferably after 60-95% ethanol extraction, use the following water soluble ingredient that partly or entirely purification step obtains: carbon tetrachloride extraction remove impurity, Sodium chloride deposit are removed toxin, decolorization and impurity removal by active carbon, polyamide column chromatography remove impurity.Particularly, described Fructus Bruceae water soluble ingredient can adopt the preparation method comprising the steps to prepare:
(1) extracting degreasing Java Brucea Fruit, be for example 200g, utilize 60%-70%(to be preferably 65%) the alcoholic solution ultrasonic lixiviate (for example 1 hour) that (is for example 50 ℃) under heating condition, filter, filtrate for later use, then medicinal residues continue to reflux with the alcoholic solution of 85%-95%, for example utilize 95% the alcoholic solution 5h that refluxes under 55-65 ℃ of condition, merge extractive liquid,, then concentrated, be for example concentrated into 100ml;
(2) for example, by concentrated solution (100ml), first use carbon tetrachloride extraction, water intaking layer, then add the sodium chloride solution (for example 100ml) of 0.15mol/L, and stir (for example, at 55 ℃, stirring 1h), filter, now can be with SiO
2for filter aid filters, obtain filtrate;
(3), to the active carbon that adds 0.5%～1% in step (2) gained filtrate, decolouring, filters, and obtains filtrate;
(4) gained filtrate is crossed to polyamide resin column, with the alcoholic solution eluting of 20%～80% concentration, add the dehydrated alcohol of 4～8 times of volumes after eluent is concentrated, to crystallization filtration, gained filtering residue is as Fructus Bruceae water soluble ingredient.
The present invention relates to a kind of Java brucea fruit oil emulsion injection, described injection contains Fructus Bruceae liposoluble constituent and Fructus Bruceae water soluble ingredient simultaneously, contains following component and content described in every 1000ml in injection:
Fructus Bruceae liposoluble constituent 50-300ml, preferably 80-200ml, more preferably 80ml;
Fructus Bruceae water soluble ingredient 0.5-15g, preferably 0.5-8g, more preferably 1g;
Emulsifying agent 5-100g, preferably 30-60g, more preferably 30g;
Glycerol is appropriate, preferably 15ml.
Wherein, emulsifying agent can mix for a kind of or its arbitrary proportion in Ovum Gallus domesticus Flavus lecithin or soybean phospholipid.
As preferably, in above-mentioned Fructus Bruceae liposoluble constituent, the content of unsaturated fatty acid is not less than 80%, is preferably greater than and equals 85%, and free fatty acid content is less than or equal to 1%, is preferably less than or equal to 0.5%, and vegetable wax content is less than or equal to 0.5%.
Above-mentioned Fructus Bruceae liposoluble constituent can adopt the preparation method comprising the steps to prepare:
Oleum Fructus Bruceae decolours after processing through active carbon and Kaolin, through secondary molecular distillation, carries out separation; Described secondary molecular distillation refers to,
First, carry out first order molecular distillation, adopt molecular distillation equipment, for example wiped film molecular distillation equipment, gets the Oleum Fructus Bruceae after decolouring, be for example 300g, at distillation equipment system pressure 0.7Pa, feeding preheating temperature 30-35 ℃, vapo(u)rizing temperature 70-110 ℃, feed rate 2.5ml/min, distills under the condition of rotating speed 140-160r/min.Retain heavy phase fluid, remove light phase fluid, described light phase fluid comprises residual organic solvent, free fatty and other low boiling impurities.When carrying out first order molecular distillation, the temperature of condensed water can be 20 ℃.
Then, carry out second level molecular distillation, adopt molecular distillation equipment, wiped film molecular distillation equipment for example, get the heavy phase fluid after one-level molecular distillation, at distillation equipment system pressure 0.4Pa, feeding preheating temperature 30-50 ℃, vapo(u)rizing temperature 130-220 ℃, feed rate 2.0ml/min, distills under the condition of rotating speed 160-200r/min, leaves and takes light phase fluid as Fructus Bruceae liposoluble constituent, remove heavy phase fluid, this heavy phase fluid comprises senior ester, vegetable wax, alkaloid and other high-boiling-point impurities.When carrying out second level molecular distillation, the temperature of condensed water can be 10 ℃.
Above-mentioned water soluble ingredient can adopt the preparation method comprising the steps to prepare:
(1) extracting degreasing Java Brucea Fruit, be for example 200g, utilize 60%-70%(to be preferably 65%) the alcoholic solution ultrasonic lixiviate (for example 1 hour) that (is for example 50 ℃) under heating condition, filter, filtrate for later use, then medicinal residues continue to reflux with the alcoholic solution of 85%-95%, for example utilize 95% the alcoholic solution 5h that refluxes under 55-65 ℃ of condition, merge extractive liquid,, then concentrated, be for example concentrated into 100ml;
(2) for example, by concentrated solution (100ml), first use carbon tetrachloride extraction, water intaking layer, then add the sodium chloride solution (for example 100ml) of 0.15mol/L, and stir (for example, at 55 ℃, stirring 1h), filter, now can be with SiO
2for filter aid filters, obtain filtrate;
(3), to the active carbon that adds 0.5%～1% in step (2) gained filtrate, decolouring, filters, and obtains filtrate;
(4) gained filtrate is crossed to polyamide resin column, with the alcoholic solution eluting of 20%～80% concentration, add the dehydrated alcohol of 4～8 times of volumes after eluent is concentrated, to crystallization filtration, gained filtering residue is as Fructus Bruceae water soluble ingredient.
The method that the invention still further relates to the above-mentioned Java brucea fruit oil emulsion injection of preparation, comprises the steps:
(1) appropriate water for injection is heated to 50～80 ℃, add after 1～50ml glycerol mixed dissolution, add described amount emulsifying agent to shear evenly, under stirring action, slowly add 50～90 ℃ of described amount Fructus Bruceae liposoluble constituents, stir and make colostrum as oil phase;
(2) separately get described water gaging soluble components, add appropriate water for injection and be heated to 45～75 ℃ of abundant dissolvings as water;
(3) oil phase and water are uniformly mixed, and regulate pH value to 6.0～8.0, inject water to 1000ml, mix by homogenizer high pressure homogenize.
The invention still further relates to above-mentioned Oleum Fructus Bruceae dairy compositions or Java brucea fruit oil emulsion injection in the application as in antitumor drug.
At least there is following useful technique effect in the present invention:
Java brucea fruit oil emulsion injection provided by the invention, is that water-soluble component and the fat-soluble ingredient by extracting from Fructus Bruceae made with certain proportioning combination, compares alone liposoluble constituent, can significantly improve therapeutic effect, and mucosa is had to protective effect; Control Oleum Fructus Bruceae free fatty acid and vegetable wax content, can significantly improve medicine use and preservation process in the safety of quality, stability and drug use.
The specific embodiment
Below enumerate embodiment and illustrate Java brucea fruit oil emulsion injection of the present invention and preparation and application.But the present invention is not limited to following embodiment.
Embodiment 1: the extraction of Fructus Bruceae chemical composition
The extracting method of the present embodiment Fructus Bruceae liposoluble constituent and water soluble ingredient is summarized as follows:
1. Fructus Bruceae pre-treatment: by Fructus Bruceae oven dry, grinding and sieving.
2. after sieving, gained Fructus Bruceae powder refluxes with petroleum ether or soaks and extract liposoluble constituent.Fructus Bruceae powder dry for standby after defat.
3. the Fructus Bruceae powder after defat is first used the ultrasonic lixiviate of alcoholic solution, after use alcohol reflux, after being concentrated, filter, decoloured, extracting solution crosses polyamide resin column, carry out separating-purifying, coordinate thin layer chromatography to detect, collect same composition eluent, the concentrated post crystallization of eluent is obtained to water soluble ingredient.
Idiographic flow is as follows:
One. the separation and Extraction of liposoluble constituent
(1) by Fructus Bruceae medical material selecting crude drugs with winnower, broken, be fed into extraction pot, the petroleum ether that adds proper volume, feed liquid circulating-heating to 40～80 ℃ (in the present embodiment being 70 ℃), after extraction 2h, miscella is delivered in distillation column and is concentrated and reclaim solvent, then rejoins petroleum ether and repeatedly extracts, merge concentrated solution, obtain Oleum Fructus Bruceae.
(2) Oleum Fructus Bruceae is heated to 80～100 ℃ (in the present embodiment, being 85 ℃), adds medicinal carbon and Kaolin decolour and filter.
(3) first, adopt wiped film molecular distillation equipment, get the Oleum Fructus Bruceae 300g after decolouring, at distillation equipment system pressure 0.7Pa, 30 ℃ of feeding preheating temperature, 90 ℃ of vapo(u)rizing temperatures, feed rate 2.5ml/min, the temperature of condensed water is 20 ℃, under the condition of blade applicator rotating speed 150r/min, distills.Retain heavy phase fluid, remove light phase fluid.
Then, adopt wiped film molecular distillation equipment, get the heavy phase fluid after first order molecular distillation, at distillation equipment system pressure 0.4Pa, feeding preheating temperature 50 C, 180 ℃ of vapo(u)rizing temperatures, feed rate 2.0ml/min, the temperature of condensed water is 10 ℃, under the condition of blade applicator rotating speed 200r/min, distills, and leaves and takes light phase fluid.
(4) in the light phase fluid of (3) gained, add purified water, stratification, then by dry Fructus Bruceae quintessence oil, i.e. the Fructus Bruceae liposoluble constituent of the present invention of obtaining of light oil.
1, the mensuration of unsaturated fatty acid content:
(1) Oleum Fructus Bruceae hydrolysis;
Precision measures the Fructus Bruceae quintessence oil 2mL of above-mentioned preparation, puts in 10mL tool plug test tube, with nitrogen, dries up, and adds 0.5molL
-1potassium hydroxide-ethanol solution 2mL, puts saponification (60min) in 60 ℃ of water-baths, lets cool, and with dilute hydrochloric acid, adjusts pH to 4-5, adds normal hexane 6mL extraction three times, volatilizes solvent on evaporating dish, in 10mL volumetric flask, standby with dissolve with methanol standardize solution.
(2) Oleum Fructus Bruceae fatty acid composition is determined
HPLC-ELSD analysis condition is as follows: evaporative light detector is analyzed, 70 ℃ of detected temperatures, N
2carrier gas flux is 1.0mLmin
-1; Chromatographic column: Eclipse XDB-C18(4.6mm * 150mm, 5 μ m), column temperature: 25 ℃; Mobile phase: methanol: water: acetic acid (88:11:1).Fructus Bruceae fatty acid chromatography result is, the retention time 12.705min of linoleic retention time 9.867min, palmitic acid, the retention time 14.240min of oleic acid, stearic retention time 23.145min.
(3) use the standard substance of oleic acid, linoleic acid, stearic acid and palmitic acid with above-mentioned HPLC-ELSD analytical method, investigate the range of linearity of its various fatty acids, and make linearity curve.
(4) each unsaturated fatty acid of Oleum Fructus Bruceae sample detection to the first step, its content of curve determination that contrast the 3rd step is made.
After measured, the mass percentage content of unsaturated fatty acid in the Fructus Bruceae liposoluble constituent of preparing in the present invention, oleic acid, linoleic total content are 85%.
The inventor finds, when the mass percentage content of unsaturated fatty acid is lower than 80% time, the raising of therapeutic effect is not obvious, and the protective effect of mucosa is reduced.
2, the assay method of free fatty acid content:
By potassium hydroxide standard solution titrimetry, take Oleum Fructus Bruceae 5～10g, be accurate to 0.001g, be placed in 250ml conical flask; Add and be neutralized to neutral alcohol-ether mixed solvent 100ml, shake it is dissolved, with 0.1M potassium hydroxide standard solution, be titrated to indicator discoloration.Phenolphthalein becomes redness from the colourless blue 6B of pink or alkali that becomes from blueness, at least maintains 10s and does not fade.While consuming 0.1M potassium hydroxide standard solution over 10ml during titration, should separately materials, the potassium hydroxide standard solution of using 0.5M instead carries out titration.
The consumption units/ml of V potassium hydroxide standard solution; The molar concentration of M potassium hydroxide standard solution; A fatty acid molecule amount, counts 282 with oleic acid; The mass unit g of W sample.
The mass percentage content of the Fructus Bruceae liposoluble constituent free fatty acid of preparing in the present invention after measured, is 0.5%.
The inventor finds, the mass percentage content of free fatty higher than 1.0% time, use and preservation process in, the quality of medicine, stability reduce, and the safety of drug use also decreases.
3, vegetable wax content assaying method:
Adopt < < animal and plant fat. the mensuration of wax content in olive oil. the method for recording in gas chromatography > > GB/T22501-2008 is measured.
After measured, in the Fructus Bruceae liposoluble constituent of preparing in the present invention, the mass percentage content of vegetable wax is 0.3%.
The inventor finds, the mass percentage content of vegetable wax higher than 0.5% time, use and preservation process in, the quality of medicine, stability reduce, and the safety of drug use also decreases.
Two. the separation and Extraction of water soluble ingredient
(1) extracting degreasing Java Brucea Fruit 200g, with 400ml, the alcoholic solution of 65% concentration is ultrasonic lixiviate 1h under 50 ℃ of conditions, filters, and obtains extracting solution.Then with 95% the alcoholic solution 5h that refluxes under 55～65 ℃ of conditions, merge extractive liquid,, then uses Rotary Evaporators distilling under reduced pressure, is concentrated into 100ml;
(2) by 100ml concentrated solution, first use carbon tetrachloride extraction, water intaking layer, then add the sodium chloride solution 100ml of 0.15mol/L, 55 ℃ are stirred 1h, to remove the brutoxin that may exist, with SiO
2for filter aid, filter;
(3) gained filtrate is transferred in 250ml single port bottle, adds 1% active carbon, and 45 ℃ are stirred 30min, decolouring, solution filter;
(4) gained filtrate is crossed to polyamide resin column, with the alcoholic solution of 20%, 40%, 60% and 80% concentration, carry out gradient elution, coordinate thin layer chromatography to detect, merge the identical part of component, the eluting part that merges 40%, 60% ethanol, adds the dehydrated alcohol of 4～8 times of volumes after eluent is concentrated, filters after waiting water soluble ingredient crystallization precipitation, obtain filtering residue, i.e. Fructus Bruceae water soluble ingredient;
(5) water soluble ingredient is put in vacuum drying oven, 40 ℃ of dry 36h, obtain Fructus Bruceae water soluble ingredient extract dry product and weigh.
Utilize Fructus Bruceae liposoluble constituent and the Fructus Bruceae water soluble ingredient of preparation in embodiment 1, the Java brucea fruit oil emulsion injection in preparation following examples.
Embodiment 2: the preparation of Java brucea fruit oil emulsion injection
(1) appropriate water for injection is heated to 80 ℃, adds after 5ml glycerol mixed dissolution, add 5g Ovum Gallus domesticus Flavus lecithin to shear evenly, under stirring action, slowly add 70 ℃ of Fructus Bruceae liposoluble constituent 50ml, stir and make colostrum, as oil phase.
(2) the soluble components 0.5g that separately fetches water, adds appropriate water for injection, is heated to 65 ℃, fully dissolves, as water.
(3) oil phase and water are being uniformly mixed, and regulate pH value to 8.0, inject water to 1000ml, mix by homogenizer high pressure homogenize, pressure is adjusted to 90MPa, continuous circulation 6 times, and microemulsion particle diameter is between 10～100nm, after filtration, fill, logical nitrogen, sealing by fusing, sterilizing, packing, obtain Java brucea fruit oil emulsion injection.
Embodiment 3: the preparation of Java brucea fruit oil emulsion injection
(1) appropriate water for injection is heated to 50 ℃, adds after 30ml glycerol mixed dissolution, add 100g Ovum Gallus domesticus Flavus lecithin to shear evenly, under stirring action, slowly add 90 ℃ of Fructus Bruceae liposoluble constituent 300ml, stir and make colostrum as oil phase.
(2) the soluble components 15g that separately fetches water, adds appropriate water for injection and is heated to 45 ℃, fully dissolves as water.
(3) oil phase and water are being uniformly mixed, and regulate pH value to 6.0, inject water to 1000ml, mix by homogenizer high pressure homogenize, pressure is adjusted to 40MPa, continuous circulation 6 times, and microemulsion particle diameter is between 10～100nm, son after filtration, fill, logical nitrogen, sealing by fusing, sterilizing, packing, obtain Java brucea fruit oil emulsion injection.
Embodiment 4: the preparation of Java brucea fruit oil emulsion injection
(1) appropriate water for injection is heated to 70 ℃, adds after 15ml glycerol mixed dissolution, add 30g soybean phospholipid to shear evenly, under stirring action, slowly add 90 ℃ of Fructus Bruceae liposoluble constituent 80ml, stir and make colostrum as oil phase.
(2) the soluble components 1g that separately fetches water, adds appropriate water for injection, is heated to 70 ℃, after fully dissolving as water.
(3) oil phase and water are being uniformly mixed, and regulate pH value to 7.0, inject water to 1000ml, mix by homogenizer high pressure homogenize, pressure is adjusted to 90MPa, continuous circulation 6 times, and microemulsion particle diameter is between 10～100nm, son after filtration, fill, logical nitrogen, sealing by fusing, sterilizing, packing, obtain Java brucea fruit oil emulsion injection.
Embodiment 5: the preparation of Java brucea fruit oil emulsion injection
(1) appropriate water for injection is heated to 50 ℃, add after a certain amount of 20ml glycerol mixed dissolution, add 60g soybean phospholipid to mix and shear evenly, under stirring action, slowly add 50 ℃ of Fructus Bruceae liposoluble constituent 200ml, stir and make colostrum as oil phase.
(2) the soluble components 8g that separately fetches water, adds appropriate water for injection and is heated to 45～75 ℃ and fully dissolves as water.
(3) oil phase and water are being uniformly mixed, and regulate pH value to 6.0～8.0, inject water to 1000ml, mix by homogenizer high pressure homogenize, pressure is adjusted to 40～90MPa, continuous circulation 3～6 times, and microemulsion particle diameter is between 10～100nm, son after filtration, fill, logical nitrogen, sealing by fusing, sterilizing, packing, obtain Java brucea fruit oil emulsion injection.
Described Fructus Bruceae liposoluble constituent and Fructus Bruceae water soluble ingredient adopt embodiment 1 method preparation.
Embodiment 6: the preparation of Java brucea fruit oil emulsion injection
(1) appropriate water for injection is heated to 50～80 ℃, add after 5～10ml glycerol mixed dissolution, add 30g soybean phospholipid to shear evenly, under stirring action, slowly add 50～90 ℃ of Fructus Bruceae liposoluble constituent 80ml, stir and make colostrum as oil phase.
(2) the soluble components 0.5g that separately fetches water, adds appropriate water for injection and is heated to 45～75 ℃ and fully dissolves as water.
(3) oil phase and water are being uniformly mixed, and regulate pH value to 6.0～8.0, inject water to 1000ml, mix by homogenizer high pressure homogenize, pressure is adjusted to 40～90MPa, continuous circulation 3～6 times, and microemulsion particle diameter is between 10～100nm, son after filtration, fill, logical nitrogen, sealing by fusing, sterilizing, packing, obtain Java brucea fruit oil emulsion injection.
Described Fructus Bruceae liposoluble constituent is refining Oleum Fructus Bruceae, it is for buying commercially available Oleum Fructus Bruceae, according to the method for Chinese patent application 03156023.7 is refining, obtains.Be specially commercially available Oleum Fructus Bruceae and be heated to 100 ℃, slowly inject warm equivalent water for injection, heated and stirred 10 minutes, standingly makes layering, discards water layer.Described water soluble ingredient is defat Java Brucea Fruit with 60% alcoholic solution reflux, extract, 3 times under 55～65 ℃ of conditions, and merge extractive liquid,, then uses Rotary Evaporators distilling under reduced pressure, concentrated obtaining.
Embodiment: 7: technique effect confirmatory experiment
One, the therapeutical effect of Java brucea fruit oil emulsion injection of the present invention to mice ehrlich carcinoma
Table 1 result shows, with commercially available Java brucea fruit oil emulsion injection 5, 10, the 20ml/kg dosage group mean survival time compared with matched group truly have increase (increase in life span is 10% to the maximum), and significantly improve (highest order 20%) with increase in life span after the Java brucea fruit oil emulsion injection of the present invention of embodiment 2-6, wherein in embodiment 4 Java brucea fruit oil emulsion injection high dose group of the present invention and embodiment 5 Java brucea fruit oil emulsion injection of the present invention, the dosage group mean survival time obviously increases (p<0.05) compared with matched group, illustrate that Java brucea fruit oil emulsion injection of the present invention is significantly improved compared with commercially available prod to the therapeutic effect of mice ehrlich carcinoma.
Table 1: Java brucea fruit oil emulsion injection of the present invention and the commercially available Java brucea fruit oil emulsion injection therapeutic effect contrast to mice ehrlich carcinoma
Note: * p<0.05(and the comparison of normal saline matched group)
Two, the therapeutical effect of Java brucea fruit oil emulsion injection of the present invention to rat liver cancer H22 ascitic type
Table 2 result shows, with commercially available Java brucea fruit oil emulsion injection 5, 10, the 20ml/kg dosage group mean survival time also increases (increase in life span is 8.3% to the maximum) to some extent compared with matched group, and significantly improve (being up to 19.6%) with increase in life span after embodiment 2-6 Java brucea fruit oil emulsion injection of the present invention, embodiment 4 Java brucea fruit oil emulsion injection 10 of the present invention wherein, the 20ml/kg dosage group mean survival time obviously increases (p<0.05) compared with matched group, illustrate that Java brucea fruit oil emulsion injection of the present invention improves obviously compared with commercially available prod the therapeutic effect of rat liver cancer H22 ascitic type.
Table 2: Java brucea fruit oil emulsion injection of the present invention and the commercially available Java brucea fruit oil emulsion injection therapeutic effect contrast to rat liver cancer H22 ascitic type
Note: * p<0.05(and the comparison of normal saline matched group)
The protective effect of the rat oral mucositis that three, Java brucea fruit oil emulsion injection of the present invention causes radiotherapy
Experiment is divided into: normal group, model control group, the basic, normal, high dosage of commercially available Java brucea fruit oil emulsion injection (be respectively 3.6,7.2,14.4ml/kg) group and the basic, normal, high dosage of embodiment 2-5 Java brucea fruit oil emulsion injection of the present invention (be respectively 3.6,7.2,14.4ml/kg) group, totally 17 groups.Except normal group, all the other are respectively organized rat cheek mucosa and all accept x-ray bombardment, and every day 1 time totally 8 times, total absorbed dose is 80Gy.Irradiate rear 3h angular vein drug administration by injection at every turn, every day 1 time, after successive administration 12d, put to death animal, observed rat oral mucosa damage degree.
Adopt the order of severity of 5 minutes assessment method (in Table 3) perusal rat oral mucositis of Sonis, result is as shown in table 4 below: administration is respectively organized oral mucosa damage degree and all alleviated to some extent, each organizes the more commercially available Java brucea fruit oil emulsion injection of Java brucea fruit oil emulsion injection of the present invention better effect, and wherein in embodiment 4 products, each dosage group of the more commercially available Java brucea fruit oil emulsion injection of dosage group has obvious statistics to improve effect (with model group than P<0.05).
5 minutes assessment methods of oral mucositis of table 3:Sonis etc.
Table 4: each Java brucea fruit oil emulsion injection is to patients with radioactive mucositis of oral cavity rat macroscopic score result
Note: * P<0.05(and model group comparison)
Four, long-term stable experiment
According to 2010 editions medicine stability guidelines of < < Chinese Pharmacopoeia > > and Java brucea fruit oil emulsion injection quality mark (accurate standard number: YBZ12472004), the product of embodiment 2-5 is carried out respectively to long-time stability and investigate experiment, investigation project is: character, relative density, differentiate, pH value, osmotic pressure, oleic acid content, anaphylaxis, undue toxicity, breast grain, content below diameter 1 μ m, diameter is greater than the breast grain of 5 μ m, aseptic, bacterial endotoxin, lamination, the project such as haemolysis and coagulation.
By the sample of every routine product, divide three groups, under the condition of 25 ± 2 ℃ of temperature, place, respectively at sampling in 3,6,9,12,15,18,21,24 months once, by stability high spot reviews project, detect, compared with 0 month, result is as shown in table 5～8.
Conclusion: test sample is investigated through the long-time stability of 24 months, each organizes sample institute investigation project does not all have significance to change, and shows to compare the commercially available Java brucea fruit oil emulsion injection effect duration of 18 months Java brucea fruit oil emulsion injection of the present invention and has better long-time stability.
The Java brucea fruit oil emulsion injection long-term stable experiment assay of the present invention of table 5: embodiment 2
The Java brucea fruit oil emulsion injection long-term stable experiment assay of table 6: embodiment 3
The Java brucea fruit oil emulsion injection long-term stable experiment assay of the present invention of table 7: embodiment 4
The Java brucea fruit oil emulsion injection long-term stable experiment assay of table 8: embodiment 5
Embodiment 8 Oleum Fructus Bruceae dairy compositions are to rat acute toxicity test
Get the SD rat in three groups of 8 week ages, every group 8 (4 male, 4 female), 2 tail vein injection administrations (interval 12h) in 24 hours, adopt the concentration of embodiment 3(water soluble ingredient maximum) and the Java brucea fruit oil emulsion injection of maximum volume (1.2ml/100g body weight) inject, Continuous Observation 13 days, general status (body weight change, diet, fur, behavior, secretions etc.) and poisoning, the death condition of observing rat.The 13rd day, dissect rat, the outward appearance of its heart of perusal, liver, spleen, lung, kidney, brain.Result shows: 24mlkg
-1d
-1, 6mlkg
-1d
-1administration, Continuous Observation 13 days, rat increases in duration of test body weight, compares no significant difference (P>0.05) with matched group; Food ration and matched group are suitable; Movable normal, without convulsions, movement disorder, sialorrhea, shed tears, the phenomenon such as watery nasal discharge, dyspnea, diarrhoea occurs; Fur is smooth, the no abnormality seen secretions such as mouth, nose, eye; The defecation of animal is normal, does not have animal dead; The outward appearance of its heart of perusal, liver, spleen, lung, kidney, brain is without extremely; Organ coefficient reduces, but with matched group (normal saline) no difference of science of statistics.As can be seen here, Oleum Fructus Bruceae dairy compositions is low to rat acute toxicity, and its maximum dosage-feeding is 24mlkg
-1d
-1(clinical people's recommended dose 144 times).
Obviously, those skilled in the art can carry out various changes and modification and not depart from the spirit and scope of the present invention the present invention.Like this, if within of the present invention these are revised and modification belongs to the scope of the claims in the present invention and equivalent technologies thereof, the present invention is also intended to comprise these changes and modification interior.
Claims (10)
1. Oleum Fructus Bruceae dairy compositions, is characterized in that, described compositions is made by the component of following proportioning:
Fructus Bruceae liposoluble constituent 50-300ml;
Fructus Bruceae water soluble ingredient 0.5-15g;
Emulsifying agent 5-100g;
Glycerol is appropriate.
2. Oleum Fructus Bruceae dairy compositions described in claim 1, is characterized in that, described compositions is made by the component of following proportioning:
Fructus Bruceae liposoluble constituent 80-200ml;
Fructus Bruceae water soluble ingredient 0.5-8g;
Emulsifying agent 30-60g;
Glycerol is appropriate.
3. Oleum Fructus Bruceae dairy compositions described in claim 2, is characterized in that, described compositions is made by the component of following proportioning:
Fructus Bruceae liposoluble constituent 80ml;
Fructus Bruceae water soluble ingredient 1g;
Emulsifying agent 30g;
Glycerol 15ml.
4. Oleum Fructus Bruceae dairy compositions described in any one in claims 1 to 3, is characterized in that, described emulsifying agent is that a kind of or its arbitrary proportion in Ovum Gallus domesticus Flavus lecithin or soybean phospholipid mixes; In described Fructus Bruceae liposoluble constituent, the mass percentage content of unsaturated fatty acid is not less than 80%, and the mass percentage content of free fatty is less than or equal to 1%, and the mass percentage content of vegetable wax is less than or equal to 0.5%.
5. Java brucea fruit oil emulsion injection, is characterized in that, described injection contains Fructus Bruceae liposoluble constituent and Fructus Bruceae water soluble ingredient simultaneously, and injection is made by the component of following proportioning described in every 1000ml:
Fructus Bruceae liposoluble constituent 50-300ml;
Fructus Bruceae water soluble ingredient 0.5-15g;
Emulsifying agent 5-100g;
Glycerol is appropriate.
6. Java brucea fruit oil emulsion injection described in claim 5, is characterized in that, injection is made by the component of following proportioning described in every 1000ml:
Fructus Bruceae liposoluble constituent 80-200ml;
Fructus Bruceae water soluble ingredient 0.5-8g;
Emulsifying agent 30-60g;
Glycerol is appropriate.
7. Java brucea fruit oil emulsion injection described in claim 6, is characterized in that, injection is made by the component of following proportioning described in every 1000ml:
Fructus Bruceae liposoluble constituent 80ml;
Fructus Bruceae water soluble ingredient 1g;
Emulsifying agent 30g;
Glycerol 15ml.
8. Java brucea fruit oil emulsion injection described in claim 5 to 7 any one, is characterized in that, described emulsifying agent is that a kind of or its arbitrary proportion in Ovum Gallus domesticus Flavus lecithin or soybean phospholipid mixes; In described Fructus Bruceae liposoluble constituent, the mass percentage content of unsaturated fatty acid is not less than 80%, and the mass percentage content of free fatty is less than or equal to 1%, and the mass percentage content of vegetable wax is less than or equal to 0.5%.
9. the method for preparing Java brucea fruit oil emulsion injection described in claim 5-6 any one, is characterized in that, comprises the steps:
(1) appropriate water for injection is heated to 50～80 ℃, add after 1～50ml glycerol mixed dissolution, add described amount emulsifying agent to shear evenly, under stirring action, slowly add 50～90 ℃ of described amount Fructus Bruceae liposoluble constituents, stir and make colostrum as oil phase;
(2) separately get described amount Fructus Bruceae water soluble ingredient, add appropriate water for injection, be heated to 45～75 ℃, dissolve as water;
(3) oil phase and water are uniformly mixed, and regulate pH value to 6.0～8.0, inject water to 1000ml.
10. the application of Java brucea fruit oil emulsion injection in preparation treatment ascitic type liver cancer medicine described in any one in Oleum Fructus Bruceae dairy compositions or claim 5-8 described in claim 1-4 any one.
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| CN101053579A (en) * | 2006-04-14 | 2007-10-17 | 首都医科大学附属北京友谊医院 | Application of brucea fruit oil nanometer emulsion in preparing gastrointestinal mucosa protective agent |
| CN101129419A (en) * | 2006-08-22 | 2008-02-27 | 浙江九旭药业有限公司 | Emulsified pharmaceutical composition containing oleum fructus bruceae and processes for producing same |
| CN101288682A (en) * | 2008-06-06 | 2008-10-22 | 广东药学院 | Microemulsion containing brucea javanica oil and preparation method thereof |
| CN101683367A (en) * | 2006-08-22 | 2010-03-31 | 浙江九旭药业有限公司 | Method for preparing emulsified medicinal composition containing oleum fructus bruceae |
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| CN101053579A (en) * | 2006-04-14 | 2007-10-17 | 首都医科大学附属北京友谊医院 | Application of brucea fruit oil nanometer emulsion in preparing gastrointestinal mucosa protective agent |
| CN101129419A (en) * | 2006-08-22 | 2008-02-27 | 浙江九旭药业有限公司 | Emulsified pharmaceutical composition containing oleum fructus bruceae and processes for producing same |
| CN101683367A (en) * | 2006-08-22 | 2010-03-31 | 浙江九旭药业有限公司 | Method for preparing emulsified medicinal composition containing oleum fructus bruceae |
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