Stone oil from stone fruits, method for extraction the same, pharmaceutical compositions and uses thereof

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to stone oil, extracted from stones of date (Phoenix pubeccens), yellow wood, or walnut containing specific amounts of triglycerides, diglycerides, monoglycerides, sitosterols, and cycloalanosterol. In one embodiment method for extraction of stone oil includes pressing of stones or powered stones, extraction with organic solvent or selectively by using of liquid in above-critical state to produce crude oil; discoloration thereof with adsorbing discoloration agent; dissolution of discolored oil in light ligroin; addition of stoichiometric amount of NaOH under stirring; settlement and aliquation; washing of organic phase with warm water to produce emulsion; addition of acetone to emulsion under stirring; layer separation and producing of oily phase in upper layer; treatment of oily phase to absorb thereof subsequently with neutral aluminum oxide and kaolin; removing after filtration of organic solvent from filtrate in nitrogen atmosphere; oily phase washing with warm water; heating of oily phase in nitrogen atmosphere to dehydrate thereof; and adsorption with neutral aluminum oxide. In another embodiment method for extraction of stone oil includes pressing of stones or powered stones, extraction with organic solvent or selectively by using of liquid in above-critical state to produce crude oil; stirring and heating of crude oil; adding of phosphorus acid to provide full degumming; addition of NaOH or Na2CO3 solution to degummed oil at the same temperature to provide full caustic purification; mixture settlement and aliquation to produce purified oil; washing of purified oil with pure water; addition of adsorbent to washed oil or heating thereof in vacuum to remove water and produce transparent dehydrated oil; discoloration thereof with adsorbing discoloration agent under heating in vacuum and under stirring in nitrogen atmosphere and oil heating up to certain temperature; passing of pure water steam at certain temperature and holding for certain time followed by stopping of purified water steam passing and nitrogen passing under stirring to remove moisture from oil. Pharmaceutical compositions improving of immunological function, increasing serum protein content and tumor growth inhibiting, which contains therapeutically effective amount of stone oil and one or more pharmaceutically acceptable adjuvants also are disclosed.

EFFECT: stone oil effectively improving of immunological function, increasing serum protein content and tumor growth inhibiting.

14 cl, 5 tbl, 11 ex

 

The technical field to which the invention relates.

The invention relates to pharmaceutical chemistry of natural compounds, in particular a stone oils extracted from the seed of fruit plants, specifically refers to the stone fruit oils extracted from the date pubescent (spine date) (Semen ziziphi spinosae), yellow wood (flatspine pricklyash) and walnut (Semen persicae), the method of production thereof, pharmaceutical compositions containing such oils and their application in medicine.

The level of technology

The seeds of the fruit of the jujube pubescent and yellow tree are the tools of traditional Chinese medicine for medical purposes and for purposes of power, with functions such as eating liver, calming effect on the heart, deterrence sweating, formation fluid, warm "internal" heating pad for pain relief, elimination of parasites and soothe itching.

The kernel of the walnut is one of the tools of traditional Chinese medicine for medical purposes and for purposes of power, and has functions such as nutrition kidney, warming effect on the lungs and moistening intestine. However, the oil from the kernels of walnuts, as a rule, used as an edible oil, and there is no message about him as a nutrient for parenteral administration. The preparation of regular peanut butter is not you is good for absorption in the human body, and its application in medicine is limited, since it can hardly meet the clinical requirements of the emulsion for intravenous administration. Known in the art, the technology of extraction and separation leads to a mismatch between the requirements for physical and chemical properties (such as acid number) and high impurity content.

As is known in the prior art to replenish the human body with nutrients and energy usually use fat emulsion obtained from soybean oil, cottonseed oil and red flower oil. More widely used fat emulsion derived from soybean oil. However, currently there are no messages about improving immunologic function, improvement of the content of serum proteins, suppression of transplanted tumors, experimental Lewis lung cancer and liver cancer in rats, nutrition and kidney function, warming the lungs, easing bowel in the study of the fatty emulsion of soybean oil.

The invention

Thus, in its first aspect the invention relates to stone the oil from the seed of fruit plants, which can be used to obtain a new emulsion for intravenous administration functions replenishment of nutrients, improve immune function and increase nigerianisation proteins.

In the second aspect of the invention relates to two special technological methods of extraction of stone fruit oil according to the invention.

In the third aspect of the invention relates to pharmaceutical compositions containing stone fruit oil according to the invention, including emulsion for intravenous injection and capsules for oral administration. This emulsion for intravenous administration can replenish nutrients, improve immune function and increase the content of whey proteins. This emulsion also has a power function of the kidney, warming the lungs and easing bowel movements. In addition, it is quite cheap.

In the fourth aspect of the invention relates to the use of stone fruit oils according to the invention when receiving drugs to treat diseases such as tumors, AIDS and the reduction of immunity, etc.

Stone fruit oil extracted from the seed of fruit plants, according to the first aspect of the invention, contains 90-99,9% of triglycerides, 0-5% of diglycerides, 0-3% of monoglycerides, 0.1 to 2.5% of sitosterol and 0-1% cycloenzaprine.

One way of extracting stone fruit oils according to the invention involves the following stages:

1) extraction of raw materials: wringing seed/powdered seeds or extraction with an organic solvent or selectively by using the liquid at the critical condition of obtaining crude oil;

2) bleaching: bleaching of crude oil decolorizing adsorbent substance with getting discolored oil;

3) caustic cleaning: dissolve discolored oil in petroleum ether, adding a stoichiometric amount of NaOH under stirring, settling and stratification of the mixture followed by washing the organic phase with formation thus emulsion;

4) destruction of the emulsion: adding acetone to the emulsion with stirring, separation of layers and getting the oil phase in the upper layer;

5) adsorption and rinsing water: treatment with the purpose of absorption of the oil phase consistently neutral alumina and kaolin, filtration, followed by removal of organic solvent from the filtrate under nitrogen atmosphere and flushing oil phase with warm water, drying and subsequent processing of aluminum oxide with getting so refined oil.

Another way of extracting stone fruit oils according to the invention involves the following stages:

1) extraction of raw materials: wringing seed/powdered seeds or extraction with an organic solvent or selectively by using the fluid in the supercritical state to obtain crude oil;

2) remove the resin with mixing and heating of the crude oil and then adding phosphoric acid to provide the treatment of the completeness of the reaction;

3) caustic cleaning: add not to the oil solution of NaOH or Na2CO3at the same temperature to ensure complete reaction, then settling and stratification of the mixture with getting so refined oil;

4) water rinse: rinse cleaned caustic cleaning oil with clean water to obtain oil, water washed;

5) dehydration: adding adsorbent in oil, rinsed with water, or heating water washed oil in vacuum to remove the water from getting so transparent dehydrated butter;

6) bleaching: bleaching dehydrated oil decolorizing adsorbent substance with getting discolored oil;

7) deodorizing: heat discolored oil with stirring under vacuum in a nitrogen atmosphere with the temperature of the oil up to 120-160°With, the supply of pure water vapor for further heating to 160-260°and exposure for 0.5-2 hours, then a quick cut of pure water vapor and thus removing moisture from the oil with getting deodorized oil.

The pharmaceutical composition according to the invention contains a therapeutically effective amount of stone fruit oil extracted from the seed of fruit plants, and a pharmaceutically acceptable carrier and one or more adjuvants.

From Britanie also relates to the use of stone fruit oil from the seeds of the fruit of plants in medicine to treat tumors, AIDS, low immunity, malnutrition in children, use after surgery and diseases that require the intake of fat elements.

Extracted from the seed of fruit plants stone fruit oil according to the invention is a light yellow oily liquid containing 90-99,9% of triglycerides, 0-5% of diglycerides, 0-3% of monoglycerides, 0.1 to 2.5% of sitosterol and 0-1% cycloenzaprine.

Lipolysis specified stone fruit oil has the following fatty acids: hexadecanoyl acid (5-8%), octadecanoic acid (1-3%), octadecanoyl acid (18-30%), octadecadienoic acid (50-65%) and calendula acid (6-14%).

Stone fruit oil according to the invention has the following physical properties tested for fatty oils: relative density 0,920-0,930 the refractive index 1,470-1,480, acid number <0,80, iodine number 120,0-155,0, the number of saponification 180,0-200,0, peroxide number <30.0 mEq. kg-1, ash 0.01 to 0.04%, arsenic, salt <2 ppm, heavy metals <10 ppm and an average molecular weight 873,96.

Preferred variants of stone fruit oils according to the invention are oils extracted from the seeds of the fruit of the jujube pubescent, yellow wood and walnut.

In the case of walnut kernels, for example, a first method of extracting stone fruit oils involves the following stages:

per the primary extraction wringing cores/powdered cores or extraction with an organic solvent or selectively by using the fluid in the supercritical state with raw nut butter;

bleaching - the addition of an appropriate amount of petroleum ether to the crude oil and thoroughly mixing it, adding an appropriate quantity of activated carbon for injection, maintaining a constant temperature, filtering the mixture and removal of petroleum ether and obtaining thus bleached oil;

caustic cleaning - download discolored oil and the corresponding number of petroleum ether in a reactor, adding with stirring a 2% NaOH solution in a quantity calculated acid number and the number of decolorized oil, settling and removing the lower layer of liquid wastes, then adding with stirring twice the amount of warm distilled water, again settling and removing the lower layer of liquid wastes, then washed again in the same way, the duration and the temperature of the water as above, and obtain the top layer of the emulsion;

destruction of the emulsion - definition of scope and transfer emulsion layer in the separator and adding acetone in a predetermined ratio to the quantity of the emulsion layer at a constant paramasivan is, after settling and separation of the layers, removing the lower layer of liquid wastes and obtain thus the oil phase in the upper layer;

rinse with water - add neutral alumina in a quantity based on the quantity of oil, for adsorption, thorough mixing, settling, and filtering with the formation of a clear oil, then pre-heating metered transparent oil in the reactor, adding with stirring the required amount of activated by heating white bol (kaolin) and continued heating, filtration under vacuum, heating the filtrate to the washing vessel, the removal of organic solvent under nitrogen atmosphere, add warm distilled water based on the amount of oil, thorough mixing, settling and removing the lower layer of liquid wastes, then heat the oil layer in a nitrogen atmosphere removal of water and drying it up until the oil layer becomes transparent, then add neutral aluminium oxide in adequate amounts, thorough mixing, settling and filtering operations for sterilization with getting so refined oil.

Protect the nitrogen in the above-described method is mainly the improvement of oil quality by preventing oxide is s fat and regulation of peroxide number.

If needed stone fruit oil from the kernels of walnuts, obtained as described above, packaged and sterilized. They fill a special container, sterilized and thus receive the stone oil for injection.

Another way of extracting stone fruit oils according to the invention involves the following stages:

1) extraction of raw materials: wringing seed/powdered seeds or selective extraction using a fluid in supercritical state to obtain a transparent crude oil;

2) removal of resin: the location of the crude oil in the reactor is filled with nitrogen, stirring, heating, addition of an appropriate amount of phosphoric acid and rapid mixing to ensure complete reaction;

3) caustic cleaning: direct addition of NaOH or Na2CO3to deresinated oil in a nitrogen atmosphere at the same temperature, rapid mixing to create opportunities fatty acids to react completely, then settling to separate layers in conditions of heat and nitrogen supply, remove the soap and obtaining refined oil;

4) rinse water: the addition of an appropriate quantity of sodium chloride solution to the oil after caustic treatment and then rinse twice with clean water in the same way, with the same duration and temperature is, what is described above, advocating for the separation of layers and removing the lower layer liquid waste to produce oil, water washed;

5) dehydration: the addition of an appropriate quantity of activated alumina to oil, washed with water, settling, and filtering to obtain a transparent dehydrated butter;

6) discoloration; adding dehydrated oil to a reactor, heating the oil to 140°with stirring under vacuum in a nitrogen atmosphere, add appropriate amount of the mixture of activated carbon and activated clay, thorough mixing in vacuum at 80-90°C, cooling, filtering, and retrieving thus bleached oil;

7) deodorizing: download discolored oil in the reactor of stainless steel, heated, bleached oil to 140°with stirring under vacuum in a nitrogen atmosphere, then the supply of pure water vapor instead of nitrogen for further heating bleached oil to 190°and holding at that temperature for 1.5 hours, then stopping the supply of clean water vapor and again stirring in nitrogen atmosphere, cooling the oil with obtaining thus deodorized oil.

If necessary, the resulting deodorized oil can also be sterilized. Deodorized oil is loaded into the vessel DL the sterilization of stainless steel and heated to 160° With under stirring in a vacuum. After holding at this temperature for 2 hours, the oil is cooled and aseptically filtered, and then in a nitrogen atmosphere fill them to capacity and sealed and receive, thus, stone oil for injection.

The pharmaceutical composition according to the invention contains a therapeutically effective amount of stone fruit oil, according to the invention is extracted as described above and one or more pharmaceutically acceptable adjuvants.

Pharmaceutically acceptable adjuvants in the compositions of the invention are one or more adjuvants selected from the group consisting of an emulsifier, solubilizer, an inert solvent, regulator isotonicity, antioxidant and stabilizer.

The pharmaceutical composition of the invention may also contain other active drugs selected among anticancer agents, anti-AIDS, immunomodulators and nutrients.

The pharmaceutical composition of the invention may also contain one or more vegetable oils, such as coconut oil from copra, peanut butter, etc.

The pharmaceutical composition of the invention can be a fat emulsion, such as a fat emulsion for intravenous injection or fat emulsion for oral in which edenia. It can also be a soft capsule or iodized oil, etc.

One of the preferred variants of the pharmaceutical composition of the invention is a fatty emulsion, where these pharmaceutically acceptable adjuvants represent the emulsifier and the regulator isotonicity. The preferred option is a fat emulsion for intravenous peanut butter.

Preferably, the fatty nut-oil emulsion for intravenous injection contains, calculated on the total volume of 100 ml, from 5 g to 30 g, preferably from 10 g to 30 g, most preferably 20 g peanut oil for parenteral administration (walnut oil for injection).

The emulsifier applicable in this invention may be phosphated (including soy lecithin, yolk lecithin and soybean phosphated), pluronic, polyglycerylmethacrylate etc. In the fat emulsion for intravenous administration is preferable to use natural emulsifier such as soy lecithin or yolk lecithin in an amount of about 1.0-3.0 g, preferably 1.0 to 2.0 g, and most preferably 1.2 g calculated on the total volume of the emulsion 100 ml

Isotonic agent used in the invention may be a glycerol, sorbitol, xylitol and glucose and the like, preferably glycerol, in an amount of from 1.5 g to 3.0 is, preferably 2.5 g calculated on the total volume of the emulsion 100 ml

Hereinafter the invention is described using examples, presented for the purpose of explanation, but not limitation.

Information confirming the possibility of carrying out the invention

Example 1

Press 1000 grams of walnut kernels and obtain 450 g of crude peanut butter.

To the crude oil type petroleum ether in an amount of about 40% of the amount of crude oil and mix thoroughly, then add activated carbon in an amount of about 1% of the amount of crude oil. After aging at 45°C for 30 minutes the mixture is filtered, and the petroleum ether removed from the filtrate, whereby receive 428 g discolored oil.

Discolored oil and petroleum ether in an amount of about 50% of the bleached oil is loaded into the reactor and the emulsion layer was added with stirring a thin stream 307 ml of 2% NaOH solution, given the acid number and the number of decolorized oil. The mixture is stirred for 10 minutes and left at rest for 24 hours, then the bottom layer of liquid wastes are removed. Add with stirring twice the amount of water heated to 45°C, then the mixture is left at rest for another 24 hours, then remove the bottom layer of liquid wastes. Perform a second washing of the W is way the same duration and the temperature of the water, above, except that the amount of water in 1.5 times amount of the emulsion layer, and then left at rest for 48 hours.

The bottom layer of liquid wastes removed and receive 342 g of the upper emulsion layer. Emulsion layer is transferred to a separator, quickly added with stirring 342 ml of acetone and left at rest for 3 hours. The bottom layer of liquid wastes are removed, thus obtaining the top layer of oil phase.

Add alumina, activated by heating at a temperature of 160°C for 2 hours in the amount of approximately 5% of the amount of oil, after thorough mixing left at rest for 30 minutes, then the mixture is filtered and receive a clear oil. Measure the volume of transparent oil and load the oil into the reactor where it is heated to 40°C. Add when mixing white bol (kaolin), activated by heating at a temperature of 160°C for 2 hours, in the amount of approximately 3% of the amount of oil, and the mixture was kept at 50°C and stirring for 30 minutes, then filtered under vacuum, and the filtrate is loaded into the wash vessel and heated to 60°C. the Organic solvent is removed under nitrogen atmosphere and quickly add distill is stimulated water heated to 45°With, in the amount equal to the amount of oil. After stirring for 15 minutes and settling for 30 minutes, the bottom layer of liquid wastes are removed. The oil layer was heated to 80°C in nitrogen atmosphere to remove the water and dry up until the oil layer becomes transparent. Add activated neutral alumina, and the mixture was thoroughly stirred and then leave in a calm state. The purified oil is obtained after sterilization by filtration.

The purified oil obtained as described above, is poured into special containers, sterilized and thus receive the 328 g of walnut oil for parenteral administration.

Example 1A. Extraction with an organic solvent

Crushed 500 g of seed nuts and extracted with ether for 7 hours to install Soxhiet. After removal of ether to obtain 270 g of the crude stone fruit oil nuts. The crude oil used to produce stone fruit oils according to the invention.

Example 1B. The extraction fluid in supercritical state

Crushed 500 g of seed nuts and extracted by the method of extraction fluid in a supercritical state (extraction with carbon dioxide in supercritical state) under the following conditions: feed rate of CO2- 4-5 kg/h, the temperature during extraction - 35°C, the pressure is in the extraction - 21-22 MPa, duration of extraction - 3 hours Getting 108 g of the crude stone fruit oil nuts. The crude oil used to produce stone fruit oils according to the invention.

Example 2

1. Extraction of raw materials. Press 30 kg of walnut kernels and receive crude oil, then the crude oil was filtered and receive 13,1 kg transparent crude oil.

2. Removal of the resin. Crude oil is loaded into the reactor and heated to a temperature of from 30°to 35°under stirring in nitrogen atmosphere, add to the oil 13,1 kg of 85% phosphoric acid and the mixture is rapidly stirred for 0.5 hours.

3. Caustic cleaning. Add 717 g of 5% NaOH solution at the same temperature, what is indicated above and in nitrogen atmosphere, not directly in the oil, the mixture is rapidly stirred for 30 minutes and then quickly heated to a temperature of 60-65°With slow stirring. Slow stirring is continued for 15 minutes and then stop. After settling at the same temperature and in a nitrogen atmosphere layers separated. Soap layer is removed and receive 12,8 kg refined oil.

4. Water rinse. At the same temperature to the oil after caustic cleaning, obtained above, was added with stirring 1.9 kg of 0.2% solution of sodium chloride. The mixture is left at rest, and the layers are separated, keeping the heat. The bottom layer is liquid waste drop. Flushing is performed twice in the same way, the same duration and at the same temperature, except that the sodium chloride solution is replaced by pure water. After settling the layers separated. The bottom layer of liquid waste on the floor and get 12,6 kg of oil, water washed.

5. The dehydration. Oil, washed with water, obtained above, add 1.3 kg of aluminum oxide, activated at 160°C for 2 hours. The mixture was mixed thoroughly, left at rest for at least 0.5 hours, then filtered and thus receive the 12.0 kg dehydrated oil.

6. The discoloration. Dehydrated oil, obtained above, is loaded into the reactor and heated to 80-90°under stirring in a vacuum 0,082 MPa. When normal pressure is added to a mixture of 22.5 g of activated charcoal and 337,5 g of kaolin, activated at 160°C for 2 hours. The mixture was thoroughly stirred for 20 minutes at 80-90°and vacuum 0,082 MPa and then cooled down to 40°and filtered. So get 11,0 kg discolored oil.

7. Deodorizing. Obtained above discolored oil is loaded into the reactor of stainless steel and heated to 140°under stirring in a vacuum 0,082 MPa. Then instead of nitrogen supplied pure water vapor and the oil is heated to 190°C. maintain This temperature for 1.5 hours for the holding of heating. Then pairs overlap, and again under stirring served nitrogen. After cooling, get 10,6 kg deodorized oil.

8. Sterilisation. Deodorized oil is loaded into a vessel for sterilization and heated to 160°under stirring in a vacuum 0,082 MPa. This temperature is maintained for 2 hours, then the oil is cooled, sterilized by filtration, packaged in a container in a nitrogen atmosphere and the vessel sealed. So get 9.6 kg of walnut oil for parenteral administration.

Further to illustrate the invention, examples of the composition of various compositions according to the invention.

Composition 1

Walnut oil for injection5-30 g
Lecithin for injection1,0-3,0 g
Glycerin for injection1.5 to 3.0 g
Vitamin E0-0,15 g
Water for injectionto 100 ml

Composition 2

Walnut oil for injection20 g
Soy lecithin for injection1.2 g
Glycerin for injection2.5 g
Vitamin E0.06 g
Water for injectionto 100 ml

Composition 3

Fluorouracil1,0-5,0 g
Walnut oil for injection5,0-30 g
Soy lecithin for injection1,0-3,0 g
Glycerin for injection1.5 to 3.0 g
Vitamin E0-0,15 g
Water for injectionto 100 ml

Composition 4

Paclitaxel (Taxol)10-60 mg
Coconut oil5-15 g
Walnut oil for injection5-15 g
Lecithin for injection1,0-3,0 g
Glycerin for injection1.5 to 3.0 g
Vitamin E0-0,15 g
Water for injectionto 100 ml

Composition 5

td align="left"> Water for injection
Paclitaxel (Taxol)10-60 mg
Polyoxyethylene castor oil1-5 g
Walnut oil for injection5-30 g
Lecithin for injection1,0-3,0 g
Glycerin for injection1.5 to 3.0 g
Vitamin E0-0,15 g
to 100 ml

Composition 6

Homoharringtonine0.05-0.2 g
Walnut oil for injection5,0-30 g
Soy lecithin for injection1,0-3,0 g
Glycerin for injection1.5 to 3.0 g
Vitamin E0-0,15 g
Water for injectionto 100 ml

Composition 7

Cyclophosphamideof 0.2-1.2 g
Walnut oil for injection5,0-30 g
Lecithin for injection1,0-3,0 g
Glycerin for injection1.5 to 3.0 g
Vitamin E0-0,15 g
Water for injectionto 100 ml

Example 3

To 25 ml of water is added 1.2 g of soya lecithin and 2.5 g of glycerol. The mixture is stirred at 5000 rpm to the formation of homogeneous translucent colloidal dispersion, then add 20 grams of peanut oil for injection and add water to a total volume of 100 ml and thus receive the primary emulsion. Adjust the pH of the primary emulsion to a value of 6-9 using NaOH solution, and then the emulsion is transferred to a homogenizer. Accordingly the state of the emulsion is homogenized at low pressure 10˜ 20 MPa and a high pressure of 40˜60 MPa, at a temperature of 60-80°C. Homogenization is repeated 6 times under the same conditions as described above. The resulting emulsion is filtered, poured into containers and sterilized, the result is 20% fat peanut emulsion for intravenous injection.

Example 4

To 20 ml of water, add 1.0 g of yolk lecithin and 1.5 g of glycerol. The mixture is stirred at the speed indicated above, to the formation of homogeneous translucent colloidal dispersion, then add 10 g of walnut oil for injection and add water to a total volume of 100 ml and thus receive the primary emulsion. Adjust the pH of the primary emulsion to a value of 6 to 9, the emulsion is homogenized, filtered, poured into containers and sterilized, the result is 10% fat peanut emulsion for intravenous injection.

Example 5

To 30 ml of water, add 2.0 g of soya lecithin and 3.0 g of glycerin. The mixture is stirred at the speed indicated above, to the formation of homogeneous translucent colloidal dispersion, then add 30 grams of walnut oil for injection and add water to a total volume of 100 ml and thus receive the primary emulsion. Adjust the pH of the primary emulsion to a value of 6 to 9, the emulsion is homogenized, filtered, poured into containers and sterilized, the result is 30% fat peanut emulsion for nutrivene introduction.

Example 6

The fat emulsion composition 3 receive the same manner as in example 3 except that first dissolve the fluorine-uracil in adequate amount of water.

Example 7

The fat emulsion composition 4 receive the same manner as in example 3, except that the first paclitaxel dissolved in coconut oil and then mixed with peanut butter for injection.

Example 8

The fat emulsion composition 5 receive the same manner as in example 3, except that the first paclitaxel dissolved in polyoxyethylene castor oil and then mixed with peanut butter for injection.

Example 9

The fat emulsion composition 6 received in the same manner as in example 3 except that first dissolved homoharringtonine in adequate amount of water.

Example 10

The fat emulsion composition 7 receive the same manner as in example 3 except that water is added to cyclophosphamide together with soy lecithin and glycerin and homogenized.

Example 11

Get capsules according to the invention for oral administration, as described below.

900 g stone fruit oil from the seeds of the fruit of the jujube pubescent or yellow wood or walnut kernels under stirring at room temperature dissolve 0,675 g of vitamin E as an antioxidant is and get bright and clear solution.

Weigh gelatin, water, glycerin and preservative in the ratio of 1:1:0,4:0,001. In the reactor download the most part distilled water and heated to a temperature of 50-60°With, then with stirring, add gelatin, glycerin and preservative. Capacity wash out the remaining distilled water, and the wash water was poured into the reactor. The mixture in the reactor is gradually heated up until it is smooth and will not dissolve all substances, then the reactor is closed and the vacuum pump, so that the residual pressure was 0,065-0,080 MPa for 30-60 minutes. The slurry is filtered through a 120 mesh mesh in a storage vessel and kept at a temperature of 50-60°C.

Get 1000 capsules by pressing forms No. 8 under the following conditions: room temperature 21-24°C, relative humidity <40%, the temperature in the chamber for bonding 50-60°With the voltage divider 110-150 In temperature bonding layer 10-15°C, the thickness of the adhesive joint of 0.8-1.0 mm. Downloadable content amount regularly check. 4 hours after pressing capsules wipe to remove oil and dried for 8 hours, then washed with petroleum ether (30-50°) and again dried. Capsule after removal of defective capsules are Packed.

Example test 1

Mice species Kunming (40 individuals) weighing 19-21 g, males and females in equal number were injected with the tail vein emulsion according to the invention in quantities of 0.5 ml per body weight 20 g The injection was repeated 3 times a day with an interval of 4 hours. The maximum tolerated dose was 75 ml/kg the animals were observed for 7 days. During the tests was not observed neither inverse action, no animals died and were not found anatomical disorders in organs.

Hemolytic test was performed in the usual way check homolytic actions. Hemolysis was not observed. Quantitative assessment of the severity of allergic reactions in Guinea pigs, not shown explicitly anaphylaxis caused by the emulsion of the invention.

Rabbits were injected emulsion according to the invention in the vein of the ear slowly once a day for 7 days at a dose of 15 ml/kg, ml/kg, respectively. Nikoh obvious irritation in the area of Vienna on the edge of the ear in rabbits were not observed.

Sample test 2

The calorific value of walnut oil, according to the invention is measured according GB384-81, was 37599 kJ/kg, which is equivalent calorific value of soybean (37243 kJ/kg), and the calorific value of nut-oil emulsion was 6303 kJ/kg.

Example of test 3. Testing the tolerance of anoxia and fatigue in mice

Healthy male mice (40 individuals) were randomly distributed in 4 groups, based on body weight, 10 animals in each group. Three groups received the emulsion walnut oil in doses of 25 ml/kg, 12.5 ml/kg and 625 ml/kg, respectively. The group "standard saline solution (NS)" received the same volume of standard saline solution. All test substances were injected with the tail vein once a day for 7 days, the test was carried out 2 hours after the last injection.

The test tolerance of anoxia

Each experimental mouse was placed in a 250-ml colorless wide-mouthed bottle containing 10 g of soda lime. Measured time from placing the mouse in the bottle until you stop breathing. Calculate the average survival time (min) and compared differences between groups treated with the emulsion, and the group receiving the standard physiological solution.

Test fatigue

Mice were weighed. Each mouse was given the load on the tail in the amount of 5% by weight of the body and immersed in a large tank of water whose temperature is 25°With the thickness of the water layer 40 see Mice were forced to swim until then, until they sank to the bottom and was not killed. Recorded the duration of the voyage each mouse (min). The results were analyzed statistically using t-test. Compare differences between groups treated with the emulsion, and the group receiving the standard physiological solution.

Table 1.
The influence of the emulsion is AI walnut oil, injected at different doses, tolerance of anoxia and fatigue in mice
Test - swimming with loadTesting the tolerance of anoxia in the atmosphere
GroupDose (ml/kg)Will continue. (min) (x±SD)The coefficient. prolong. (%)Survival time (min) (x±80)The coefficient. prolong. (%).
NS9,18±5,030,46±5,33
Emulsion6,2518,13±16,6497,5834,91±to 7.5914,61
nuts.12,519,96±9,65**17,5641,77±9,38**37,13
oil2522,88±7,89**149,3143,73±lower than the 5.37**43,56
Comparison with standard saline, *P<0,05, **P<0,01

Here and below: SD = the standard deviation is

The test results are given in table 1. Statistical analysis tests the tolerance of anoxia shows a very significant difference between the average survival time of mice that injected emulsion'or the new oil in high and in moderate doses, and mice, which injected a standard saline solution (P<0,01). The above results also show that the effect of nut-oil emulsion tolerance of anoxia and nonspecific ergotropic mice depends on its dose.

Statistical analysis tests for fatigue shows a very significant difference between the duration of the voyage mice, which injected emulsion walnut oil both the high and medium doses, and mice, which injected a standard saline solution (P<0,01). The above results also show that the emulsion walnut oil at the dose of 25 ml/kg causes significant dose-dependent prolongation of the duration of the voyage mice and a significant dose-dependent increase in the period before the onset of fatigue.

Example of test 4. Effect on immune function in mice

Effect on lymphocyte proliferation

Mice C57BL/6 (30 individuals) randomly distributed into 5 groups (6 animals each), which is injected emulsion nut-oil - 25 ml/kg, 12.5 ml/kg and 6.25 ml/kg; intralipid - 12.5 ml/kg and a standard saline solution (0.5 ml/mouse). All songs administered intravenously once a day for 7 days. Animals killed after the last injection, spleen extract in aseptic conditions and receive suspensionlakeside.

Splenocytes count and bring their content to 1×107cells/ml Into each well of 96-well microplate was added 100 μl of cell suspension, 50 μl of ConA and 50 μl of RPMI-1640 medium at a threefold repetition. Tablet incubated for 48 hours at 37°C in an atmosphere with 5% CO2. Then add3H-TdR in the amount of 0.5 µci per well, and the plate is incubated for another 18 hours. Cells are harvested using a device for collecting cells and determine CPM (counts per minute) using a liquid scintillation counter. Compare results for groups treated with intralipid and standard physiological solution, and the treated groups and control groups.

Effects on the activity of NK cells in mice

Mice C57BL/6 (30 individuals) randomly distributed into 5 groups (6 animals each), which is injected emulsion nut-oil - 25 ml/kg, 12.5 ml/kg and 6.25 ml/kg; intralipid - 12.5 ml/kg and a standard saline solution (0.5 ml/mouse). All songs administered intravenously once a day for 7 days. Animals killed after the last injection, spleen extract in aseptic conditions and receive suspensions of splenocytes.

Splenocytes consider using RPMI-1640 medium (manufactured Difco, contains 15% bovine serum, mercaptoethanol, Hepes, etc.) bring their concentration as effector cells to 1×106 cells/ml

The concentration of cells YAC-1 target cells, incubated for 24 hours, adjusted with RPMI-1640 medium to 1×104cells/ml

In wells of 96-well microplate was added 100 μl of effector cells and 100 μl of target cells and add 0.5 µci3H-TdR in each well. The test is repeated three times. Tablet incubated at 37°C in an atmosphere with 5% CO2and the cells harvested. Define CPM, and calculate the specific inhibition percentage (Pi)representing the activity of NK-cells.

The effect on IL-2 in mice

Mice C57BL/6 (30 individuals) randomly distributed into 5 groups (6 animals each), which is injected emulsion nut-oil - 25 ml/kg, 12.5 ml/kg and 6.25 ml/kg; intralipid - 12.5 ml/kg and a standard saline solution (0.5 ml/mouse). All songs administered intravenously once a day for 7 days. Animals killed after the last injection, spleen extract in aseptic conditions and receive suspensions of splenocytes.

Suspension of splenocytes was adjusted with RPMI-1640 medium (manufactured Difco, contains 15% bovine serum, mercaptoethanol, Hepes, and the like) to a concentration of 1×107cells/ml

In each well of a 24-hole tablet add 2 ml of cells and 5 μg/ml ConA. Tablet incubated at 37°C in an atmosphere with 5% CO2within 24 hours, and sitemobile supernatant. The activity of IL-2 detected by the method of introduction of3H-TdR using IL-2-dependent clone CTLL. In each well of 96-well tiralongo of the microplate was added 100 μl of cell suspension CTLL content 1×105cells/ml, 20 ál3H-TdR and 100 µl of the supernatant. Define CPM and conduct a comparison of the differences between treated groups and control.

compare the action of the emulsion peanut butter and intralipid.

The above results show that the emulsion nut oil injected i.v. at the dose of 25, 12.5 or 6.25 ml/kg for 7 days, clearly can promote the proliferation of lymphocytes, increase the activity of natural killer cells (NK-cells) and promote the formation of IL-2 in mice, i.e. the influence of the emulsion of the invention on immune function significantly superior effect of the emulsion of soybean oil.

Example test 5

Mice (40 individuals) randomly distributed in 4 groups. Animals injected with 10 ml/kg standard physiological solution, emulsion peanut butter and 6.25 ml/kg, 12.5 ml/kg and 25 ml/kg, respectively, intravenously for 7 days. Animals killed after the last injection and take blood samples to test for total serum protein.

The results are given in table 3.

Example test 6. Podavini the liver cancer US and Lewis lung cancer in mice

Collect peritoneal fluid with a well-developed US, diluted with standard saline solution in a ratio of 1:4 and cell suspension. Each mouse inoculant subcutaneously with 0.2 ml of cell suspension armpit. Animals randomly distributed into 4 groups: a group receiving standard saline solution, and the group receiving the emulsion nut-oil - 25 ml/kg, 12.5 ml/kg and 6.25 ml/kg the next day, begin intravenous injection for 7 days. Ten days after inoculation of animals killed by displacement of the cervical spine. Tumor extract and compare the masses of tumors. The ratio of tumor suppression is calculated using the formula below. The results are shown in table 4.

Collect the mass well developed tumors lung cancer Lewis, homogenized in a standard saline solution in a ratio of 1:4 and cell suspension. Each mouse inoculant subcutaneously with 0.2 ml of cell suspension armpit. Animals randomly distributed into 4 groups: a group receiving standard saline solution, and the group receiving the emulsion nut-oil - 25 ml/kg, 12.5 ml/kg and 6.25 ml/kg the next day, begin intravenous injection for 7 days. Through desyatina after inoculation of animals killed by displacement of the cervical spine. Tumor extract and compare their weights. The ratio of tumor suppression is calculated using the formula below.

The results are shown in table 5.

From table 4 and table 5 it is seen that the nut-oil emulsion in the above doses can, to some extent, to suppress liver cancer US and Lewis lung cancer in mice.

Upon further research discovered that the emulsion derived from nut oils, also has the above properties when used as an energy source. It can be associated with its supply of the kidney, warming the lungs and easing bowel movements.

Industrial applicability

The nut-oil emulsion according to the invention for parenteral administration has a constant composition and emulsifier used is safe and trustworthy. In addition to the functions of the supply of nutrients and energy, anoxia endurance and increase stamina, boost immune function and increase total serum protein, emulsion also to some extent suppresses liver cancer US and Lewis lung cancer in mice. In addition, the emulsion has a supply of the kidney, warming the lungs and easing bowel, which has the original substance. She is one the Xia energy emulsion with a variety of efficiency and can be used to treat tumors, venereal diseases, AIDS, low immunity, nutritional deficiencies in children after surgery and diseases that require the intake of fat elements.

Extraction according to the method of the invention provides good quality emulsion with high yield, and the extract obtained has the desired medical effect. In particular, by introducing nitrogen to protect the oil from oxidation effectively improving the quality of stone fruit oils.

The biggest advantage of the second method according to the invention is that it does not use an organic solvent, so that eliminates contamination. Peroxide number of stone fruit oil extracted using the above method, can reach values less than 6.0 mEq. kg-1.

1. Stone fruit oil extracted from the seed of the jujube pubescent, yellow wood or walnut containing 90-99,9% of triglycerides, 0-5% of diglycerides, 0-3% of monoglycerides, 0.1 to 2.5% of sitosterol and 0-1% cycloenzaprine.

2. Stone fruit oil according to claim 1, characterized in that when lipolysis specified stone fruit oil causes the following fatty acids:

hexadecanoate acid (5-8%), octadecanoic acid (1-3%), octadecenoate acid (18-30%), octadecadienoic acid (50-65%) and calendula acid (6-14%).

3. Stone fruit oil according to claim 1, characterized is to be so, that it possesses physical properties of fatty oil, namely: relative density 0,920-0,930, refractive index 1,470-1,480, acid value of 0.80, iodine number 120,0-155,0, saponification number 180,0-200,0, peroxide number <30.0 mEq. kg-1while ash is 0.01 to 0.04%, arsenic salts are <2 ppm, heavy metals are <10 ppm and average mol. weight is 873,96.

4. The method of extracting stone fruit oil, characterized in claims 1 to 3, including wringing seed or seed, crushed into powder, extraction with an organic solvent or selectively by using the fluid in the supercritical state to obtain crude oil; bleaching the crude oil decolorizing adsorbent substance; the dissolution of the bleached oil in petroleum ether, adding a stoichiometric amount of NaOH under stirring, settling and stratification, washing the organic phase with warm water to obtain an emulsion; adding acetone to the emulsion with stirring, separation of layers and getting the oil phase in the upper layer; processing of oil phase to absorption consistently neutral alumina and kaolin, remove after filtration of the organic solvent from the filtrate under nitrogen atmosphere, flushing oil phase with warm water, heating masla the phase in nitrogen atmosphere for its dehydration, the adsorption is carried by neutral aluminum oxide.

5. The method of extracting stone fruit oil, characterized in claims 1 to 3, including wringing seed or seed, crushed into powder, extraction with an organic solvent or selectively by using the fluid in the supercritical state to obtain crude oil; mixing and heating of crude oil, adding phosphoric acid to ensure complete obessmolivanija; add not to the oil solution of NaOH or Na2CO3at the same temperature to ensure complete caustic cleaning, settling and stratification of the mixture with getting so refined oil; washing the purified caustic cleaning oil with clean water to obtain oil, rinsed with water; adding the adsorbent in the water-washed oil or heating water washed oil in vacuum to remove the water from getting so transparent dehydrated oil; bleaching the dehydrated oil decolorizing adsorbent substance when heated under vacuum; heating the bleached oil under vacuum and with stirring in nitrogen atmosphere with the temperature of the oil up to 120-160°With, the transmission of water vapor of pure water at 160-260°and holding for 0.5-2 h, and then the supply of purified water vapour and prop the Scania nitrogen with stirring to remove moisture from oil.

6. Pharmaceutical composition, improve immune function, increase the content of whey proteins and inhibits the growth of tumors containing a therapeutically effective amount of stone fruit oil, characterized in claims 1 to 3, and one or more pharmaceutically acceptable adjuvants.

7. The pharmaceutical composition according to claim 6, further containing one or more anticancer agents.

8. The pharmaceutical composition according to claim 6, further containing one or more vegetable oils.

9. The pharmaceutical composition according to claim 6, characterized in that the said pharmaceutically acceptable carriers include one or more substances selected from the group consisting of an emulsifier, solubilizer, an inert solvent, regulator isotonicity, antioxidant and stabilizer.

10. The pharmaceutical composition according to claim 9, containing, g:

Walnut oil for injection5-30
Lecithin for injection1,0-3,0
Glycerin for injection1,5-3,0
Vitamin E0-0,15
Water for injection, ml100

11. The pharmaceutical composition of claim 10 containing, g:

Walnut oil for injection20
Soy lecithin for injection1,2
Glycerin for injection2,5
Vitamin E0,06
Water for injection, ml100

12. The pharmaceutical composition according to claim 7 or 9, containing, g:

Fluorouracil1,0-5,0
Walnut oil for injection5,0-30
Soy lecithin for injection1,0-3,0
Glycerin for injection1,5-3,0
Vitamin E0-0,15
Water for injection, ml100

13. The pharmaceutical composition according to any one of claims 7 to 9, containing, g:

Paclitaxel (Taxol)10-60
Coconut oil5-15
Walnut oil for injection5-15
Soy lecithin for injection1,0-3,0
Glycerin for injection1,5-3,0
Vitamin E0-0,15
Water for injection, ml100

14. The pharmaceutical composition according to claim 6, ex the different topics that it is made in the form of capsules containing stone fruit oil, characterized in claims 1 to 3.



 

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EFFECT: enhanced effectiveness of treatment.

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