CN101982176B - Compound sodium selenite-vitamin E oral nano-emulsion preparation for livestock and preparation method thereof - Google Patents
Compound sodium selenite-vitamin E oral nano-emulsion preparation for livestock and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a compound sodium selenite-vitamin E oral nano-emulsion preparation for livestock and a preparation method thereof. The compound sodium selenite-vitamin E oral nano-emulsion preparation for livestock is prepared from the following raw materials by mass volume percent: 5 to 10% of vitamin E, 15 to 35% of emulsifier, 7.5 to 17.5% of auxiliary emulsifier, 0.1% of sodium selenite, 0.1% of antioxidant and preservative and the balance solvent. The sodium selenite-vitamin E nano-emulsion of the invention is clear and bright emulsion which consists of self-emulsified nano-particles and is a self-emulsified clear and transparent thermodynamically stable system; and the production process is simple and facilitates mass production.
Description
Technical Field
The invention belongs to the technical field of veterinary medicines, and particularly relates to a compound sodium selenite-vitamin E oral nanoemulsion preparation for veterinary use and a preparation method thereof.
Background
Selenium is a mineral trace element and is a constituent of glutathione peroxidase, which decomposes intracellular peroxides, prevents oxidative damage to cell membranes, protects biological membranes from damage, and is usually stored in hemoglobin and organs of humans or animals. Modern science shows that: the selenium supplement for animals can improve the antibody titer of animal organisms to Sheep Red Blood Cell (SRBC) antigen or tetanus toxoid and improve the autoimmunity. On the contrary, when the animals are lack of selenium, the humoral immune response is reduced, including the reduction of antibody titer and the time delay of the immune response, which affect the metabolism of the organism to amino acid and the synthesis of protein, and also cause the brain softening disease and seriously affect the growth, development and reproductive function of the livestock and poultry. In addition, selenium can counteract immunosuppression caused by immunosuppressive agents.
Vitamin E, also known as tocopherol, is a fat-soluble organic compound, and eight kinds of vitamin E are known at present, have similar physiological functions and have an antioxidant effect. Vitamin E can protect unsaturated fatty acids of lipids constituting the biological membrane from oxidation, protect the integrity of lipid membrane, participate in maintaining normal reproductive function of animals, promote gonadal development, promote conception and prevent abortion. But also can enhance the resistance of skin capillary vessels, maintain normal permeability, improve the blood circulation of human and animals, and have the functions of adjusting fertility, resisting aging and the like.
The combination of sodium selenite and vitamin E has a synergistic effect, selenium can protect vitamin E from being completely absorbed and utilized through mucous membrane, promote enzyme secretion, prevent pancreas fibrosis, enhance the antioxidation effect of the vitamin E, prevent the selenium from being damaged by oxidation, and greatly enhance the clinical effect compared with the single use. Sodium selenite-vitamin E oral liquid and injection are loaded into the second and fifth pharmacopoeias of Chinese animals. The sodium selenite-vitamin E is mainly used for preventing the livestock and poultry vitamin E and symptoms such as sow oestrus failure, piglet white diarrhea, foot rot, nutritional liver necrosis and the like caused by selenium deficiency, and can enhance the immunity of the organism, promote the growth and improve the meat-feed ratio; if the egg yolk is used for laying hens and laying ducks, the egg weight can be increased, the laying rate can be improved, the eggshell firmness can be enhanced, and the breakage rate can be reduced.
In the veterinary drugs of sodium selenite-vitamin E premix, oral liquid and injection in the prior art, because the effective dose of sodium selenite is very close to the poisoning dose, the premix has the problem of selenium poisoning caused by difficulty in fully mixing with feed. The existing oral liquid and injection are both conventional emulsions and have the defects of unstable preparation, easy oxidation and unstable quality. Although the injection has high bioavailability, the injection administration is inconvenient under the condition of intensive breeding, the oral liquid has low bioavailability, and the classical medicament formulations can not adjust the behavior (distribution and elimination) of the medicament in the body and can not meet the requirements of the animal medicament market under the current intensive breeding condition.
In the field of human medicine, Chinese patent application CN200910154931.6 discloses a vitamin E oil nanoemulsion preparation and a preparation method thereof, and the patent document provides a vitamin E nanoemulsion with the content of 1 percent, belongs to human injection and is used for treating human vitamin E deficiency. However, the product can not be directly used for animals, 1, due to technical limitation, the preparation can only prepare the nanoemulsion with low content (the vitamin E content is below 5%) suitable for human use according to the method, and can not prepare the nanoemulsion which is suitable for animals and still stable under high content condition (the vitamin E content is between 5% and 10%); 2. the preparation is a single-component preparation of vitamin E, belongs to human medicine, does not meet relevant regulations of agriculture, cannot be used for livestock and poultry, and has limited application range; 3. the injection administration route is not suitable for the market requirement under the current large-scale intensive feeding condition.
So far, no technical disclosure about sodium selenite-vitamin E compound oral nanoemulsion in the field of veterinary medicines is found.
Disclosure of Invention
The invention aims to provide a high-content sodium selenite-vitamin E compound oral nanoemulsion special for animals and a preparation method thereof aiming at the defects of the prior art.
The invention takes sodium selenite and vitamin E as raw materials to prepare a nutritional compound medicine for livestock and poultry, and can be used for preventing and treating sow oestrus failure, white scour of piglets, foot rot and other diseases caused by selenium deficiency and vitamin E deficiency.
The technical scheme of the invention is as follows:
a sodium selenite-vitamin E compound oral nanoemulsion preparation for animals is prepared from the following raw materials:
the nano-emulsion comprises, by mass volume, 5-10% of vitamin E, 15-30% of an emulsifier, 7.5-15% of an auxiliary emulsifier, 0.1% of sodium selenite, 0.1% of an antioxidant and a preservative, and the balance of a solvent; wherein the vitamin E and the sodium selenite are both calculated by pure products, and the unit of mass volume percentage is gram to milliliter.
Preferably, the emulsifier is one or a combination of more of tween-80 (TW-80), span-80, polyoxyethylene castor oil EL-40 and polyoxyethylene monostearate, wherein tween-80 or polyoxyethylene castor oil EL-40 is further preferred; the auxiliary emulsifier is one or a combination of more of propylene glycol, ethylene glycol, glycerol, isopropanol and absolute ethyl alcohol.
Preferably, the solvent is water; the preservative is selected from ethyl paraben, methyl paraben or benzoic acid; the antioxidant is selected from 2, 6-dibutyl hydroxy toluene (BHT), tert-Butyl Hydroxy Anisol (BHA) or Na2SO3. The mass ratio of the preservative to the antioxidant is preferably 1: 1.
The preparation method of the sodium selenite-vitamin E nanoemulsion preparation for livestock comprises the following steps:
(1) firstly, mixing and stirring the vitamin E, the emulsifier and the co-emulsifier uniformly, then adding the antioxidant and the preservative, and stirring until the antioxidant and the preservative are completely dissolved to obtain a mixed solution;
(2) weighing sodium selenite, adding into solvent, stirring to dissolve completely;
(3) dripping the mixed liquid obtained in the step (2) into the mixed liquid obtained in the step (1), and stirring while dripping; and continuously stirring for 15-30 minutes after the dropwise addition is finished to obtain the sodium selenite-vitamin E nano emulsion.
Then, the mixture was packaged and sterilized at 121 ℃ for 15 minutes.
The steps (1) to (3) are all carried out at normal temperature.
The pH value of the sodium selenite-vitamin E nano emulsion product is 7.0-8.0.
The emulsifier is a stabilizer of the nano-emulsion, is a surfactant, and forms a film or an electric double layer when dispersed on the surface of a dispersoid, so that the dispersed phase can be charged, droplets of the dispersed phase can be prevented from coagulating with each other, and the formed nano-emulsion is relatively stable. In the invention, Tween-80 and polyoxyethylene castor oil are preferably used as the emulsifier of the nano-emulsion, which has the advantages of reducing the toxicity of the emulsion and reducing the irritation to the organism.
The auxiliary emulsifier can assist the emulsifier to reduce interfacial tension, reduce repulsive force among emulsifier molecules, increase interfacial fluidity, reduce interfacial bending energy formed by the nanoemulsion, enable the nanoemulsion to form spontaneously, and simultaneously adjust the HLB (hydrophilic-lipophilic balance) value of the emulsifier to enable the emulsifier to have larger adsorption on an oil-water interface. In the invention, one or more of propylene glycol, ethylene glycol, glycerol, isopropanol and absolute ethyl alcohol are preferably selected as the co-emulsifier.
Adding water as a solvent into the sodium selenite-vitamin E nanoemulsion to enable the sodium selenite-vitamin E nanoemulsion to form a stable system, wherein purified water is preferably selected as the solvent in the nanoemulsion.
The invention relates to a sodium selenite-vitamin E compound oral nanoemulsion for livestock, which has the following preferable technical scheme:
the formula I is as follows: vitamin E5 g
Sodium selenite 0.1g
TW-80 15g
Anhydrous ethanol 7.5g
2, 6-dibutylhydroxytoluene 0.05g
Nipagin ethyl ester 0.05g
Purified water was added to 100 ml.
And a second formula: vitamin E8 g
Sodium selenite 0.1g
Polyoxyethylene Castor oil EL-4018 g
Isopropanol 9g
2, 6-dibutylhydroxytoluene 0.05g
Nipagin ethyl ester 0.05g
Purified water was added to 100 ml.
And the formula III: vitamin E10 g
Sodium selenite 0.1g
TW-80 30g
Anhydrous ethanol 15g
2, 6-dibutylhydroxytoluene 0.05g
Nipagin ethyl ester 0.05g
Purified water was added to 100 ml.
The invention has the beneficial effects that:
1. the sodium selenite-vitamin E nanoemulsion is a clear and transparent emulsion, is a clear and transparent thermal stability system formed by self-emulsifying nano particles and self-emulsifying nano particles, and is simple in production process, easy to operate and easy for mass production.
2. The sodium selenite-vitamin E nano emulsion has the emulsion particle size of 10-100 nm, is uniform in distribution, transparent and good in stability, has small particle size and low viscosity, has good drug dispersibility in the nano emulsion, can be quickly absorbed through mucous membrane, and can greatly improve the bioavailability of the drug.
3. The selenium-enriched compound preparation is a selenium-enriched product, can effectively promote the growth, development and reproduction functions of livestock and poultry, can synergistically promote the absorption of vitamin E, is used as a special compound preparation for livestock, and can prevent and treat diseases such as sow oestrus failure, piglet white diarrhea, foot rot and the like caused by selenium deficiency and vitamin E deficiency. Has the advantages of convenient use, high bioavailability by oral absorption, definite curative effect and the like.
4. The product of the invention is oil-in-water type nano-emulsion, can be diluted by water in any proportion, can be administrated by drinking water, does not block a waterline, and is suitable for large-scale intensive culture. The sodium selenite-vitamin E nano-emulsion can greatly improve the solubility of insoluble drugs and can simultaneously solubilize the solubility of different fat-soluble drugs in water;
5. the pH value of the nano-emulsion is 7.0-8.0, so that the nano-emulsion can meet the adaptability requirement of an organism, accelerate the absorption of organism tissues, reduce the local stimulation of gastrointestinal tracts and maintain the stability of the nano-emulsion.
The sodium selenite-vitamin E nano-emulsion preparation can completely replace the original common emulsion preparation, can be produced in large scale, and is proved to have stable property by long-term stability investigation, little influence from the external ambient environment, long action time after animal administration, small local stimulation, convenient use and reliable curative effect.
Drawings
Fig. 1 is a transmission electron micrograph (× 100000) of a nanoemulsion according to example 1 of the present invention.
Detailed Description
The present invention is further illustrated by, but not limited to, the following examples. Among them, the emulsifier polyoxyethylene castor oil EL-40 Pasteur chemical Co., Ltd is available. Other raw material components are all available on the market.
Example 1 sodium selenite-vitamin E nanoemulsion formulation containing 10% vitamin E
The sodium selenite-vitamin E nanoemulsion comprises the following components (calculated by 100 ml): 10g of vitamin E, 0.1g of sodium selenite, 30g of emulsifier, 15g of co-emulsifier, 0.1g of antioxidant and preservative (the mass ratio of the antioxidant to the preservative is 1: 1), and purified water is added to 100 ml.
The emulsifier is Tween-80, the co-emulsifier is absolute ethyl alcohol, the antioxidant is 2, 6-dibutyl hydroxy toluene, and the preservative is ethylparaben.
The preparation method comprises the following steps:
mixing vitamin E, emulsifier and auxiliary emulsifier, and stirring to obtain mixed solution; adding the preservative and the antioxidant into the mixed solution, and stirring until the preservative and the antioxidant are completely dissolved to obtain a mixed solution I; weighing sodium selenite, dissolving in purified water to prepare mixed liquid; slowly dripping the mixed solution II into the mixed solution I while stirring until the mixed solution I reaches 100ml, and continuously stirring for 15 minutes to obtain the clear and transparent sodium selenite-vitamin E nano-emulsion. Then, the mixture was packaged and sterilized at 121 ℃ for 15 minutes.
Clinical use effect of veterinary drug compound sodium selenite-vitamin E oral nano-emulsion preparation
1. The product can be used for piglets
Selecting 3 newborn piglets with good health status of sow, spraying 1mL compound sodium selenite-vitamin E oral nano-emulsion into the oral cavity of each piglet by using an injector without a needle on the 3 rd day after the birth of each piglet, spraying sodium selenite-vitamin E oral liquid into the oral cavity of each piglet by the same method, spraying sodium selenite-vitamin E conventional oral liquid into the oral cavity of each piglet by the same method, and taking 10 piglets in the third nest as a control group to supply tap water by the same method. After 5 days, the same method is applied for 1 time. Respectively measuring the weight of each group of piglets before use and the weight of each group of piglets at weaning, recording the number of piglets suffering from diarrhea, and calculating the average weight before use, the average weight at weaning, the average weight gain and the diarrhea incidence rate.
Compared with the use of sodium selenite-vitamin E normal milk oral liquid piglets, the invention has the following experimental results:
TABLE 1 weight record of piglets of the test group of the invention before use and after weaning
The experimental results show that the sodium selenite-vitamin E nanoemulsion orally taken by the piglets can obviously improve the generation performance of the piglets and obviously reduce the diarrhea incidence rate, and the effect is superior to that of the conventional oral liquid.
2. The product is used for chickling
Selecting 9415 chicks of 1 day old bred in a certain commercial white feather broiler farm, dividing the chicks into 3 groups, namely 3669 chicks in the first group, and adding 2mL of sodium selenite-vitamin E nanoemulsion into 20L of drinking water for the chicks to freely drink; 3076 the second group is administered with sodium selenite-vitamin E oral liquid by the same method; 2670 in the third group, no drug was administered, and all groups were administered for 3 days continuously to observe the growth and death of chickens in each group.
TABLE 2 chick mortality record before use and at 4 weeks of age
| Grouping | Number/number before use | 4 weeks old/body | Average mortality/%) | Growth conditions |
| First group | 3669 | 3610 | 1.63 | Good effect |
| Second group | 3076 | 2977 | 3.25 | Good effect |
| Third group | 2670 | 2544 | 4.72 | Good effect |
As can be seen from the table above, the oral administration of the sodium selenite-vitamin E nanoemulsion to the chicks can obviously reduce the death rate of the chicks, and the effect is superior to that of the conventional oral liquid of sodium selenite-vitamin E.
In addition, 50000 broiler chickens are fed to a certain breeding farm in Harbin city, and are bred in two fields (divided into a first field and a second field), 30000 broiler chickens are bred in the first field, and 20000 broiler chickens are bred in the second field. The second site started using the nanoemulsion formulation of the present invention at 3 days of age, and the first site adopted the traditional breeding method. At the end of the brooding period (4 weeks of age), 27830 broilers remained on site one and 19220 broilers remained on site two. The mortality rate of the first field is 3.9%, and the mortality rate of the second field is 7.2%. It can be seen that the mortality rate of field one without the nanoemulsion formulation of the present invention is nearly 2 times higher than field two.
Second, safety analysis
The product can be added into drinking water for chicken without death. After 30 days of observation, the chickens after administration have good growth vigor and no diseases. The product is safe for clinical use.
Thirdly, the stability experimental result of the compound sodium selenite-vitamin E oral nano-emulsion preparation
3.1 accelerated test (standing at 30 ℃. + -. 2 ℃ C., relative humidity 60%. + -. 10% for 6 months)
Table 3: product batch number: 200909001
Table 4: product batch number: 200909002
Table 5: product batch number: 200909003
3.2 Long-term test (12 months at 25 ℃. + -. 2 ℃ C. and 60% + -10% relative humidity)
Table 6: product batch number: 200909001
Table 7: product batch number: 200909002
Table 8: product batch number: 200909003
Under the conditions of accelerated test and long-term test, the appearance of the compound sodium selenite-vitamin E oral nano-emulsion preparation is consistent, clear and uniform, and the phenomena of layering, color change, flocculation, emulsion breaking and the like are not seen. The results of accelerated test and long-term test show that the vitamin E and sodium selenite content of the compound sodium selenite-vitamin E oral nano-emulsion preparation has no obvious change, which indicates that the compound nano-emulsion preparation is stable.
Example 2 sodium selenite-vitamin E nanoemulsion formulation containing 8% vitamin E
The sodium selenite-vitamin E nanoemulsion comprises the following components (calculated by 100 ml): 8g of vitamin E, 0.1g of sodium selenite, 18g of emulsifier, 9g of co-emulsifier, 0.1g of antioxidant and preservative (the mass ratio of the antioxidant to the preservative is 1: 1), and purified water is added to 100 ml. The preparation method is the same as example 1.
The emulsifier is polyoxyethylene castor oil EL-40, the co-emulsifier is isopropanol, the antioxidant is 2, 6-dibutyl hydroxy toluene, and the preservative is ethylparaben.
Example 3 sodium selenite-vitamin E nanoemulsion formulation containing 5% vitamin E
The sodium selenite-vitamin E nanoemulsion comprises the following components (calculated by 100 ml): 5g of vitamin E, 0.1g of sodium selenite, 15g of emulsifier, 7.5g of co-emulsifier, 0.1g of antioxidant and preservative (the mass ratio of the antioxidant to the preservative is 1: 1), and purified water is added to 100 ml. The preparation method is the same as example 1.
The emulsifier is Tween-80, the co-emulsifier is absolute ethyl alcohol, the antioxidant is 2, 6-dibutyl hydroxy toluene, and the preservative is ethylparaben.
Claims (1)
1. A sodium selenite-vitamin E compound oral nanoemulsion preparation for animals is prepared from the following raw materials:
8g of vitamin E, 0.1g of sodium selenite, 0.4018 g of polyoxyethylene castor oil EL-4018 g, 9g of isopropanol, 0.05g of 2, 6-dibutyl hydroxy toluene, 0.05g of ethylparaben and purified water which is added to 100 ml;
or,
10g of vitamin E, 0.1g of sodium selenite, 8030 g of Tween-8030 g of absolute ethyl alcohol, 15g of 2, 6-dibutyl hydroxy toluene, 0.05g of ethylparaben and purified water added to 100 ml;
the preparation method comprises the following steps:
(1) mixing vitamin E, emulsifier polyoxyethylene castor oil EL-40 or Tween-80, and auxiliary emulsifier isopropanol or anhydrous ethanol, stirring, adding antioxidant 2, 6-dibutyl hydroxy toluene and antiseptic ethylparaben, and stirring to dissolve completely to obtain mixed solution;
(2) weighing sodium selenite, adding into solvent, stirring to dissolve completely;
(3) dripping the mixed liquid obtained in the step (2) into the mixed liquid obtained in the step (1), and stirring while dripping; and continuously stirring for 15-30 minutes after the dropwise addition is finished to obtain the sodium selenite-vitamin E nano emulsion.
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| 卜仕金.亚硒酸钠维生素E.《畜禽药物应用表解》.江苏科学技术出版社,2002,188. * |
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