CN111514157A - Application of composition in preparation of veterinary anti-parasitic drug, veterinary anti-parasitic transdermal solution and preparation method thereof - Google Patents
Application of composition in preparation of veterinary anti-parasitic drug, veterinary anti-parasitic transdermal solution and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of antiparasitic drugs, and particularly relates to application of a composition containing ivermectin and levamisole hydrochloride in preparation of a veterinary antiparasitic drug, a veterinary antiparasitic transdermal solution and a preparation method thereof. The transdermal solution comprises the following components in parts by volume: 20-50 parts of isopropanol; 10-40 parts of glycerol; 10-30 parts of absolute ethyl alcohol; 5-20 parts of dimethyl sulfoxide; 2-6 parts of azone; the content of ivermectin is 0.3-1g per 100mL of solution, and the content of levamisole hydrochloride is 5-15g per 100mL of solution. According to the invention, the ivermectin and the levamisole hydrochloride are compatible, and the ivermectin and the levamisole hydrochloride have a synergistic interaction effect when used at the same time, so that the insect resistance spectrum is improved; meanwhile, the invention adopts a transdermal absorption preparation formulation, reduces the toxic and side effects caused by the correlation of the medicament and the dosage, and achieves the effect of killing insects inside and outside a preparation at the same time.
Description
Technical Field
The invention belongs to the technical field of antiparasitic drugs, and particularly relates to application of a composition in preparation of a veterinary antiparasitic drug, a veterinary antiparasitic transdermal solution and a preparation method thereof.
Background
The parasites mainly cause mechanical damage or lack of nutrition by consuming nutrient substances in cattle and sheep bodies, so that the utilization rate of the feed by the animals is reduced, the cattle and sheep grow slowly, and the utilization rate of the feed is reduced. Current antiparasitic drugs are mainly divided into anthelmintics, antiprotozoals and ectoparasiticides. Because animal parasitic diseases are mostly mixed infection, antiparasitic drugs with high efficiency, broad spectrum, low toxicity and convenient administration should be selected.
At present, the antiparasitic drugs for livestock are all prepared according to different action mechanisms, and the anti-insect spectrum is limited. For example, ivermectin, although it has good parasiticidal action against ectoparasites, particularly scabies, is not effective against cestodes, trematodes and protozoa. Levamisole hydrochloride is a broad-spectrum nematocide, and although the levamisole hydrochloride has the anthelmintic activity and can also obviously improve the immune response, the levamisole hydrochloride has poor anthelmintic effect on ectoparasites.
In addition, the existing dosage forms of the antiparasitic drugs widely adopt injections, powder, tablets and pour-on agents, and the treatment is carried out step by step in an internal and external administration mode, so that the toxic and side effects of the drugs and the dosage are increased, and a large amount of labor cost is increased due to the inconvenience in use.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provides application of a composition comprising ivermectin and levamisole hydrochloride in preparing veterinary anti-parasitic diseases, a veterinary anti-parasitic transdermal solution and a preparation method thereof.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides an application of a composition containing ivermectin and levamisole hydrochloride in preparation of veterinary anti-parasitic drugs, wherein the mass ratio of the ivermectin to the levamisole hydrochloride is (0.3-1): 5 to 15.
Preferably, the medicament is used for repelling one or more of scabies, nematodes, cestodes, trematodes, coccidia and roundworms.
The invention also provides an anti-parasitic-disease transdermal solution for livestock, which comprises the following components in parts by volume:
the ratio of the mass of ivermectin to the volume of the transdermal solution is 0.3-1 g: 100 mL;
the mass ratio of the levamisole hydrochloride to the volume of the transdermal solution is 5-15 g: 100 mL.
Preferably, the veterinary anti-parasitic transdermal solution comprises the following components in parts by volume:
the ratio of the mass of ivermectin to the volume of the transdermal solution is 0.5-1 g: 100 mL;
the ratio of the mass of the levamisole hydrochloride to the volume of the transdermal liquid medicine is 10-15 g: 100 mL.
Preferably, the transdermal solution contains the following components per 100 mL: 40mL of isopropanol, 30mL of glycerol, 20mL of absolute ethyl alcohol, 8mL of dimethyl sulfoxide, 2mL of azone, 1g of ivermectin and 10g of levamisole hydrochloride.
The invention provides a preparation method of the transdermal solution in the technical scheme, which comprises the following steps:
(1) mixing the isopropanol, the glycerol, the absolute ethyl alcohol, the dimethyl sulfoxide, the azone, the ivermectin and the levamisole hydrochloride to obtain a mixed solution;
(2) and (3) sterilizing and filtering the mixed solution by adopting a microporous filter membrane to obtain the veterinary anti-parasitic-disease transdermal solution.
Preferably, the mixing manner in the step (1) is as follows:
(a) mixing and dissolving isopropanol and ivermectin to obtain a first solution;
(b) mixing and dissolving absolute ethyl alcohol and levamisole hydrochloride to obtain levamisole hydrochloride ethanol solution; mixing dimethyl sulfoxide, glycerol, azone and levamisole hydrochloride ethanol solution to obtain a second solution;
(c) mixing the first solution and the second solution.
Preferably, the aperture of the microporous filter membrane is 0.1-0.45 μm.
Preferably, the pore diameter of the microfiltration membrane is 0.22 μm.
The invention provides an application of a composition containing ivermectin and levamisole hydrochloride in preparation of veterinary anti-parasitic drugs, wherein the mass ratio of the ivermectin to the levamisole hydrochloride is (0.3-1): 5 to 15. The method comprises the steps of combining ivermectin mainly used for in vitro disinsection and levamisole hydrochloride used for in vivo disinsectization, wherein the mass ratio of the ivermectin to the levamisole hydrochloride is 0.3-1: 5-15 percent. The problem that the range of desinsectization is small when ivermectin or levamisole hydrochloride is independently applied is solved, and the labor cost of independently applying the medicaments at different parts can be reduced when two main acting parts are simultaneously applied.
The invention also provides an anti-parasitic-disease transdermal solution for livestock, which comprises the following components in parts by volume: 20-50 parts of isopropanol; 10-40 parts of glycerol; 10-30 parts of absolute ethyl alcohol; 5-20 parts of dimethyl sulfoxide; 2-6 parts of azone; the ratio of the mass of ivermectin to the volume of the transdermal liquid medicine is 0.3-1 g: 100 mL; the ratio of the mass of the levamisole hydrochloride to the volume of the transdermal liquid medicine is 5-15 g: 100 mL.
The transdermal drug delivery preparation adopted by the invention is prepared by dissolving ivermectin and levamisole hydrochloride in isopropanol, glycerol, absolute ethyl alcohol and dimethyl sulfoxide, and the solvent can promote the percutaneous absorption of the drug; the azone can enable the medicine to enter the systemic menstrual blood circulation through capillary vessels of the skin to achieve effective blood concentration, and further enable the medicine to have the advantages of avoiding side effects caused by oral administration, gastrointestinal administration and the like such as liver passing effect, gastrointestinal inactivation and the like, maintaining constant blood concentration, prolonging effective action time and the like. The invention combines two medicines with different action mechanisms of ivermectin and levamisole hydrochloride to prepare a transdermal absorption preparation formulation, which improves the insect resistance spectrum, has synergistic effect when the ivermectin and the levamisole hydrochloride are used simultaneously, has better mutual promotion effect than the single use effect of the ivermectin and the levamisole hydrochloride, achieves the effect of killing insects inside and outside one preparation simultaneously, reduces the labor cost of administration, and is more suitable for preventing and treating animal parasitosis than other preparation formulations.
Detailed Description
The invention provides application of a composition containing ivermectin and levamisole hydrochloride in preparation of veterinary anti-parasitic drugs. In the invention, the mass ratio of ivermectin to levamisole hydrochloride is preferably 0.3-1: 5 to 15, and more preferably 0.5 to 1: 10 to 15. In the present invention, the drug is preferably used to repel one or more of sarcoptic mites, nematodes, cestodes, trematodes, coccidia and roundworms; it is particularly suitable for animals such as cattle, sheep, and pig.
The invention also provides an anti-parasitic-disease transdermal solution for livestock, which comprises the following components in parts by volume:
the ratio of the mass of ivermectin to the volume of the transdermal solution is 0.3-1 g: 100 mL;
the mass ratio of the levamisole hydrochloride to the volume of the transdermal solution is 5-15 g: 100 mL.
Unless otherwise specified, the present invention does not require any particular source for the components of the transdermal solution, and any commercially available product known to those skilled in the art may be used.
The veterinary anti-parasitic transdermal solution provided by the invention comprises 20-50 parts by volume of isopropanol, preferably 18-40 parts by volume of isopropanol, and more preferably 40 parts by volume of isopropanol.
The veterinary anti-parasitic transdermal solution provided by the invention comprises 10-40 parts of glycerol, preferably 18-40 parts of glycerol, and more preferably 30 parts of isopropanol by volume.
Based on the volume part of the isopropanol, the veterinary anti-parasitic transdermal solution provided by the invention comprises 10-30 parts of absolute ethyl alcohol, preferably 20-30 parts, and more preferably 20 parts.
Based on the volume part of the isopropanol, the veterinary anti-parasitic transdermal solution provided by the invention comprises 5-20 parts of dimethyl sulfoxide, preferably 8-20 parts of dimethyl sulfoxide, and more preferably 8 parts of dimethyl sulfoxide.
Based on the volume parts of the isopropanol, the veterinary anti-parasitic transdermal solution provided by the invention comprises 2-6 parts of azone, preferably 2-5 parts, and more preferably 2 parts.
The veterinary anti-parasitic transdermal solution provided by the invention comprises ivermectin; the mass of ivermectin is preferably 0.3-1g, more preferably 0.5-1 g, and even more preferably 1g, based on 100mL of transdermal solution.
The veterinary anti-parasitic transdermal solution provided by the invention comprises levamisole hydrochloride, and the mass of the levamisole hydrochloride is 5-15g, preferably 10-15 g, and more preferably 10g based on 100mL of transdermal solution.
The isopropanol, the glycerol, the absolute ethyl alcohol and the dimethyl sulfoxide in the invention are organic solvents of ivermectin and levamisole hydrochloride, and can promote percutaneous absorption of the medicine; the azone is used as a penetrating agent, and can promote levamisole hydrochloride and ivermectin to penetrate through capillary vessels of the skin and enter the systemic menstrual blood circulation to achieve effective blood concentration.
The invention also provides a preparation method of the anti-parasitic-disease transdermal solution for the livestock, which comprises the following steps:
(1) mixing the isopropanol, the glycerol, the absolute ethyl alcohol, the dimethyl sulfoxide, the azone, the ivermectin and the levamisole hydrochloride to obtain a mixed solution;
(2) and (3) sterilizing and filtering the mixed solution by adopting a microporous filter membrane to obtain the veterinary anti-parasitic-disease transdermal solution.
The isopropanol, the glycerol, the absolute ethyl alcohol, the dimethyl sulfoxide, the azone, the ivermectin and the levamisole hydrochloride are mixed to obtain a mixed solution. In the present invention, the mixing means preferably includes the steps of:
(a) mixing and dissolving isopropanol and ivermectin to obtain a first solution;
(b) mixing and dissolving absolute ethyl alcohol and levamisole hydrochloride to obtain levamisole hydrochloride ethanol solution; mixing dimethyl sulfoxide, glycerol, azone and levamisole hydrochloride ethanol solution to obtain a second solution;
(c) mixing the first solution and the second solution.
According to the characteristics of different dissolution behaviors of ivermectin and levamisole hydrochloride, different specific solvents are utilized to dissolve the ivermectin and the levamisole hydrochloride respectively, so that the dissolution rate of the medicine is increased, and the preparation is convenient.
After the mixed solution is obtained, the mixed solution is subjected to sterilization and filtration by adopting a microporous filter membrane to obtain the veterinary anti-parasitic-disease transdermal solution. In the invention, the pore diameter of the microporous filter membrane is preferably 0.1-0.45 μm, and is preferably 0.22 μm. The source of the microfiltration membrane is not particularly limited, and a source of a microfiltration membrane known to those skilled in the art may be used.
To further illustrate the present invention, the following examples are provided to describe the use of the composition comprising ivermectin and levamisole hydrochloride in the preparation of veterinary anti-parasitic drugs, the transdermal solution for veterinary anti-parasitic diseases and the preparation method thereof in detail, but they should not be construed as limiting the scope of the present invention.
Example 1
An anti-parasitic ivermectin levamisole transdermal solution for animals comprises the following components in parts by weight (per 100mL of raw and auxiliary materials, the same as in the following embodiment):
preparation of the transdermal solution:
(1) weighing isopropanol and ivermectin according to the proportion, adding the isopropanol into the ivermectin, and stirring until the isopropanol and the ivermectin are completely dissolved to obtain a first solution;
(2) weighing absolute ethyl alcohol and levamisole hydrochloride according to a ratio, adding the absolute ethyl alcohol into the levamisole hydrochloride, stirring until the absolute ethyl alcohol is completely dissolved, weighing dimethyl sulfoxide, glycerol and azone according to the ratio, adding the mixture into the levamisole hydrochloride ethanol solution, and stirring until the mixture is completely dissolved to obtain a second solution;
(3) mixing the first solution and the second solution, and uniformly stirring to obtain a third solution;
(4) and sterilizing and filtering the third solution by a 0.22 mu microporous filter membrane to obtain a finished product of the veterinary ivermectin levamisole transdermal solution for resisting the parasitic disease.
Example 2
An anti-parasitic ivermectin levamisole transdermal solution for animals comprises the following components in parts by weight (per 100mL of raw and auxiliary materials, the same as in the following embodiment):
the procedure for the preparation is the same as in example 1.
Example 3
An anti-parasitic ivermectin levamisole transdermal solution for animals comprises the following components in parts by weight (per 100mL of raw and auxiliary materials, the same as in the following embodiment):
the procedure for the preparation is the same as in example 1.
Application example 1
Irritation test of antiparasitic transdermal solution for animals
A test scheme is designed according to the requirements of the Chinese food and drug administration guidance principles of research technology on irritation, allergy and hemolysis of chemical drugs. The test animals are first-class New Zealand rabbits with the weight of 2.0-2.5 kg, 8 healthy rabbits with half of male and female are randomly divided into 2 groups, and an intact skin administration group and a damaged skin administration group are provided, wherein each group is provided with 4 rabbits, and each rabbit is coated with 0.5mL of the transdermal solution obtained in the example 1. Meanwhile, a blank solvent control group is arranged, and compared with a complete skin administration group and a damaged skin administration group, the method adopts a homomorphic left-right self-contrast method.
The protocol designed using the transdermal solutions obtained in example 2 and example 3 was the same as described above.
24h before administration, the test rabbits were depilated with depilatory on both sides of the spinal column at the back, and the area was about 3cm × 3 cm. Before administration, whether the dehaired skin is damaged due to dehairing is checked, after 75% alcohol disinfection, a blank solvent is coated on the left side dehaired area of the spine of the test rabbit, and the blank solvent is used as a blank solvent control group; applying the veterinary anti-parasitic transdermal solution to the intact skin of the epilation area on the right side of the spine to form an intact skin group; a No. 16 needle is adopted, a # -shaped mark is marked on the skin depilated on the right side, and the animal anti-parasitic disease transdermal solution is coated on the damaged skin of the spinal depilatory area by taking skin bleeding as a degree, so that a damaged skin group is formed.
After 24h, the test substance on the skin surface was removed with warm water and alcohol cotton, observed, and then the same test substance was applied, and the operation was repeated in the same manner for 3 consecutive days. And observing the irritation degree of the depilated skin of the test rabbit 24, 48 and 72 hours after the last application of the medicine. The skin irritation response scoring criteria are shown in table 1, the skin irritation intensity evaluation criteria are shown in table 2, and the experimental results of the test rabbit skin irritation response are shown in table 3.
TABLE 1 Scoring Scale for skin allergy/irritation response levels
TABLE 2 evaluation criteria for skin irritation intensity
TABLE 3 test results on skin irritation response of test rabbits
As is clear from data in Table 3 by comparing tables 1 to 2, in examples 1 to 3, the total score of skin irritation of the intact skin administration group and the damaged skin administration group was less than 0.5, and the skin irritation was not irritant. Therefore, the veterinary anti-parasitic-disease transdermal solution provided by the invention has no irritation to test rabbits, and is safe and feasible in clinical medication.
Comparative example 1
An anti-parasitic ivermectin transdermal solution for animals comprises the following components in parts by weight (per 100mL of raw and auxiliary materials, the same as in the following embodiment):
the transdermal solution was prepared in the same manner as in example 1.
Comparative example 2
An anti-parasitic-disease levamisole hydrochloride transdermal solution for animals comprises the following components in parts by weight (per 100mL of raw and auxiliary materials, the same as in the following examples):
the transdermal solution was prepared in the same manner as in example 1.
Application example 2
Parasite expelling effect experiment of veterinary anti-parasitic ivermectin levamisole transdermal solution
1. Grouping and treatment regimens
The transdermal solution of the veterinary anti-parasitic ivermectin levamisole is used for treating mice infected with trichina in 3 periods, and the parasite expelling effect of the transdermal solution of the veterinary anti-parasitic ivermectin levamisole is detected. The adult stage, the transitional larva stage and the cyst larva stage are divided into 3 treatment stages according to 3 development stages of the trichina respectively. The transdermal solution obtained in comparative example 1, comparative example 2 and example 1 was used for insect repelling test in each treatment period, and the transdermal solution was divided into adult, migratory and cyst larvae groups, 9 treatment groups were added, 3 positive control groups were added, and the adult, migratory and cyst larvae of trichina were infected with 5 mice each having the same number.
8% Na before treatment2S is smeared on the back of a mouse, and the medicine is applied after 5 min. The treatment group using the formulation of comparative example 1, comparative example 2 and the formulation of example 1 was administered at a dose of 0.2 mL/kg. Because the weight of the mice is too low and the volume of the transdermal solution is too small, the clinical use is influenced, and the content of the drug in the transdermal solution is reduced by 5 times to increase the use volume. And verified by an in vitro transdermal diffusion experimentAffecting the osmotic absorption of the drug.
(1) Treatment of trichina adult group: healthy Kunming mice are infected with trichina, 300 larvae each, and after the trichina is infected, the trichina is treated for 3 days to 5 days continuously, and each group is killed with a positive control group on the 8 th day. Collecting the trichina imagoes and calculating the insect reduction rate. The positive control group was not treated with the drug, and the post-treatment method was the same as the treatment group.
(2) Treatment of trichina transitional larva group: each healthy Kunming mouse is infected with 50 larvae of trichina, the dosage of each group is continuously 3 days in 10-12 days, each group is uniformly cut and killed with a positive control group in 45 days, and the reduction rate is calculated according to collected trichina muscle larvae. The positive control group was not treated with the drug, and the post-treatment method was the same as the treatment group.
(3) Treatment of trichina cyst larval group: each healthy Kunming mouse is infected with 50 larvae trichina, each group is treated for 3 days continuously at 38-40 days, and is killed with the positive control group at 45 days. Collecting trichina muscle larvae, and calculating the insect reduction rate. The positive control group was not treated with the drug, and the post-treatment method was the same as the treatment group.
The obtained reduction rates are shown in tables 4, 5 and 6.
TABLE 4 Trichinella spiralis adult treatment results
TABLE 5 Trichinella spiralis transitional stage larva treatment results
TABLE 6 Trichinella spiralis cyst stage larva treatment results
As can be seen from Table 4, the compound transdermal solution had the highest insect reduction rate of 81.9% in the adult trichina treatment group. Therefore, the compound transdermal solution provided by the invention has relatively best curative effect on trichina adults, is superior to the transdermal solution which singly uses ivermectin and levamisole hydrochloride, and achieves synergistic desinsectization effect.
As shown in Table 5, the maximum pest reduction rate of the compound transdermal solution in the trichina transitional stage larva treatment group is 92.9%. Therefore, the compound transdermal solution provided by the invention has relatively best curative effect on trichina transitional stage larvae, is superior to the transdermal solution which singly uses ivermectin and levamisole hydrochloride, and achieves synergistic insect expelling effect.
As shown in Table 6, the maximum insect reduction rate of the compound transdermal solution in the trichina cyst stage larva treatment group was 91.7%. Therefore, the compound transdermal solution provided by the invention has relatively best curative effect on trichina cyst stage larvae, is superior to the transdermal solution which singly uses ivermectin and levamisole hydrochloride, and achieves synergistic desinsectization effect.
According to the embodiment, the animal anti-parasitic ivermectin levamisole transdermal solution provided by the invention has the insect reduction rate of 92.9% of transitional larva, 91.7% of cyst stage larva and 81.9% of adult larva on the mouse trichinella spiralis in sequence in each period, and the insect reduction rate is higher than that of the ivermectin transdermal solution and the levamisole hydrochloride transdermal solution which are used independently. In the treatment period, the mice in each treatment group have good mental state, no abnormal state of diet and drinking water, no damage to skin, red swelling and the like of the mice in the transdermal administration group, and the compound transdermal solution is proved to be safe and non-irritant.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
Claims (10)
1. The application of a composition containing ivermectin and levamisole hydrochloride in preparation of veterinary anti-parasitic drugs is disclosed, wherein the mass ratio of the ivermectin to the levamisole hydrochloride is (0.3-1): 5 to 15.
2. The use of claim 1, wherein the medicament is for repelling one or more of scabies, nematodes, cestodes, trematodes, coccidia and roundworms.
3. The veterinary anti-parasitic transdermal solution is characterized by comprising the following components in parts by volume:
the ratio of the mass of ivermectin to the volume of the transdermal solution is 0.3-1 g: 100 mL;
the mass ratio of the levamisole hydrochloride to the volume of the transdermal solution is 5-15 g: 100 mL.
4. The transdermal solution of claim 3, comprising the following components in parts by volume:
the ratio of the mass of ivermectin to the volume of the transdermal solution is 0.5-1 g: 100 mL;
the ratio of the mass of the levamisole hydrochloride to the volume of the transdermal solution is 10-15 g: 100 mL.
5. The transdermal solution according to claim 3 or 4, characterized in that the ratio of the mass of ivermectin to the volume of transdermal solution is between 0.5 and 1 g: 100 mL; the mass ratio of the levamisole hydrochloride to the volume of the transdermal liquid medicine is 10-15 g: 100 mL.
6. The transdermal solution according to claim 3 or 4, characterized in that per 100mL of transdermal solution the following components are present: 40mL of isopropanol, 30mL of glycerol, 20mL of absolute ethyl alcohol, 8mL of dimethyl sulfoxide, 2mL of azone, 1g of ivermectin and 10g of levamisole hydrochloride.
7. A process for preparing a transdermal solution according to any of claims 3 to 6 comprising the steps of:
(1) mixing the isopropanol, the glycerol, the absolute ethyl alcohol, the dimethyl sulfoxide, the azone, the ivermectin and the levamisole hydrochloride to obtain a mixed solution;
(2) and (3) sterilizing and filtering the mixed solution by adopting a microporous filter membrane to obtain the veterinary anti-parasitic-disease transdermal solution.
8. The method according to claim 7, wherein the step (1) is carried out by mixing:
(a) mixing and dissolving isopropanol and ivermectin to obtain a first solution;
(b) mixing and dissolving absolute ethyl alcohol and levamisole hydrochloride to obtain levamisole hydrochloride ethanol solution; mixing dimethyl sulfoxide, glycerol, azone and levamisole hydrochloride ethanol solution to obtain a second solution;
(c) mixing the first solution and the second solution.
9. The method according to claim 7 or 8, wherein the pore size of the microfiltration membrane is 0.1 to 0.45 μm.
10. The production method according to claim 7 or 8, wherein the pore size of the microfiltration membrane is 0.22 μm.
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